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1. Minigene-based splicing analysis and ACMG/AMP-based tentative classification of 56 ATM variants

Author: Elena Bueno‐Martínez, Lara Sanoguera‐Miralles, Alberto Valenzuela‐Palomo, Ada Esteban‐Sánchez, Víctor Lorca, Inés Llinares‐Burguet, Jamie Allen, Alicia García‐Álvarez, Pedro Pérez‐Segura, Mercedes Durán, Douglas F Easton, Peter Devilee, Maaike PG Vreeswijk, Miguel de la Hoya, Eladio A Velasco‐Sampedro, de la Hoya, Miguel [0000-0002-8113-1410], Velasco-Sampedro, Eladio A [0000-0002-9682-5589], Apollo - University of Cambridge Repository, European Commission, Instituto de Salud Carlos III, Junta de Castilla y León, CSIC-UVA - Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid, Asociación Española Contra el Cáncer, Comunidad de Madrid, and Easton, Douglas [0000-0003-2444-3247]
Subjects: Susceptibility genes, RNA Splicing, Minigenes, hereditary breast cancer, Ataxia Telangiectasia Mutated Proteins, Splicing, Aberrant splicing, Pathology and Forensic Medicine, VUS, aberrant splicing, splicing, Alternative Splicing, Ataxia Telangiectasia, splicing assay, Splicing assay, Variant classification, ATM, MCF-7 Cells, Humans, minigenes, susceptibility genes, variant classification, Hereditary breast cancer, HeLa Cells
Abstract: The ataxia telangiectasia-mutated (ATM) protein is a major coordinator of the DNA damage response pathway. ATM loss-of-function variants are associated with 2-fold increased breast cancer risk. We aimed at identifying and classifying spliceogenic ATM variants detected in subjects of the large-scale sequencing project BRIDGES. A total of 381 variants at the intron-exon boundaries were identified, 128 of which were predicted to be spliceogenic. After further filtering, we ended up selecting 56 variants for splicing analysis. Four functional minigenes (mgATM) spanning exons 4-9, 11-17, 25-29, and 49-52 were constructed in the splicing plasmid pSAD. Selected variants were genetically engineered into the four constructs and assayed in MCF-7/HeLa cells. Forty-eight variants (85.7%) impaired splicing, 32 of which did not show any trace of the full-length (FL) transcript. A total of 43 transcripts were identified where the most prevalent event was exon/multi-exon skipping. Twenty-seven transcripts were predicted to truncate the ATM protein. A tentative ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme that integrates mgATM data allowed us to classify 29 ATM variants as pathogenic/likely pathogenic and seven variants as likely benign. Interestingly, the likely pathogenic variant c.1898+2T>G generated 13% of the minigene FL-transcript due to the use of a noncanonical GG-5'-splice-site (0.014% of human donor sites). Circumstantial evidence in three ATM variants (leakiness uncovered by our mgATM analysis together with clinical data) provides some support for a dosage-sensitive expression model in which variants producing ¿30% of FL-transcripts would be predicted benign, while variants producing ¿13% of FL-transcripts might be pathogenic., PD, MPGV, DFE, MdlH and EAV received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 634935. The EAV lab is supported by grants from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013-2016, ISCIII (PI17/00227 and PI20/00225) co-funded by the FEDER from Regional Development European Funds (European Union) and from the Consejería de Educación, Junta de Castilla y León, ref. CSI242P18 (actuación cofinanciada P.O. FEDER 2014-2020 de Castilla y León). The MdlH lab is supported by a grant from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013-2016, ISCIII (PI20/00110) co-funded by FEDER from Regional Development European Funds (European Union). Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Escalera de Excelencia, Junta de Castilla y León (Ref. CLU-2019-2002). EB-M is a postdoctoral researcher funded by the University of Valladolid (POSTDOC-UVA05, 2022-2025). AV-P and IL-B are supported by predoctoral fellowships from the Consejería de Educación, Junta de Castilla y León. LS-M is supported by a predoctoral fellowship from the AECC-Scientific Foundation, Sede Provincial de Valladolid (2019–2023). AE-S is supported through the Operational Program for Youth Employment and Youth Employment Initiative (YEI), called by the Community of Madrid in 2020, and co-financed by the European Social Fund.
Published: 2022
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2. Cancer Risks Associated With

Author: Shuai, Li, Valentina, Silvestri, Goska, Leslie, Timothy R, Rebbeck, Susan L, Neuhausen, John L, Hopper, Henriette Roed, Nielsen, Andrew, Lee, Xin, Yang, Lesley, McGuffog, Michael T, Parsons, Irene L, Andrulis, Norbert, Arnold, Muriel, Belotti, Åke, Borg, Bruno, Buecher, Saundra S, Buys, Sandrine M, Caputo, Wendy K, Chung, Chrystelle, Colas, Sarah V, Colonna, Jackie, Cook, Mary B, Daly, Miguel, de la Hoya, Antoine, de Pauw, Hélène, Delhomelle, Jacqueline, Eason, Christoph, Engel, D Gareth, Evans, Ulrike, Faust, Tanja N, Fehm, Florentia, Fostira, George, Fountzilas, Megan, Frone, Vanesa, Garcia-Barberan, Pilar, Garre, Marion, Gauthier-Villars, Andrea, Gehrig, Gord, Glendon, David E, Goldgar, Lisa, Golmard, Mark H, Greene, Eric, Hahnen, Ute, Hamann, Helen, Hanson, Tiara, Hassan, Julia, Hentschel, Judit, Horvath, Louise, Izatt, Ramunas, Janavicius, Yue, Jiao, Esther M, John, Beth Y, Karlan, Sung-Won, Kim, Irene, Konstantopoulou, Ava, Kwong, Anthony, Laugé, Jong Won, Lee, Fabienne, Lesueur, Noura, Mebirouk, Alfons, Meindl, Emmanuelle, Mouret-Fourme, Hannah, Musgrave, Joanne, Ngeow Yuen Yie, Dieter, Niederacher, Sue K, Park, Inge Sokilde, Pedersen, Juliane, Ramser, Susan J, Ramus, Johanna, Rantala, Muhammad U, Rashid, Florian, Reichl, Julia, Ritter, Andreas, Rump, Marta, Santamariña, Claire, Saule, Gunnar, Schmidt, Rita K, Schmutzler, Leigha, Senter, Saba, Shariff, Christian F, Singer, Melissa C, Southey, Dominique, Stoppa-Lyonnet, Christian, Sutter, Yen, Tan, Soo Hwang, Teo, Mary Beth, Terry, Mads, Thomassen, Marc, Tischkowitz, Amanda E, Toland, Diana, Torres, Ana, Vega, Sebastian A, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Bernhard H F, Weber, Drakoulis, Yannoukakos, Amanda B, Spurdle, Douglas F, Easton, Georgia, Chenevix-Trench, Laura, Ottini, and Antonis C, Antoniou
Subjects: BRCA2 Protein, Male, Ovarian Neoplasms, Risk, Heterozygote, BRCA1 Protein, Infant, Newborn, Breast Neoplasms, Breast Neoplasms, Male, Pancreatic Neoplasms, Mutation, Humans, Female, Genetic Predisposition to Disease
Abstract: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) inWe used data from 3,184In addition to female breast and ovarian cancers
Published: 2022

3. Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Author: Georgia Chenevix-Trench, Melissa C. Southey, Ramunas Janavicius, Abigail Thomas, Mads Thomassen, Ana Vega, Paul A. James, David E. Goldgar, Xin Yang, Marco Montagna, Charlotte Kvist Lautrup, Trinidad Caldés, Åke Borg, Henriette Roed Nielsen, Christi J. van Asperen, Amanda E. Toland, Diana Eccles, Siranoush Manoukian, Barbara Wappenschmidt, Angela R. Solano, Pål Møller, Tina Selkirk, John L. Hopper, Maria A. Caligo, Judy Kirk, Paolo Peterlongo, Susanne E. Boonen, Alberto Zambelli, Amanda B. Spurdle, Conxi Lázaro, Paolo Radice, Lone Kroeldrup, Fergus J. Couch, Irene L. Andrulis, Thomas Hansen, Ute Hamann, Esther M. John, Hongyan Li, Christoph Engel, Edenir Inêz Palmero, Sarah M. Nielsen, Mary Beth Terry, Judy Garber, Goska Leslie, Drakoulis Yannoukakos, Antonis C. Antoniou, Luca Livraghi, Ava Kwong, Inge Søkilde Pedersen, Miguel de la Hoya, Rita K. Schmutzler, Barbara Pasini, Michael T. Parsons, Mark H. Greene, Liliana Varesco, Lenka Foretova, Marc Tischkowitz, Susan M. Domchek, Heather Thorne, Anne-Marie Gerdes, Sandrine M. Caputo, Antoniou, Antonis [0000-0001-9223-3116], Leslie, Goska [0000-0001-5756-6222], Tischkowitz, Marc [0000-0002-7880-0628], and Apollo - University of Cambridge Repository
Subjects: Oncology, medicine.medical_specialty, BRCA1, BRCA2, Cancer risks, Missense variants, BRCA1 Protein, BRCA2 Protein, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Middle Aged, Breast Neoplasms, Ovarian Neoplasms, endocrine system diseases, Pedigree chart, Germline, Article, Breast cancer, Internal medicine, medicine, Missense mutation, skin and connective tissue diseases, Genetics (clinical), Genetic testing, medicine.diagnostic_test, business.industry, Hazard ratio, Cancer, medicine.disease, Genes, cardiovascular system, business, Ovarian cancer
Abstract: Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P =.01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P =.005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
Published: 2022
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4. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Marco Montagna, Mark E. Robson, Daniel Barrowdale, Mark H. Greene, Adrià López-Fernández, Miquel Angel Pujana, Paul Brennan, Lucy Side, Jackie Cook, Munaza Ahmed, Christi J. van Asperen, Katherine L. Nathanson, Ian G. Campbell, Shan Wang-Gohrke, Gero Kramer, Debra Frost, Noura Mebirouk, Angel Izquierdo, Conxi Lázaro, Douglas F. Easton, Joe Dennis, Kenneth Offit, Esther Darder, Stefania Tommasi, Angela Toss, Brca, Virginia Valentini, Tu Nguyen-Dumont, Charlotte Kvist Lautrup, Manuel R. Teixeira, Mads Thomassen, Xin Yang, Susan M. Domchek, Valentina Silvestri, Paolo Radice, Marta Venturelli, Joseph Vijai, Pedro Pinto, Caroline Pottinger, Karina Rønlund, Lone Kroeldrup, Paul A. James, Alan Donaldson, Rita K. Schmutzler, Muriel Belotti, Kim De Leeneer, Lesley McGuffog, Susan L. Neuhausen, Amanda E. Toland, Siranoush Manoukian, Vishakha Tripathi, Adalgeir Arason, Pascaline Berthet, Linda Steele, Judit Horvath, Gord Glendon, Goska Leslie, Eva Gross, Anna Coppa, D. J. Gallagher, Payal D. Shah, Hebon Investigators, Alfons Meindl, Orland Diez, Irene L. Andrulis, Angela F. Brady, Giuseppe Damante, Paolo Peterlongo, Ana Sánchez de Abajo, Maria A. Caligo, Alison H. Trainer, Sophie Giraud, Saba Sharif, Christian Sutter, Johanna Rantala, Javier Benitez, Mark T. Rogers, kConFab Investigators, Lídia Feliubadaló, Inge Søkilde Pedersen, Annabeth Høgh Petersen, Jesús del Valle, Agostino Bucalo, Andrea Gehrig, Megan N. Frone, Judith Balmaña, Marc Tischkowitz, Thomas Hansen, Joan Brunet, Ines Zanna, Torben A Kruse, Carole Brewer, Bernard Peissel, Helen Gregory, Mary Porteous, Rosa B. Barkardottir, Andreas Rump, Ros Eeles, Anna Whaite, Saundra S. Buys, Fabienne Lesueur, Lisa Walker, Laura Ottini, Louise Izatt, Antonis C. Antoniou, Georgia Chenevix-Trench, Susanne E. Boonen, Hayley Cassingham, Jacques Simard, Christoph Engel, Patrick J. Morrison, Lise Lotte Christensen, Giulia Cini, Alvaro N.A. Monteiro, Kathleen Claes, Jacqueline Eason, Zoltan Matrai, Uffe Birk Jensen, Kristiina Aittomäki, Ramunas Janavicius, Olufunmilayo I. Olopade, Bjarni A. Agnarsson, Kara N. Maxwell, Julian Barwell, Bernd Auber, Julian Adlard, Esther M. John, Alex Teulé, Miguel de la Hoya, Darcy L. Thull, David E. Goldgar, Alessandra Viel, Dominique Stoppa-Lyonnet, Barbara Wappenschmidt, Phuong L. Mai, Taru A. Muranen, Eric Hahnen, Fergus J. Couch, Laura Matricardi, Domenico Palli, Yen Y. Tan, Julia Hentschel, Florentia Fostira, Ute Hamann, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Åke Borg, Pedro Pérez-Segura, Aniko Bozsik, Yuan Chun Ding, Dieter Niederacher, Heli Nevanlinna, Helen Hanson, Norbert Arnold, Robin de Putter, Juliane Ramser, Alex Murray, Laura Cortesi, Christian F. Singer, Jacopo Azzollini, Zsofia K. Stadler, Oskar T. Johannsson, Andrew K. Godwin, D. Gareth Evans, Edith Olah, Michael T. Parsons, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital Area, Research Program in Systems Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Clinicum, Institut Català de la Salut, [Barnes DR, Leslie G, McGuffog L, Dennis J, Yang X] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Silvestri V] Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. [Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Male, Cancer Research, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Diàtesi, polygenic, male breast cancer, PRS, Medical Oncology, Prostate cancer, Breast cancer, 0302 clinical medicine, Prostate, Risk Factors, Medicine and Health Sciences, 80 and over, genetics, skin and connective tissue diseases, Aged, 80 and over, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], 0303 health sciences, education.field_of_study, BRCA1 Protein, Men, Articles, ASSOCIATION, Single Nucleotide, prostate cancer, OVARIAN, BRCA1, BRCA2, 3. Good health, Mutation carriers, medicine.anatomical_structure, Ovarian, 030220 oncology & carcinogenesis, Male breast cancer, Pròstata - Càncer - Aspectes genètics, BRCA2 Protein, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Risk Assessment, Breast Neoplasms, Prostatic Neoplasms, AcademicSubjects/MED00010, medicine.medical_specialty, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], Urology, 3122 Cancers, Population, Single-nucleotide polymorphism, MUTATION CARRIERS, Càncer de mama, Association, 03 medical and health sciences, Internal medicine, medicine, Polymorphism, education, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], 030304 developmental biology, Aged, Càncer de pròstata, business.industry, Cancer, Odds ratio, medicine.disease, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], Homes, Mama - Càncer - Aspectes genètics, business
Abstract: Breast and prostate cancer risks; Pathogenic variant Riscos de càncer de mama i pròstata; Variants patogèniques Riesgos de cáncer de mama y próstata; Variantes patogénicas Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 and PPRPGM-Nov20\100002. The research leading to these results has received funding from the Italian Association for Cancer Research (AIRC) under IG 2018 - ID. 21389 and the Italian League for the Fight Against Cancer (LILT) under IG 2019 projects, P.I. Ottini Laura and Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016. CIMBA: GCT is a National Health and Medical Research Council (NHMRC) Research Fellow. iCOGS and OncoArray data: the European Community’s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH) (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) and PERSPECTIVE I&I projects were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation and the Ontario Research Fund. Breast Cancer Family Registry (BCFR): UM1 CA164920 from the National Cancer Institute (NCI). Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. Beth Israel Deaconess Medical Center (BIDMC): Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA): Cancer Association of South Africa (PI Elizabeth J. van Rensburg). Spanish National Cancer Centre (CNIO): Spanish Ministry of Health PI16/00440 supported by Fondo Europeo de Desarrollo Regional (FEDER) funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). City of Hope - Clinical Cancer Genomics Community Research Network (COH-CCGCRN): Research reported in this publication was supported by the NCI of the NIH under grant No. R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the NCI and the Office of the Director, NIH. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 No.15547) to P. Radice. Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000’) to S. Manoukian. Associazione CAOS Varese to M.G. Tibiletti. AIRC (IG2015 No.16732) to P. Peterlongo. National Centre for Scientific Research Demokritos (DEMOKRITOS): European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. German Cancer Research Center (DFKZ): German Cancer Research Center. Epidemiological Study of Familial Breast Cancer (EMBRACE): Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Fox Chase Cancer Center (FCCC): The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was in part funded by the NCI (R01 CA214545 and R01 CA140323), The Kansas Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences Professor. Fundación Pública Galega de Medicina Xenómica (FPGMX): FISPI05/2275 and Mutua Madrileña Foundation (FMMA). German Familial Breast Group (GC-HBOC): German Cancer Aid (grant No. 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE—Leipzig Research Centre for Civilization Diseases, project No. 713-241202, No. 713-241202, No. 14505/2470, and No. 14575/2470). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). Georgetown University (GEORGETOWN): the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Ghent University Hospital (G-FAST): Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. Hospital Clinico San Carlos (HCSC): Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Helsinki Breast Cancer Study (HEBCS): Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. Hereditary Breast and Ovarian cancer study the Netherlands (HEBON): the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary (HUNBOCS): Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. Institut Català d’Oncologia (ICO): The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “FEDER, una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). International Hereditary Cancer Centre (IHCC): PBZ_KBN_122/P05/2004. Iceland Landspitali – University Hospital (ILUH): Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program—grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant No. PSR-SIIRI-701. Istituto Oncologico Veneto (IOVHBOCS): Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. Portuguese Oncology Institute-Porto Breast Cancer Study (IPOBCS): Liga Portuguesa Contra o Cancro. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Korean Hereditary Breast Cancer Study (KOHBRA): the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). Mayo Clinic (MAYO): NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. McGill University (MCGILL): Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). Modifier Study of Quantitative Effects on Disease (MODSQUAD): MH CZ—DRO (MMCI, 00209805), MEYS—NPS I—LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). Memorial Sloane Kettering Cancer Center (MSKCC): the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Women’s College Research Institute Hereditary Breast and Ovarian Cancer Study (NAROD): 1R01 CA149429-01. National Cancer Institute (NCI): the Intramural Research Program of the US NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. National Israeli Cancer Control Center (NICCC): Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N.N. Petrov Institute of Oncology (NNPIO): the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. The Ohio State University Comprehensive Cancer Center (OSUCCG): Ohio State University Comprehensive Cancer Center. Università di Pisa (PBCS): AIRC [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. South East Asian Breast Cancer Association Study (SEABASS): Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): the Israeli Cancer Association. Swedish Breast Cancer Study (SWE-BRCA): the Swedish Cancer Society. University of Chicago (UCHICAGO): NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society (ACS) Clinical Research Professor. University of California Los Angeles (UCLA): Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. University of California San Francisco (UCSF): UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UK Familial Ovarian Cancer Registry (UKFOCR): Cancer Research UK. University of Pennsylvania (UPENN): NIH (R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. Cancer Family Registry University of Pittsburg (UPITT/MWH): Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Women’s Cancer Program at Cedars-Sinai Medical Center (WCP): Dr Karlan is funded by the ACS Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. TN-D is a recipient of a Career Development Fellow from the National Breast Cancer Foundation (Australia, ECF-17-001).
Published: 2022
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5. Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants

Author: Alberto, Valenzuela-Palomo, Elena, Bueno-Martínez, Lara, Sanoguera-Miralles, Víctor, Lorca, Eugenia, Fraile-Bethencourt, Ada, Esteban-Sánchez, Susana, Gómez-Barrero, Sara, Carvalho, Jamie, Allen, Alicia, García-Álvarez, Pedro, Pérez-Segura, Leila, Dorling, Douglas F, Easton, Peter, Devilee, Maaike Pg, Vreeswijk, Miguel, de la Hoya, and Eladio A, Velasco
Subjects: Alternative Splicing, Case-Control Studies, Databases, Genetic, Biomarkers, Tumor, MCF-7 Cells, Humans, Protein Isoforms, Breast Neoplasms, Female, Exons, RNA Splice Sites, Fanconi Anemia Complementation Group N Protein
Abstract: PALB2 loss-of-function variants confer high risk of developing breast cancer. Here we present a systematic functional analysis of PALB2 splice-site variants detected in approximately 113,000 women in the large-scale sequencing project Breast Cancer After Diagnostic Gene Sequencing (BRIDGES; https://bridges-research.eu/). Eighty-two PALB2 variants at the intron-exon boundaries were analyzed with MaxEntScan. Forty-two variants were selected for the subsequent splicing functional assays. For this purpose, three splicing reporter minigenes comprising exons 1-12 were constructed. The 42 potential spliceogenic variants were introduced into the minigenes by site-directed mutagenesis and assayed in MCF-7/MDA-MB-231 cells. Splicing anomalies were observed in 35 variants, 23 of which showed no traces or minimal amounts of the expected full-length transcripts of each minigene. More than 30 different variant-induced transcripts were characterized, 23 of which were predicted to truncate the PALB2 protein. The pathogenicity of all variants was interpreted according to an in-house adaptation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) variant classification scheme. Up to 23 variants were classified as pathogenic/likely pathogenic. Remarkably, three ±1,2 variants (c.49-2AT, c.108+2TC, and c.211+1GA) were classified as variants of unknown significance, as they produced significant amounts of either in-frame transcripts of unknown impact on the PALB2 protein function or the minigene full-length transcripts. In conclusion, we have significantly contributed to the ongoing effort of identifying spliceogenic variants in the clinically relevant PALB2 cancer susceptibility gene. Moreover, we suggest some approaches to classify the findings in accordance with the ACMG-AMP rationale. © 2021 The Authors. The Journal of Pathology published by John WileySons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Published: 2021

6. Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes

Author: Ana Vega, Logan C. Walker, Demis Tserpelis, Rita D. Brandão, Tim De Meyer, Klaas Mensaert, Amanda B. Spurdle, Anders Kvist, Vanessa Lattimore, M.N. Xenakis, Irene López-Perolio, Marinus J. Blok, Orland Diez, Miguel de la Hoya, Sara Gutiérrez-Enríquez, RS: FSE MSP, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Genetica & Celbiologie, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: HEREDITARY BREAST, Cancer Research, endocrine system diseases, PREDICTION, inherited breast, targeted RNA‐seq, 0302 clinical medicine, lynch syndrome, skin and connective tissue diseases, Genetics, RISK, RAD51C, BRCA1 Protein, GERMLINE MUTATIONS, Lynch syndrome, 3. Good health, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, RNA splicing, Hereditary Breast and Ovarian Cancer Syndrome, Female, RNA Splicing, Biology, MLH1, inherited breast/ovarian cancer syndrome, OVARIAN-CANCER, CLASSIFICATION, Cancer Genetics and Epigenetics, 03 medical and health sciences, alternative splicing, targeted RNA-seq, BRCA1/2, Cell Line, Tumor, medicine, UNCLASSIFIED VARIANTS, Humans, Genetic Predisposition to Disease, ASSAYS, Gene, BRCA2 Protein, Sequence Analysis, RNA, Alternative splicing, Electrophoresis, Capillary, medicine.disease, BRCA1, Colorectal Neoplasms, Hereditary Nonpolyposis, MSH6, MSH2, Mutation, ovarian cancer syndrome
Abstract: A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep‐sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA‐seq approach was used to analyse the naturally‐occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non‐BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non‐targeted RNA‐seq approach. We also compared splicing events from lymphoblastoid cell‐lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA‐seq to detect pathogenic changes in RNA‐splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted‐RNA‐seq can be very useful to classify variants based on their putative pathogenic impact on splicing., What's new? Hereditary familial breast/ovarian cancer (HBOC) syndrome involves numerous pathogenic variants, including variants of uncertain clinical significance (VUS). A subset of VUS, however, is suspected to influence RNA splicing, leading to the expression of potentially pathological transcript isoforms. Here, using a targeted RNA‐seq approach, naturally occurring splice isoforms were described for BRCA1/2, RAD51C, RAD51D, and eight additional tumor‐suppressor genes that are associated with HBOC and Lynch syndrome. The targeted RNA‐seq approach also identified aberrant splicing events associated with the presence of BRCA1/2 genetic variants and successfully distinguished complete from incomplete splicing events, which is of major importance in determining pathogenicity.
Published: 2019
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7. Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants

Author: Gemo, Francesca Mateo, Mads Thomassen, Cimba, Daniel Jimenez, Julio Castaño, Miquel Angel Pujana, Diana Baralle, Antonis C. Antoniou, Laure Barjhoux, Carmen Herranz, Joan Brunet, Sylvie Mazoyer, Luis Palomero, Núria Bonifaci, Conxi Lázaro, Gorka Ruiz de Garibay, Paolo Radice, Eduardo Eyras, Roderic Espín, Miguel de la Hoya, Antonio Gomez, Angel Raya, Daniel R. Barnes, Nadia García, Ana I. Extremera, Xose S. Puente, Ignacio Fernandez-Garcia, Sangeeta Haydeliz Martinez-Ruiz, Pietro Ameri, Flávia Leme de Calais, Mary Helen Barcellos-Hoff, Amanda B. Spurdle, Francesca Damiola, Lars v. B. Andersen, Barnes, Daniel [0000-0002-3781-7570], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: RNA Splicing, Genes, BRCA1, Breast Neoplasms, Biology, Gene product, Exon, splicing, Breast cancer, breast cancer, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), risk, Genetic Carrier Screening, Alternative splicing, Intron, Cancer, isoform, Exons, medicine.disease, BRCA1, Introns, variant, RNA splicing, Female
Abstract: Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11:g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene. This article is protected by copyright. All rights reserved.
Published: 2021
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8. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020
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9. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants:Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author: Christi J. van Asperen, Leigha Senter, Javier Benitez, Kenneth Offit, Marco Montagna, Irene L. Andrulis, Phuong L. Mai, Yen Y. Tan, Lidia Moserle, Sara Torres-Esquius, Trinidad Caldés, Orland Diez, Daniel R. Barnes, Åke Borg, Daniel Barrowdale, Joanne Ngeow, Siranoush Manoukian, Soo Hwang Teo, Maria A. Caligo, Inge Søkilde Pedersen, Jennifer T. Loud, Marta Santamariña, Amanda E. Toland, Anna Marie Mulligan, Irene Konstantopoulou, Antonis C. Antoniou, Paul A. James, Eitan Friedman, Barbara Wappenschmidt, Marc Tischkowitz, Laura Papi, Ana Osorio, Georgia Chenevix-Trench, Eva Machackova, Pedro Pinto, Keivan Majidzadeh-A, Bernardo Bonanni, Kristiina Aittomäki, Berardino Porfirio, Johanna Rantala, Valentina Silvestri, Bent Ejlertsen, Melissa C. Southey, Ramunas Janavicius, Elisabetta Landucci, Liene Nikitina-Zake, Lajos Géczi, Saundra S. Buys, Angela R. Solano, Sarah Colonna, Ana Vega, Fabienne Lesueur, Frans B. L. Hogervorst, Goska Leslie, David E. Goldgar, Peter J. Hulick, Rosa B. Barkardottir, Kristin K. Zorn, Elisa Alducci, Miguel de la Hoya, Fergus J. Couch, Laura Ottini, Anne-Marie Gerdes, Uffe Birk Jensen, Ute Hamann, Christoph Engel, Allison W. Kurian, Douglas F. Easton, Annabeth Høgh Petersen, Alessandra Viel, Linda Steele, Zoe Steinsnyder, Ava Kwong, Alicia Barroso, Eric Hahnen, Mads Thomassen, Maria Rossing, Rita K. Schmutzler, Wendy K. Chung, Angel Izquierdo, Barak Rosenzweig, Jeroen Vierstraete, Mark H. Greene, Lenka Foretova, Jeffrey N. Weitzel, Paolo Radice, Muhammad Usman Rashid, Katherine L. Nathanson, Lesley McGuffog, Ian G. Campbell, John L. Hopper, Laura Cortesi, Christian F. Singer, Sook-Yee Yoon, Lídia Feliubadaló, Bjarni A. Agnarsson, Susan M. Domchek, Vijai Joseph, Manuel R. Teixeira, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Jacques Simard, Yuan Chun Ding, Carlo Capalbo, Florentia Fostira, Greet Wieme, Mary Beth Terry, Kathleen Claes, Olufunmilayo I. Olopade, Pedro Pérez-Segura, Heli Nevanlinna, D. Gareth Evans, Edith Olah, Michael T. Parsons, Claudine Isaacs, Miquel Angel Pujana, Timothy R. Rebbeck, Gord Glendon, Susan L. Neuhausen, Judy Kirk, Sue K. Park, Esther M. John, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, University of Helsinki, HUS Gynecology and Obstetrics, Biosciences, and Department of Obstetrics and Gynecology
Subjects: Male, Cancer Research, endocrine system diseases, GUIDELINES, 0302 clinical medicine, Neoplasms, Medicine, 030212 general & internal medicine, Prospective cohort study, skin and connective tissue diseases, GENE-ENVIRONMENT INTERACTION, Original Investigation, RISK, Aged, 80 and over, education.field_of_study, BRCA1 Protein, Middle Aged, BRCA2 Protein/genetics, 3. Good health, PROSTATE-CANCER, Phenotype, Oncology, 030220 oncology & carcinogenesis, Male breast cancer, Cohort study, Adult, medicine.medical_specialty, Adolescent, Population, 3122 Cancers, MUTATION CARRIERS, 03 medical and health sciences, Young Adult, Breast cancer, Internal medicine, BREAST-CANCER, Humans, education, Germ-Line Mutation, Aged, Retrospective Studies, BRCA2 Protein, business.industry, Cancer, Correction, Retrospective cohort study, Odds ratio, medicine.disease, BRCA1 Protein/genetics, business, Neoplasms/diagnosis
Abstract: Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P
Published: 2020
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10. A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients

Author: Ana Vega, Orland Diez, Alejandro Moles-Fernández, Xavier de la Cruz, Gabriel Capellá, Luz-Marina Porras, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Daniel Rueda, Conxi Lázaro, Anael López-Novo, Clara Ruiz-Ponte, Marta Pineda, Ana Blanco, Ignacio J. Molina, Lídia Feliubadaló, Ana Osorio, Marta Santamariña-Pena, and Alysson T Sánchez
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Computer science, Clinical Biochemistry, Genomics, Computational biology, Disease, Ataxia Telangiectasia Mutated Proteins, Spanish database, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Neoplasms, medicine, Malalties hereditàries, Humans, Genetic Predisposition to Disease, ACMG/AMP guidelines, Espanya, Curació de dades, Massive parallel sequencing, Data curation, Molecular pathology, Biochemistry (medical), Genetic Variation, High-Throughput Nucleotide Sequencing, Cancer patients, medicine.disease, Hereditary cancer, Data sharing, Malalts de càncer, 030104 developmental biology, Spain, 030220 oncology & carcinogenesis, Variant classification, Medical genetics, Female, Genetic diseases
Abstract: Background Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene. Methods Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants. Results Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%. Conclusions Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management., FEDER funds-a way to build Europe PI19/00553 PI16/00563 PI16/01898 SAF2015-68016-R, Generalitat de Catalunya 2017SGR1282 2017SGR496, CERCA Program: Government of Catalonia, Xunta de Galicia, Instituto de Salud Carlos III. AES PI19/00340, Spanish Government SAF2016-80255-R, European Commission EFA086/15, Instituto de Salud Carlos III European Commission
Published: 2020

11. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Author: Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, PHENOTYPE, INCREASE, Prostate cancer, 0302 clinical medicine, Risk Factors, Young adult, skin and connective tissue diseases, Aged, 80 and over, Prostate cancer risk, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESSENGER-RNA DECAY, BRCA1 Protein, Genomics, GERMLINE MUTATIONS, Middle Aged, Prognosis, OVARIAN, CARRIERS, 3. Good health, 030220 oncology & carcinogenesis, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Tumor suppressor gene, Urology, Association (object-oriented programming), 3122 Cancers, MEDLINE, Article, Young Adult, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation, Journal Article, Genetic predisposition, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Risk factor, Genetic Association Studies, Aged, BRCA2 Protein, IDENTIFICATION, business.industry, Prostatic Neoplasms, medicine.disease, GENE, Confidence interval, APC, 030104 developmental biology, Mutation, 3111 Biomedicine, business
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Published: 2020
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12. Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

Author: Georgia Chenevix-Trench, Bernd Auber, Douglas F. Easton, Kristiina Aittomäki, Andy C. H. Lee, Ramunas Janavicius, Ana Vega, Paul D.P. Pharoah, Xin Yang, Liisa M. Pelttari, Malene Djursby, Eric Hahnen, Åke Borg, Mark E. Robson, Stephen B. Gruber, Susan J. Ramus, kConFab Investigators, Lisa Golmard, Ian Jacobs, Jill S. Dolinsky, Holly LaDuca, Karin Kast, Clare Turnbull, Fergus J. Couch, W. D. Foulkes, Thomas Hansen, Simon A. Gayther, Allan Jensen, Christoph Engel, Heli Nevanlinna, Ana Osorio, Jacek Gronwald, Judy Garber, Helen Hanson, Susanne K. Kjaer, Julie O. Culver, Goska Leslie, Ed Dicks, Honglin Song, Barbara Rivera, Richard S. Houlston, Anders Kvist, Estrid Høgdall, Antonis C. Antoniou, Dieter Niederacher, Nadia Traficante, Miguel de la Hoya, Rita K. Schmutzler, Alfons Meindl, Judit Horvath, Orland Diez, Adam N. Rosenthal, Laurent Castera, Chey Loveday, David D.L. Bowtell, Joe Dennis, Marc Tischkowitz, Susan M. Domchek, Judith Balmaña, Hans Ehrencrona, Usha Menon, Leslie, Goska [0000-0001-5756-6222], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, and Department of Medical and Clinical Genetics
Subjects: Oncology, Cancer Research, ASCERTAINMENT SAMPLING PROBLEM, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, CONFER SUSCEPTIBILITY, Young adult, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, medicine.diagnostic_test, Articles, GERMLINE MUTATIONS, Middle Aged, 3. Good health, DNA-Binding Proteins, SUSCEPTIBILITY GENES, 030220 oncology & carcinogenesis, Female, AcademicSubjects/MED00010, Adult, medicine.medical_specialty, Heterozygote, Adolescent, Genetic counseling, 3122 Cancers, Breast Neoplasms, 03 medical and health sciences, Young Adult, Breast cancer, Internal medicine, medicine, Cancer Family, Humans, Genetic Predisposition to Disease, Genetic Testing, First-degree relatives, Genetic Association Studies, Germ-Line Mutation, 030304 developmental biology, Genetic testing, Aged, business.industry, Cancer, Complex segregation analysis, medicine.disease, BRCA2, MODEL, RESOLUTION, business
Abstract: Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
Published: 2020
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13. Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report

Author: kConFab Investigators, Melissa C. Southey, John F. Pearson, Tina Pesaran, Logan C. Walker, Miguel de la Hoya, Sitao Wu, Dominique Vaur, Peter Devilee, Vickie Hsuan, Vanesa García-Barberán, Raphaël Leman, Patricia Llovet, Johan Vallon-Christersson, Irene López-Perolio, Raquel Behar, Alexandra Martins, Grégoire Davy, Anders Kvist, Vanessa Lattimore, Nicolas Goardon, Trinidad Caldés, Åke Borg, Laurent Castera, Pedro Pérez-Segura, Maaike P.G. Vreeswijk, Rachid Karam, Pilar Garre, Eduardo Díaz-Rubio, Eladio Velasco, Sophie Krieger, Kathleen S. Hruska, Alberto Valenzuela-Palomo, Amanda B. Spurdle, American Breast Cancer Foundation, Cancer Australia, National Institutes of Health (US), National Health and Medical Research Council (Australia), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Otago [Dunedin, Nouvelle-Zélande], GeneDx [Gaithersburg, MD, USA], Ambry Genetics [Aliso Viejo, CA, USA], Lund University [Lund], University of Melbourne, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, 'Dr. Héctor N. Torres' [Buenos Aires] (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Ciencias Exactas y Naturales [Buenos Aires] (FCEyN), Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA), Leiden University Medical Center (LUMC), QIMR Berghofer Medical Research Institute, Normandie, Université, and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)
Subjects: 0301 basic medicine, medicine.medical_specialty, palb2, PALB2, Computational biology, Biology, acmg-amp guidelines, 03 medical and health sciences, Exon, splicing, 0302 clinical medicine, Neoplasms, Genetics, medicine, Cancer Genetics, Humans, splice, Genetic Predisposition to Disease, variant classification, Gene, Genetics (clinical), Alleles, Genetic Association Studies, Germ-Line Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Molecular pathology, Gene Expression Profiling, Alternative splicing, pvs1, 3. Good health, Nonsense Mediated mRNA Decay, Alternative Splicing, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, Mutation, Medical genetics, RNA Splice Sites, Fanconi Anemia Complementation Group N Protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Cancer genetics: Original article., [Background] PALB2 monoallelic loss-of-function germ-line variants confer a breast cancer risk comparable to the average BRCA2 pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-function variants in PALB2—without incurring overprediction—is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines., [Methods] Alternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2 c.212–1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant., [Results] We identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies., [Conclusions] PVS1 is not necessarily warranted for splice site variants targeting four PALB2 acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenic without further evidences. Our study puts a warning in up to five PALB2 genetic variants that are currently reported as pathogenic/likely pathogenic in ClinVar., Received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health [USA].
Published: 2019
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14. Association of Genomic Domains in

Author: Vivek L, Patel, Evan L, Busch, Tara M, Friebel, Angel, Cronin, Goska, Leslie, Lesley, McGuffog, Julian, Adlard, Simona, Agata, Bjarni A, Agnarsson, Munaza, Ahmed, Kristiina, Aittomäki, Elisa, Alducci, Irene L, Andrulis, Adalgeir, Arason, Norbert, Arnold, Grazia, Artioli, Brita, Arver, Bernd, Auber, Jacopo, Azzollini, Judith, Balmaña, Rosa B, Barkardottir, Daniel R, Barnes, Alicia, Barroso, Daniel, Barrowdale, Muriel, Belotti, Javier, Benitez, Birgitte, Bertelsen, Marinus J, Blok, Istvan, Bodrogi, Valérie, Bonadona, Bernardo, Bonanni, Davide, Bondavalli, Susanne E, Boonen, Julika, Borde, Ake, Borg, Angela R, Bradbury, Angela, Brady, Carole, Brewer, Joan, Brunet, Bruno, Buecher, Saundra S, Buys, Santiago, Cabezas-Camarero, Trinidad, Caldés, Almuth, Caliebe, Maria A, Caligo, Mariarosaria, Calvello, Ian G, Campbell, Ileana, Carnevali, Estela, Carrasco, Tsun L, Chan, Annie T W, Chu, Wendy K, Chung, Kathleen B M, Claes, Gemo Study, Collaborators, Embrace, Collaborators, Jackie, Cook, Laura, Cortesi, Fergus J, Couch, Mary B, Daly, Giuseppe, Damante, Esther, Darder, Rosemarie, Davidson, Miguel, de la Hoya, Lara Della, Puppa, Joe, Dennis, Orland, Díez, Yuan Chun, Ding, Nina, Ditsch, Susan M, Domchek, Alan, Donaldson, Bernd, Dworniczak, Douglas F, Easton, Diana M, Eccles, Rosalind A, Eeles, Hans, Ehrencrona, Bent, Ejlertsen, Christoph, Engel, D Gareth, Evans, Laurence, Faivre, Ulrike, Faust, Lídia, Feliubadaló, Lenka, Foretova, Florentia, Fostira, George, Fountzilas, Debra, Frost, Vanesa, García-Barberán, Pilar, Garre, Marion, Gauthier-Villars, Lajos, Géczi, Andrea, Gehrig, Anne-Marie, Gerdes, Paul, Gesta, Giuseppe, Giannini, Gord, Glendon, Andrew K, Godwin, David E, Goldgar, Mark H, Greene, Angelica M, Gutierrez-Barrera, Eric, Hahnen, Ute, Hamann, Jan, Hauke, Natalie, Herold, Frans B L, Hogervorst, Ellen, Honisch, John L, Hopper, Peter J, Hulick, KConFab, Investigators, Hebon, Investigators, Louise, Izatt, Agnes, Jager, Paul, James, Ramunas, Janavicius, Uffe Birk, Jensen, Thomas Dyrso, Jensen, Oskar Th, Johannsson, Esther M, John, Vijai, Joseph, Eunyoung, Kang, Karin, Kast, Johanna I, Kiiski, Sung-Won, Kim, Zisun, Kim, Kwang-Pil, Ko, Irene, Konstantopoulou, Gero, Kramer, Lotte, Krogh, Torben A, Kruse, Ava, Kwong, Mirjam, Larsen, Christine, Lasset, Charlotte, Lautrup, Conxi, Lazaro, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lee, Johannes, Lemke, Fabienne, Lesueur, Annelie, Liljegren, Annika, Lindblom, Patricia, Llovet, Adria, Lopez-Fernández, Irene, Lopez-Perolio, Victor, Lorca, Jennifer T, Loud, Edmond S K, Ma, Phuong L, Mai, Siranoush, Manoukian, Veronique, Mari, Lynn, Martin, Laura, Matricardi, Noura, Mebirouk, Veronica, Medici, Hanne E J, Meijers-Heijboer, Alfons, Meindl, Arjen R, Mensenkamp, Clare, Miller, Denise Molina, Gomes, Marco, Montagna, Thea M, Mooij, Lidia, Moserle, Emmanuelle, Mouret-Fourme, Anna Marie, Mulligan, Katherine L, Nathanson, Marie, Navratilova, Heli, Nevanlinna, Dieter, Niederacher, Finn C Cilius, Nielsen, Liene, Nikitina-Zake, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Kai-Ren, Ong, Ana, Osorio, Claus-Eric, Ott, Domenico, Palli, Sue K, Park, Michael T, Parsons, Inge Sokilde, Pedersen, Bernard, Peissel, Ana, Peixoto, Pedro, Pérez-Segura, Paolo, Peterlongo, Annabeth Høgh, Petersen, Mary E, Porteous, Miguel Angel, Pujana, Paolo, Radice, Juliane, Ramser, Johanna, Rantala, Muhammad U, Rashid, Kerstin, Rhiem, Piera, Rizzolo, Mark E, Robson, Matti A, Rookus, Caroline M, Rossing, Kathryn J, Ruddy, Catarina, Santos, Claire, Saule, Rosa, Scarpitta, Rita K, Schmutzler, Hélène, Schuster, Leigha, Senter, Caroline M, Seynaeve, Payal D, Shah, Priyanka, Sharma, Vivian Y, Shin, Valentina, Silvestri, Jacques, Simard, Christian F, Singer, Anne-Bine, Skytte, Katie, Snape, Angela R, Solano, Penny, Soucy, Melissa C, Southey, Amanda B, Spurdle, Linda, Steele, Doris, Steinemann, Dominique, Stoppa-Lyonnet, Agostina, Stradella, Lone, Sunde, Christian, Sutter, Yen Y, Tan, Manuel R, Teixeira, Soo Hwang, Teo, Mads, Thomassen, Maria Grazia, Tibiletti, Marc, Tischkowitz, Silvia, Tognazzo, Amanda E, Toland, Stefania, Tommasi, Diana, Torres, Angela, Toss, Alison H, Trainer, Nadine, Tung, Christi J, van Asperen, Frederieke H, van der Baan, Lizet E, van der Kolk, Rob B, van der Luijt, Liselotte P, van Hest, Liliana, Varesco, Raymonda, Varon-Mateeva, Alessandra, Viel, Jeroen, Vierstraete, Roberta, Villa, Anna, von Wachenfeldt, Philipp, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Jeffrey N, Weitzel, Greet, Wieme, Siddhartha, Yadav, Drakoulis, Yannoukakos, Sook-Yee, Yoon, Cristina, Zanzottera, Kristin K, Zorn, Anthony V, D'Amico, Matthew L, Freedman, Mark M, Pomerantz, Georgia, Chenevix-Trench, Antonis C, Antoniou, Susan L, Neuhausen, Laura, Ottini, Henriette Roed, Nielsen, and Timothy R, Rebbeck
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, Adolescent, BRCA1 Protein, Prostatic Neoplasms, Genomics, Middle Aged, Prognosis, Young Adult, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged
Abstract: Pathogenic sequence variants (PSV) in
Published: 2019

15. Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples

Author: Orland Diez, Mads Thomassen, Rita D. Brandão, Samantha C Ayoub, Phillip J. Whiley, Olufunmilayo I. Olopade, Mara Colombo, Claude Houdayer, Gorka Ruiz de Garibay, Diana Baralle, Conxi Lázaro, Kumar Lal, Paolo Radice, Demis Tserpelis, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Gemma Montalban, Logan C. Walker, Barbara Wappenschmidt, Michael T. Parsons, Ana Vega, Ana Blanco, Alexandra Becker, Marta Santamariña, Irene López-Perolio, Bifeng Zhang, Marinus J. Blok, Amanda B. Spurdle, James D. Fackenthal, kConFab Investigators, Giovanna De Vecchi, Toshio F. Yoshimatsu, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, and Genetica & Celbiologie
Subjects: 0301 basic medicine, medicine.medical_specialty, Breast Neoplasms, Biology, medicine.disease_cause, Germline, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, Cell Line, Tumor, Genetics, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Genetic Testing, RNA, Messenger, Allele, skin and connective tissue diseases, Gene, Genetics (clinical), BRCA2 Protein, Ovarian Neoplasms, Mutation, BRCA1 Protein, Alternative splicing, Alternative Splicing, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, MCF-7 Cells, Female, RNA Splice Sites
Abstract: BACKGROUND: BRCA1 and BRCA2 are the two principal tumour suppressor genes associated with inherited high risk of breast and ovarian cancer. Genetic testing of BRCA1/2 will often reveal one or more sequence variants of uncertain clinical significance, some of which may affect normal splicing patterns and thereby disrupt gene function. mRNA analyses are therefore among the tests used to interpret the clinical significance of some genetic variants. However, these could be confounded by the appearance of naturally occurring alternative transcripts unrelated to germline sequence variation or defects in gene function. To understand which novel splicing events are associated with splicing mutations and which are part of the normal BRCA2 splicing repertoire, a study was undertaken by members of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium to characterise the spectrum of naturally occurring BRCA2 mRNA alternate-splicing events.METHODS: mRNA was prepared from several blood and breast tissue-derived cells and cell lines by contributing ENIGMA laboratories. cDNA representing BRCA2 alternate splice sites was amplified and visualised using capillary or agarose gel electrophoresis, followed by sequencing.RESULTS: We demonstrate the existence of 24 different BRCA2 mRNA alternate-splicing events in lymphoblastoid cell lines and both breast cancer and non-cancerous breast cell lines.CONCLUSIONS: These naturally occurring alternate-splicing events contribute to the array of cDNA fragments that may be seen in assays for mutation-associated splicing defects. Caution must be observed in assigning alternate-splicing events to potential splicing mutations.
Published: 2016
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16. Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report

Author: Arjen R. Mensenkamp, Paolo Radice, Mark E. Robson, Emma Tudini, Amanda B. Spurdle, Susan M. Domchek, Melissa A. Brown, Logan C. Walker, Miguel de la Hoya, Sean V. Tavtigian, Diana Eccles, Leslie Burke, Thilo Dörk, Clare Turnbull, Antonis C. Antoniou, Michael T. Parsons, Stephanie Greville-Heygate, Maaike P.G. Vreeswijk, Marc Tischkowitz, Alvaro N.A. Monteiro, Helen V. Firth, Spurdle, Amanda B [0000-0003-1337-7897], de la Hoya, Miguel [0000-0002-8113-1410], Parsons, Michael T [0000-0003-3242-8477], Radice, Paolo [0000-0001-6298-4111], Eccles, Diana M [0000-0002-9935-3169], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, genetic variant, Vocabulary, media_common.quotation_subject, Genes, BRCA2, Genes, BRCA1, Computational biology, Biology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, International Classification of Diseases, Terminology as Topic, Genetic variation, Controlled vocabulary, Genetics, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetics (clinical), interpretation, Germ-Line Mutation, Genetic testing, media_common, vocabulary, reporting, Massive parallel sequencing, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, Gene Expression Profiling, Cancer, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Neoplasms, Germ Cell and Embryonal, medicine.disease, cancer susceptibility, Genetic architecture, 3. Good health, 030104 developmental biology, Vocabulary, Controlled, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols
Abstract: The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.
Published: 2019

17. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author: Luigi Mori, Sara González, Elia Grau, Dieter Niederacher, Alexandra C. Kölbl, Ares Solanes, Cassandra B. Nichols, Marine Guillaud-Bataille, Ulrike Schoenwiese, Katherine L. Nathanson, Alfons Meindl, Ellen Honisch, Hans Ehrencrona, Ute Enders, Anke Waha, Trinidad Caldés, Inge Søkilde Pedersen, Ana Blanco, Emma Tudini, Conxi Lázaro, Paolo Radice, Torben A Kruse, María Concepción Alonso-Cerezo, Chantal Farra, Shan Wang-Gohrke, Wilko Weichert, Heli Nevanlinna, Setareh Moghadasi, Bernd Auber, Carla Bruzzone, Aliana Guerrieri-Gonzaga, Sabine Grill, Raymonda Varon, Nicolas Derive, Ana Vega, Nicolai Maass, Åke Borg, Cora M. Aalfs, Nadia Naldi, Silvia Iglesias, Kai Ren Ong, Encarna B. Gomez Garcia, Karl Hackmann, Emma R. Woodward, Norbert Arnold, David E. Goldgar, Bernard Peissel, Karolin Bucksch, Berardino Porfirio, Françoise Révillion, Angel Izquierdo, Isabell Witzel, Sebastian Wagner, Silke Zachariae, Elisa Alducci, Mads Thomassen, Jesús del Valle, Valentina Zampiga, Kerstin Rhiem, Lidia Moserle, Edenir Inêz Palmero, Maaike P.G. Vreeswijk, Christoph Mundhenke, Laura Papi, Alejandro Moles-Fernández, Paula Rofes, Ulrike Faust, Andrea Gehrig, Sandrine M. Caputo, Logan C. Walker, Fiona Lalloo, Ute Felbor, Joan Brunet, Henriette Roed Nielsen, Sean V. Tavtigian, Beatrice Bortesi, Thomas Hansen, Maria Grazia Tibiletti, Estela Carrasco, Lisa Wiesmüller, Viviana Gismondi, Sophie Krieger, Pedro Pérez-Segura, Esther Pohl-Rescigno, Emanuela Lucci-Cordisco, Barbara Wappenschmidt, Rui Manuel Reis, Gabriele Lorenzo Capone, Ileana Carnevali, Christi J. van Asperen, KCon Fab Investigators, Jochen Seggewiß, Rhiannon J. Walters, Irmgard Debatin, Susan M. Domchek, Marco Montagna, Francesca Gensini, Kristiina Aittomäki, Véronique Dutrannoy, Arcangela De Nicolo, Giulia Cagnoli, Elisa J. Cops, Henrique de Campos Reis Galvão, Giulia Cini, Barbara Riboli, Eva Tornero, Paul A. James, Judith Balmaña, Anne-Marie Gerdes, Heide Hellebrand, Miriam Fine, Mathias Stiller, Aldo Germani, Diana Eccles, Britta Blümcke, Dominique Stoppa-Lyonnet, Elena Leinert, Alexandra Lewis, Daniela Rivera, Verena Hübbel, Fergus J. Couch, Gunnar Schmidt, Katharina Keupp, Bernhard H. F. Weber, Tilman Heinrich, Mariarosaria Calvello, Michael Dean, Udo Jeschke, Vanessa Lattimore, Linda A.M. Janssen, Siranoush Manoukian, Eva Gross, Kelly J. Sullivan, Doris Steinemann, Susanne Ledig, Alessandra Viel, Christoph Engel, Ana Sánchez de Abajo, Nina Ditsch, Sandra Bonache, Maria A. Caligo, Katharina Pfeifer, Thomas Haaf, Christian Sutter, Eric Hahnen, Laura Matricardi, Marc Tischkowitz, Alex Teulé, Katherine M. Tucker, Jutta Giesecke, Silvia Tognazzo, Gemma Montalban, Carolina Gómez, Anders Kvist, Joanna Lim, Alison H. Trainer, Rachel Susman, Judit Horvath, Amanda B. Spurdle, Mirjam Larsen, Therese Törngren, Mónica Salinas, Nicholas Pachter, Rachel Austin, Nicola K. Poplawski, C Zeder-Göß, Juliane Ramser, Julia Ritter, Anne Sophie Vesper, Paola Concolino, D. Gareth Evans, Clemens R. Müller, Matilde Navarro, Sara Torres-Esquius, Claus R. Bartram, Laura Cortesi, Jacopo Azzollini, Marion Harris, Edward M. Clarke, Marion Kiechle, Lídia Feliubadaló, Almuth Caliebe, Karen N. Herold, Charlotte Kvist Lautrup, Anne S. Quante, Gardenia Vargas-Parra, Michael T. Parsons, Pietro Cavalli, Hongyan Li, Rodrigo Augusto Depieri Michelli, Irene Feroce, Achim Wöckel, Kerstin Wieland, Silke Kaulfuß, Soo Hwang Teo, Angela Velasco, Capucine Delnatte, Marta Pineda, Marion van Mackelenbergh, Eva Montes, Angela Toss, Rita K. Schmutzler, William D. Foulkes, Alvaro N.A. Monteiro, Jan Hauke, Monica Marabelli, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Esther Darder, Simona Agata, Amanda E. Toland, Bernardo Bonanni, Liliana Varesco, Orland Diez, Andreas Rump, Virginie Caux-Moncoutier, Gaetana Gambino, Markus Loeffler, Claude Houdayer, Elena Barbieri, Adrià López-Fernández, et. al., Universidade do Minho, QIMR Berghofer Medical Research Institute, Chinese Academy of Geological Sciences [Beijing] (CAGS), Ministry of Land and Resources (MLR), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Programa de Càncer Hereditari, Unitat de Diagnòstic Molecular, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Helsinki University Central Hospital, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Università degli Studi di Milano [Milano] (UNIMI), Medical Oncology Department, Vall d'Hebron University Hospital [Barcelona], Institute of Human Genetics, Universität Heidelberg [Heidelberg], Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC, CIBER-ER, Division of Cancer Prevention and Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Genetic Counseling and Hereditary Cancer Programme, Catalan Institute of Oncology, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Institut Curie [Paris], Programa de Consell Genètic en Càncer, Institut Català d'Oncologia, Girona-IdIBGi, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre René Gauducheau, CRLCC René Gauducheau, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Ludwig-Maximilians-Universität München (LMU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetics, University of Southampton, Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Genomic Medicine, University of Manchester [Manchester], Department of Medical Genetics, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Obstetrics and Gynaecology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institüt für Humangenetik [Würzburg], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institute of Chemistry [Budapest], Faculty of Sciences [Budapest], Eötvös Loránd University (ELTE)-Eötvös Loránd University (ELTE), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universitaet, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Department of Oncology, Lund University [Lund]-Clinical Sciences, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Institute for Medical Informatics, Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, University Medical Center Kiel, Department of Obstetrics and Gynecology, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Biochemistry, Section of Molecular Diagnostics, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Institute of Cell and Molecular Pathology, Medizinische Hochschule Hannover (MHH), University of California [Santa Cruz] (UCSC), University of California, Heidelberg University Hospital [Heidelberg], International Agency for Cancer Research (IACR), Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología-IDIBELL, L'Hospitalet, Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, CIBER de Enfermedades Raras (CIBERER), Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, University of Otago [Dunedin, Nouvelle-Zélande], Institute of Pathology, Department of Gynecology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), King‘s College London, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, University Management, University of Helsinki, Università degli Studi di Milano = University of Milan (UNIMI), Universität Heidelberg [Heidelberg] = Heidelberg University, Department of Genetics and Pathology, Uppsala University, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Julius-Maximilians-Universität Würzburg (JMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Firenze = University of Florence (UniFI), Université de Lille-UNICANCER-Université de Lille-UNICANCER, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Universität Leipzig, University of Cologne, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: Male, Multifactorial Inheritance, BRCA1, BRCA2, classification, clinical, multifactorial, quantitative, uncertain significance, variant, Alternative Splicing, BRCA1 Protein, BRCA2 Protein, Computational Biology, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Neoplasms, Mutation, Missense, Medicina Básica [Ciências Médicas], Settore MED/03 - GENETICA MEDICA, GUIDELINES, Genetic analysis, CLINGEN, SEQUENCE VARIANTS, Missense mutation, FUNCTIONAL ASSAYS, Genetics (clinical), BRCA1, BRCA2, quantitative, clinical, classification, multifactorial, variant, uncertain significance, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, SPLICING ANALYSIS, OVARIAN, BRCA2 Protein/genetics, 3. Good health, ddc, Mutation (genetic algorithm), Ciências Médicas::Medicina Básica, Medical genetics, Special Articles, medicine.medical_specialty, Posterior probability, Population, Computational biology, Biology, INTEGRATED EVALUATION, 03 medical and health sciences, Special Article, medicine, Genetics, BREAST-CANCER, Genetic variability, ddc:610, education, 030304 developmental biology, Tumors, Science & Technology, Proteins, Computational Biology/methods, RISKS, Mutation, BRCA1 Protein/genetics, 3111 Biomedicine, Missense, Proteïnes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genètica, Neoplasms/diagnosis
Abstract: The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis
Published: 2019
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18. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing

Author: Patricia Llovet, Miguel de la Hoya, Pedro Pérez-Segura, Víctor Lorca, Sandra Tapial, Daniel Rueda, Trinidad Caldés, Lorena Martín-Morales, Pilar Garre, Vanesa García-Barberán, Eduardo Díaz-Rubio, Richarda M. de Voer, Carmen Poves, María Jesús Fernández-Aceñero, Judith E. Grolleman, and Julián Sanz
Subjects: Adult, Male, 0301 basic medicine, Proband, Genetic testing, DNA Mutational Analysis, Population, lcsh:Medicine, Penetrance, Biology, Article, Frameshift mutation, Cohort Studies, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, MUTYH, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Genetic predisposition, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Allele, lcsh:Science, education, Cancer genetics, Germ-Line Mutation, Aged, Aged, 80 and over, Genetics, education.field_of_study, Multidisciplinary, Sequence Analysis, RNA, Genetic heterogeneity, Gene Expression Profiling, lcsh:R, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Middle Aged, Colorectal cancer, Pedigree, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Adenomatous Polyposis Coli, Spain, lcsh:Q, Female, 030217 neurology & neurosurgery
Abstract: Attenuated adenomatous polyposis (AAP) is a heterogeneous syndrome in terms of clinical manifestations, heritability and etiology of the disease. Genetic heterogeneity and low penetrance alleles are probably the best explanation for this variability. Certainly, it is known that APC and MUTYH are high penetrance predisposition genes for adenomatous polyposis, but they only account for 5–10% of AAP. Other new predisposition genes, such as POLE, POLD1, NTHL1, AXIN2 or MSH3, have been recently described and have been associated with AAP, but their relative contribution is still not well defined. In order to evaluate the genetic predisposition to AAP in a hospital based population, germline DNAs from 158 AAP subjects were screened for genetic variants in the coding regions and intron-exon boundaries of seven associated genes through a next-generation sequencing (NGS) custom gene panel. Splicing, segregation studies, somatic mutational screening and RNA quantitative expression assays were conducted for selected variants. In four of the probands the adenoma susceptibility could be explained by actionable mutations in APC or MUTYH, and one other patient was a double carrier of two truncating variants in both POLE and NTHL1. Furthermore, 16 additional patients harbored uncertain significance variants in the remaining tested genes. This report gives information about the contribution of the newly described adenomatous polyposis predisposition genes in a Spanish attenuated polyposis cohort. Our results highly support the convenience of NGS multigene panels for attenuated polyposis genetic screening and reveals POLE frameshift variants as a plausible susceptibility mechanism for AAP.
Published: 2019

19. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Olufunmilayo I. Olopade, Darcy L. Thull, Raanan Berger, Mary Beth Terry, Michel Longy, Timothy R. Rebbeck, Gord Glendon, Min Hyuk Lee, Javier Benitez, Mark T. Rogers, Mark H. Greene, Dezheng Huo, Adalgeir Arason, Carole Brewer, Siranoush Manoukian, Jackie Cook, Louise Izatt, Yuan Chun Ding, Dieter Niederacher, Nadine Tung, Sophie Giraud, Henriette Roed Nielsen, Antonis C. Antoniou, Bernhard H. F. Weber, Bruno Buecher, Goska Leslie, Amanda E. Toland, Anna Marie Mulligan, Ane Y. Schmidt, Noralane M. Lindor, Véronique Mari, Tara M. Friebel, Cecilia M. Dorfling, Ugnius Mickys, Lenka Foretova, Andrew K. Godwin, Bernd Dworniczak, Tsun Leung Chan, Monica Barile, Angela R. Solano, Susan J. Ramus, Laurence Faivre, Susan L. Neuhausen, Ana Peixoto, Julio Abugattas, Mattias Van Heetvelde, Jacqueline Eason, Muhammad Usman Rashid, Barbara Pasini, Henrique de Campos Reis Galvão, Heli Nevanlinna, Lucy Side, Nina Peruga, Marco Montagna, Amie Blanco, Alison H. Trainer, Cristina Zanzottera, Arjen R. Mensenkamp, Douglas F. Easton, Inge Søkilde Pedersen, Kenneth Offit, Judy Garber, Sook-Yee Yoon, Uffe Birk Jensen, Irene Konstantopoulou, Barbara Wappenschmidt, Stefanie Engert, Robert L. Nussbaum, Kai-ren Ong, Ros Eeles, Marinus J. Blok, Yael Laitman, Alex Teulé, Marion Gauthier-Villars, Daniel Barrowdale, Mads Thomassen, Torben A Kruse, Hanne Meijers-Heijboer, Abigail Thomas, Susan M. Domchek, Jacques Simard, Jamal Zidan, Paul A. James, Rob B. van der Luijt, Nina Ditsch, Annette Lee, Joseph Vijai, Kathleen R. Blazer, Elizabeth J. van Rensburg, János Papp, Lizet E. van der Kolk, Eitan Friedman, Pascal Pujol, Johanna Rantala, Patricia A. Ganz, Esther M. John, Conxi Lázaro, Jacek Gronwald, Paul Gesta, Jan Hauke, Simona Agata, Leo Auerbach, Paolo Radice, Fabienne Prieur, Beth Y. Karlan, Antoine De Pauw, Paolo Peterlongo, Sandrine M. Caputo, Sue K. Park, Marc Tischkowitz, Jocelyne Chiquette, Karin Kast, Annemieke H. van der Hout, Eric Hahnen, Grzegorz Sukiennicki, Debra Frost, Noura Mebirouk, Angel Izquierdo, Alex Henderson, Carolina Velázquez, Raymonda Varon-Mateeva, J. Margriet Collée, Soo-Hwang Teo, Esther Pohl, Rosa B. Barkardottir, Rita K. Schmutzler, Kim De Leeneer, Andrea Gehrig, D. Gareth Evans, Jeffrey N. Weitzel, Katherine L. Nathanson, Lesley McGuffog, Christoph Engel, Amanda B. Spurdle, Austin Miller, Edith Olah, Hans Ehrencrona, Almuth Caliebe, Zoltan Matrai, Ian G. Campbell, Christina G. Selkirk, Kirsten B. Moysich, Ella Asseryanis, Wendy K. Chung, Michael T. Parsons, Shan Wang-Gohrke, Thomas P. Slavin, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Christian F. Singer, Lesley Andrews, Jacopo Azzollini, Peter J. Hulick, Judith Balmaña, Anne-Marie Gerdes, Frans B. L. Hogervorst, Capucine Delnatte, Miguel de la Hoya, Katarzyna Kaczmarek, Angelica M. Gutierrez-Barrera, Claudine Isaacs, Lisa Walker, Doris Steinemann, Huu Phuc Nguyen, Anna von Wachenfeldt, Saundra S. Buys, Fabienne Lesueur, Kristin K. Zorn, Kerstin Rhiem, Manuel R. Teixeira, Linda Steele, Ava Kwong, Alfons Meindl, Evgeny N. Imyanitov, Giuseppe Giannini, Banu Arun, Vilius Rudaitis, Norbert Arnold, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Jacob Korach, Ana Vega, Nisha Pradhan, David E. Goldgar, Anna Jakubowska, Angela R. Bradbury, Cora M. Aalfs, kConFab Investigators, Lídia Feliubadaló, Annelie Liljegren, Ana Osorio, Sabine Topka, Julia Hentschel, Katie Snape, Fergus J. Couch, Ute Hamann, Anna Öfverholm, Edenir Inêz Palmero, Jacob Musinsky, Adriana Lasa, Silvia Tognazzo, Payal D. Shah, Drakoulis Yannoukakos, Valérie Bonadona, Laura Papi, Georgia Chenevix-Trench, Christi J. van Asperen, Hagay Sobol, Kristiina Aittomäki, Cristina Martínez-Bouzas, Jan Lubinski, Csilla Szabo, Joanne Ngeow, Hebon, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Christian Sutter, Yen Y. Tan, Trinidad Caldés, Rosemarie Davidson, Jenny Lester, Andreas Berger, Mark E. Robson, Jennifer T. Loud, Cynthia Villarreal-Garza, Eva Machackova, Leigha Senter, Irene L. Andrulis, Sandra Fert Ferrer, Diana Torres, Sung-Won Kim, Karolina Prajzendanc, Christine Lasset, Embrace, Jeffrey M. Fowler, Bernardo Bonanni, Bent Ejlertsen, Liliana Varesco, Orland Diez, Kathleen Claes, Leslie, Goska [0000-0001-5756-6222], Easton, Douglas [0000-0003-2444-3247], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Centre Léon Bérard [Lyon], Institut Curie [Paris], CRLCC René Gauducheau, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Métropole Savoie [Chambéry], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Clinical Genetics, Human genetics, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Fundações de Amparo à Pesquisa (Brasil), Research Foundation - Flanders, University of Helsinki, Sigrid Juselius Foundation, Dutch Cancer Society, Netherlands Organization for Scientific Research, Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministero della Salute, Istituto Oncologico Veneto, University of Tasmania, Australian Cancer Research Foundation, Ministry of Health and Welfare (South Korea), Charles University (Czech Republic), National Research Foundation Singapore, Russian Foundation for Basic Research, Istituto Toscano Tumori, Israel Cancer Association USA, Swedish Cancer Society, Foundation for Women's Cancer, University of Pittsburgh, Cancer Australia, American Cancer Society, The Ohio State University, National Institutes of Health (US), Cancer Research UK, European Commission, Canadian Institutes of Health Research, Department of Trade and Industry (UK), Susan G. Komen Foundation, Breast Cancer Research Foundation, Genome Canada, National Cancer Institute (US), Research Council of Lithuania, Cancer Association of South Africa, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Sanidad y Política Social (España), Associazione Italiana per la Ricerca sul Cancro, Fondazione Italiana per la Ricerca sul Cancro, Ministero dell'Istruzione, dell'Università e della Ricerca, Institut Pasteur, Fondazione Cenci Bolognetti, Greek Government, Pontificia Universidad Javeriana, Royal Marsden NHS Foundation Trust, Kansas State University, Fundación Mutua Madrileña, Ligue Nationale contre le Cancer (France), Georgetown University, Human Genetics, Other departments, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, HEREDITARY BREAST, Mutation rate, Internationality, endocrine system diseases, Càncer d'ovari, Gene mutation, medicine.disease_cause, geography, Race (biology), 0302 clinical medicine, Breast cancer, FOUNDER MUTATIONS, Databases, Genetic, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], skin and connective tissue diseases, Genetics (clinical), Genetics, Mutation, medicine.diagnostic_test, Geography, RISK HISPANIC FAMILIES, BRCA1 Protein, 185DELAG MUTATION, GERMLINE MUTATIONS, 3. Good health, PROSTATE-CANCER, ovarian cancer, 030220 oncology & carcinogenesis, Medical genetics, ethnicity, BREAST-CANCER PATIENTS, BRCA1, BRCA2, breast cancer, mutation, medicine.medical_specialty, Biology, OVARIAN-CANCER, Article, Càncer de mama, BRCA2 Protein, Family, Humans, 03 medical and health sciences, Databases, Germline mutation, Genetic, Ovarian cancer, medicine, ddc:610, Genotyping, Genetic testing, PHENOTYPE ANALYSIS, BRCA1, BRCA2, Breast Cancer, HAPLOTYPE ANALYSIS, Mutació (Biologia), Mutation (Biology), 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018
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20. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

Author: Caroline Seynaeve, Katja Harbst, Eric A. Ross, Nandita Mitra, Elisa Alducci, Marco Montagna, Janusz Menkiszak, Marion Gauthier-Villars, Javier Benitez, Carole Brewer, Etienne Rouleau, Inge Søkilde Pedersen, Orland Diez, Anya Kushnir, Antonis C. Antoniou, Christine Rappaport, Florentia Fostira, Maurizio Genuardi, Simona Agata, Mark H. Greene, Mary Beth Terry, Nicola Dikow, David E. Goldgar, Anna Jakubowska, Min Hyuk Lee, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Anne-Marie Gerdes, Alexander Miron, Laima Tihomirova, Alan Donaldson, Adalgeir Arason, Rosalind A. Eeles, Fergus J. Couch, Hans Jörg Plendl, Francesca Vignolo-Lutati, Ute Hamann, Jackie Cook, Torben A Kruse, Shani Paluch-Shimon, Lisa Walker, Doris Steinemann, Dorothea Gadzicki, Juul T. Wijnen, Markus C. Fleisch, Kenneth Offit, Mary B. Daly, Jamal Zidan, Georgia Chenevix-Trench, Stephanie V. Blank, Marc Tischkowitz, Esther Darder, Annette Fontaine, Louise Izatt, Elżbieta Złowocka-Perłowska, Nadia Boutry-Kryza, Frans B. L. Hogervorst, Stefanie Engert, Danièle Muller, Susan M. Domchek, Phuong L. Mai, Senno Verhoef, Bernhard H. F. Weber, Cecilia M. Dorfling, Kathleen Claes, Kristiina Aittomäki, Annemarie H. van der Hout, Sharon Sand, Olufunmilayo I. Olopade, Margreet G. E. M. Ausems, Aleksandra Tołoczko-Grabarek, Trevor Cole, Giulietta Scuvera, Ana Osorio, Niklas Loman, Timothy R. Rebbeck, Riccardo Dolcetti, Marit Beer, Harsh B. Pathak, Douglas F. Easton, Lone Sunde, Conxi Lázaro, Raanan Berger, Paolo Radice, Mads Thomassen, Ignacio Blanco, Joseph Vijai, Kristie Bobolis, János Papp, Jean-Pierre Fricker, Christine Walsh, Patricia A. Ganz, Marie Stenmark-Askmalm, Andrea Gehrig, Vernon S. Pankratz, Atocha Romero, Xianshu Wang, Loris Bernard, Viviana Gismondi, Mary Porteous, Muy-Kheng Tea, Karen H. Lu, Gustavo C. Rodriguez, Bernardo Bonanni, Christoph Mundhenke, Julian Adlard, Bent Ejlertsen, Dominique Stoppa-Lyonnet, Nadine Tung, Patrick J. Morrison, Dezheng Huo, Cezary Cybulski, Jack Basil, Georg Pfeiler, Daphne Gschwantler-Kaulich, Heli Nevanlinna, Anders Bojesen, Marion Piedmonte, Katherine L. Nathanson, Amanda E. Toland, Sung-Won Kim, Judy Garber, Amanda B. Spurdle, Noralane M. Lindor, Sanne Traasdahl Moeller, Hans Ehrencrona, Trinidad Caldés, Rosemarie Davidson, Karin Kast, Jenny Lester, Shan Wang-Gohrke, Norbert Arnold, Ana Peixoto, Christine Lasset, Andreas Berger, Olga M. Sinilnikova, Katie Wakely, Claude Houdayer, Mercedes Durán, Robert L. Nussbaum, Ramūnas Janavičius, Christina G. Selkirk, Paolo Aretini, Nina Ditsch, J. Margriet Collée, Rosa B. Barkardottir, Sue Healey, Tomasz Huzarski, Cora M. Aalfs, Gillian Mitchell, Peter J. Hulick, Encarna B. Gomez Garcia, Zakaria Einbeigi, Christian F. Singer, Leigha Senter, Yuan Chun Ding, Dieter Niederacher, Yael Laitman, Siranoush Manoukian, Christoph Engel, Anne De Paepe, Anneliese Fink-Retter, Irene L. Andrulis, Rachel Laframboise, Maria A. Caligo, Priyanka Sharma, Miguel de la Hoya, Teresa Ramón y Cajal, Bruce Poppe, Thomas Hansen, Francesca Damiola, Anne-Bine Skytte, Susan L. Neuhausen, Christian Sutter, Marie-Agnès Collonge-Rame, Johannes J. P. Gille, Barbara Pasini, Wendy K. Chung, Noah D. Kauff, M. John Kennedy, Diana Torres, Salina B. Chan, Mark E. Robson, Elizabeth J. van Rensburg, Eric Hahnen, Barbara Wappenschmidt, Grzegorz Sukiennicki, Esther M. John, Rohini Rau-Murthy, Alice S. Whittemore, Kunle Odunsi, Masoud Azodi, John F. Boggess, Sue K. Park, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Simon A. Gayther, Fei Wan, Andrew K. Godwin, Arjen R. Mensenkamp, Daniela Zaffaroni, Jacques Simard, Susan Peock, Soo Hwang Teo, Claus R. Bartram, Evgeny N. Imyanitov, Maria-Isabel Tejada, Giuseppe Giannini, Mónica Salinas, Banu Arun, Jan C. Oosterwijk, Jacek Gronwald, Alexandra Becker, Tara M. Friebel, Lenka Foretova, Catherine Noguès, Muhammad Usman Rashid, Valeria Pensotti, Antonella Savarese, Debra Frost, Beatrice Melin, Drakoulis Yannoukakos, Steve Ellis, Jean-Philippe Peyrat, Hagay Sobol, Kim De Leeneer, Radka Platte, Jan Lubinski, Javier Godino, Lesley McGuffog, Tomasz Byrski, Claudine Isaacs, Johanna Rantala, Kelly-Anne Phillips, Carolien M. Kets, Uffe Birk Jensen, Katarzyna Durda, Linda Steele, Beth Y. Karlan, Ava Kwong, Alfons Meindl, Lucia Guidugli, Raymonda Varon-Mateeva, D. Gareth Evans, Edith Olah, Isabelle Mortemousque, Manuel R. Teixeira, Joyce Seldon, Katarzyna Jaworska-Bieniek, Bernard Peissel, Saundra S. Buys, Peter Devilee, Kerstin Rhiem, Eitan Friedman, RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Cancer Research UK, National Institutes of Health (US), University of Pennsylvania, Breast Cancer Research Foundation, Human Genetics, Human genetics, and Epidemiology and Data Science
Subjects: endocrine system diseases, Genes, BRCA2, MathematicsofComputing_GENERAL, Genes, BRCA1, cancer risk, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, MOUSE MODELS, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Age of Onset, POSITION, skin and connective tissue diseases, Adult, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Ovarian Neoplasms, Genetic Predisposition to Disease, Mutation, Medicine (all), MESSENGER-RNA DECAY, UNKNOWN CLINICAL-SIGNIFICANCE, BRCA1 and BRCA2 genes, mutation type and position, cancer risk, TheoryofComputation_GENERAL, General Medicine, GERMLINE MUTATIONS, CARRIERS, 3. Good health, SUSCEPTIBILITY GENE, Medical genetics, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, PROTEINS, mutation type and position, BRCA1 and BRCA2 genes, DNA-SEQUENCE VARIANTS, Article, REGION, Breast cancer, Germline mutation, medicine, BRCA1 or BRCA2, business.industry, Cancer, Heterozygote advantage, medicine.disease, Cancer research, Age of onset, Ovarian cancer, business
Abstract: CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.
Published: 2015
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21. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet 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Network, Clin Canc Genet, Duarte, CA 91010 USA [ 104 ] Netherlands Canc Inst, Family Canc Clin, NL-1000 BE Amsterdam, Netherlands [ 105 ] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 106 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 107 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia [ 108 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 109 ] NN Petrov Oncol Res Inst, St Petersburg 197758, Russia [ 110 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA [ 111 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 8006, Australia [ 112 ] Univ Melbourne, Dept Oncol, Melbourne, Vic 8006, Australia [ 113 ] State Res Inst, Ctr Innovat Med, LT-08661 Vilnius, Lithuania [ 114 ] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark [ 115 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 116 ] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England [ 117 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland [ 119 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 120 ] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England [ 121 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 122 ] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany [ 123 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland [ 124 ] Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong Sanat & Hosp, Hong Kong, Hong Kong, Peoples R China [ 125 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 126 ] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium [ 127 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain [ 128 ] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA [ 129 ] Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA [ 130 ] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden [ 131 ] Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA [ 132 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 133 ] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore [ 134 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 135 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 136 ] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA [ 137 ] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA [ 138 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 139 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany [ 140 ] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA [ 141 ] Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA [ 142 ] Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada [ 143 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 144 ] Invitae Corp, San Francisco, CA 94107 USA [ 145 ] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA [ 146 ] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary [ 147 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 148 ] Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea [ 149 ] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea [ 150 ] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands [ 151 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England [ 152 ] Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy [ 153 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 154 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 155 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 156 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland [ 157 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 158 ] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England [ 159 ] Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden [ 160 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 161 ] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel [ 162 ] Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel [ 163 ] B Rappaport Fac Med, IL-34362 Haifa, Israel [ 164 ] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA [ 165 ] Int Agcy Res Canc, F-69008 Lyon, France [ 166 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands [ 167 ] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain [ 168 ] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain [ 169 ] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA [ 170 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 171 ] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany [ 172 ] Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany [ 173 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 174 ] John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia [ 175 ] Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA [ 176 ] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada [ 177 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France [ 178 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 179 ] Hannover Med Sch, D-30625 Hannover, Germany [ 180 ] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden [ 181 ] Inst Curie, Dept Tumour Biol, F-75248 Paris, France [ 182 ] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France [ 183 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 184 ] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal [ 185 ] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal [ 186 ] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia [ 187 ] Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands [ 201 ] Charite, Inst Human Genet, D-13353 Berlin, Germany [ 202 ] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [ 203 ] Univ Hosp Ulm, D-89075 Ulm, Germany [ 204 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [ 205 ] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland [ 206 ] Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA [ 207 ] Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium [ 208 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 209 ] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain [ 210 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 211 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia [ 212 ] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA
Subjects: 0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.
Published: 2018
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22. Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11

Author: Jennifer Nuk, Carol Cremin, Kathleen Claes, Wendy McKinnon, Martin Trbusek, Anne Vral, Lenka Foretova, Sean D. Young, Annelot Baert, Ilse Coene, Tom Van Maerken, William D. Foulkes, Marie Jill Asrat, Ana Vega, Marie E. Wood, Andrée MacMillan, Miguel de la Hoya, Bruce Poppe, Kim De Leeneer, Allison Mindlin, Toon Rosseel, Cheryl Portigal-Todd, Marta Santamariña, Kristin Turner, and Eva Machackova
Subjects: 0301 basic medicine, DNA, Complementary, In silico, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Computational biology, Biology, 03 medical and health sciences, Exon, Genetics, Humans, Computer Simulation, splice, RNA, Messenger, Genetics (clinical), Ovarian Neoplasms, Breakpoint, Alternative splicing, Intron, Genetic Variation, Exons, Alternative Splicing, 030104 developmental biology, Mutation, RNA splicing, Female, RNA Splice Sites, Tandem exon duplication
Abstract: For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.
Published: 2018
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23. Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome

Author: Pedro Pérez-Segura, David Marrupe, Carmen Poves, Vanesa García-Barberán, Patricia Llovet, Víctor Lorca, Miguel de la Hoya, Daniel Rueda, Beatriz García-Paredes, María Jesús Fernández-Aceñero, Pilar Garre, Clara Ruiz-Ponte, Eduardo Díaz-Rubio, Trinidad Caldés, and Lorena Martín-Morales
Subjects: 0301 basic medicine, Male, Genetic Screens, Glycosylation, Colorectal cancer, Carcinogenesis, Gene Identification and Analysis, Glycobiology, lcsh:Medicine, Loss of Heterozygosity, medicine.disease_cause, Biochemistry, Germline, Loss of heterozygosity, Cohort Studies, Medicine and Health Sciences, Medicine, Gardner Syndrome, Post-Translational Modification, lcsh:Science, Aged, 80 and over, Multidisciplinary, Middle Aged, Adenomas, Pedigree, Oncology, Research Design, N-Acetylgalactosaminyltransferases, Female, Research Article, Adult, Adenoma, Genetic Predisposition, Research and Analysis Methods, 03 medical and health sciences, Genetic predisposition, Genetics, Humans, Genetic Predisposition to Disease, Allele, neoplasms, Alleles, Aged, Colorectal Cancer, business.industry, lcsh:R, Case-control study, Cancers and Neoplasms, Biology and Life Sciences, Proteins, medicine.disease, digestive system diseases, 030104 developmental biology, Genetic Loci, Case-Control Studies, Genetics of Disease, Cancer research, lcsh:Q, business
Abstract: The involvement of GALNT12 in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that GALNT12 could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the GALNT12 gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.
Published: 2017

24. A novel TP53 germline inframe deletion identified in a Spanish series of Li-fraumeni syndrome suspected families

Author: Francisco J. Illana, Vanesa García-Barberán, Pilar Garre, Patricia Llovet, Lorena Martín-Morales, Trinidad Caldés, Miguel de la Hoya, M. Dolores Ibañez-Royo, and Pedro Pérez-Segura
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Loss of Heterozygosity, Biology, medicine.disease_cause, Germline, Loss of heterozygosity, Li-Fraumeni Syndrome, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Genetics, medicine, Missense mutation, Humans, Genetics (clinical), Germ-Line Mutation, Mutation, Point mutation, medicine.disease, Pedigree, 030104 developmental biology, Oncology, Inframe Mutation, Li–Fraumeni syndrome, Spain, 030220 oncology & carcinogenesis, Female, Tumor Suppressor Protein p53
Abstract: Li-Fraumeni syndrome (LFS) is an autosomal dominant, inherited tumor predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. The molecular diagnosis of LFS is important to develop strategies for early detection and access to the genetic counseling. Our study evaluated germline TP53 mutations in Spanish families with a history suggestive of LFS. Germline TP53 alterations in 22 families with a history suggestive of LFS were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Loss of heterozygosity analysis and immunohistochemistry of the protein in the tumor were performed in order to evaluate the pathogenicity of a novel alteration detected. A total of seven TP53 mutations were detected, six point mutations (4 missense and 2 nonsense) and a novel inframe deletion. 93% of mutation carriers developed at least one malignancy (mainly breast cancer and sarcomas), with a mean age at diagnosis of the first tumor of 30.2 years. Two missense mutations acted as dominant-negative. The novel inframe mutation c.437_445del was located in the DNA-binding domain. This mutation segregated with cancer in the family, and both high expression of the protein and loss of the wild-type TP53 allele were detected in the tumor of the carrier. We have found a novel inframe deletion in TP53 that likely results in the loss of p53 function and acts in a non-dominant negative way, although further studies are necessary to clarify this issue. The identification of novel TP53 alterations is crucial for a personalized cancer-risk management of the Li-Fraumeni syndrome.
Published: 2017

25. The BRCA2 c.68-7T A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Author: Mara, Colombo, Irene, Lòpez-Perolio, Huong D, Meeks, Laura, Caleca, Michael T, Parsons, Hongyan, Li, Giovanna, De Vecchi, Emma, Tudini, Claudia, Foglia, Patrizia, Mondini, Siranoush, Manoukian, Raquel, Behar, Encarna B Gómez, Garcia, Alfons, Meindl, Marco, Montagna, Dieter, Niederacher, Ane Y, Schmidt, Liliana, Varesco, Barbara, Wappenschmidt, Manjeet K, Bolla, Joe, Dennis, Kyriaki, Michailidou, Qin, Wang, Kristiina, Aittomäki, Irene L, Andrulis, Hoda, Anton-Culver, Volker, Arndt, Matthias W, Beckmann, Alicia, Beeghly-Fadel, Javier, Benitez, Bram, Boeckx, Natalia V, Bogdanova, Stig E, Bojesen, Bernardo, Bonanni, Hiltrud, Brauch, Hermann, Brenner, Barbara, Burwinkel, Jenny, Chang-Claude, Don M, Conroy, Fergus J, Couch, Angela, Cox, Simon S, Cross, Kamila, Czene, Peter, Devilee, Thilo, Dörk, Mikael, Eriksson, Peter A, Fasching, Jonine, Figueroa, Olivia, Fletcher, Henrik, Flyger, Marike, Gabrielson, Montserrat, García-Closas, Graham G, Giles, Anna, González-Neira, Pascal, Guénel, Christopher A, Haiman, Per, Hall, Ute, Hamann, Mikael, Hartman, Jan, Hauke, Antoinette, Hollestelle, John L, Hopper, Anna, Jakubowska, Audrey, Jung, Veli-Matti, Kosma, Diether, Lambrechts, Loid, Le Marchand, Annika, Lindblom, Jan, Lubinski, Arto, Mannermaa, Sara, Margolin, Hui, Miao, Roger L, Milne, Susan L, Neuhausen, Heli, Nevanlinna, Janet E, Olson, Paolo, Peterlongo, Julian, Peto, Katri, Pylkäs, Elinor J, Sawyer, Marjanka K, Schmidt, Rita K, Schmutzler, Andreas, Schneeweiss, Minouk J, Schoemaker, Mee Hoong, See, Melissa C, Southey, Anthony, Swerdlow, Soo H, Teo, Amanda E, Toland, Ian, Tomlinson, Thérèse, Truong, Christi J, van Asperen, Ans M W, van den Ouweland, Lizet E, van der Kolk, Robert, Winqvist, Drakoulis, Yannoukakos, Wei, Zheng, Alison M, Dunning, Douglas F, Easton, Alex, Henderson, Frans B L, Hogervorst, Louise, Izatt, Kenneth, Offitt, Lucy E, Side, Elizabeth J, van Rensburg, Study, Embrace, Study, Hebon, Lesley, McGuffog, Antonis C, Antoniou, Georgia, Chenevix-Trench, Amanda B, Spurdle, David E, Goldgar, Miguel de la, Hoya, and Paolo, Radice
Subjects: BRCA2 Protein, Base Sequence, Models, Genetic, digital PCR, multifactorial likelihood analysis, Mitomycin, RNA Splicing, spliceogenic variants, Genetic Variation, Exons, BRCA2, Cell Line, Calibration, Humans, Female, Genetic Predisposition to Disease, RNA, Messenger, Research Articles, quantitative real‐time PCR, Research Article
Abstract: Although the spliceogenic nature of the BRCA2 c.68‐7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real‐time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case‐control analysis in 83,636 individuals. Co‐occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5‐fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68‐7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10−115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86–1.24) nor for a deleterious effect of the variant when co‐occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68‐7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2017

26. Limited family structure and triple-negative breast cancer (TNBC) subtype as predictors of BRCA mutations in a genetic counseling cohort of early-onset sporadic breast cancers

Author: Isabel Chirivella, Beatriz Martínez, Rogelio González-Sarmiento, Ana Custodio, Ana Vega, Juan J. Cruz-Hernández, Atocha Romero, A. Manzano, Ignacio Blanco, Trinidad Caldés, Miguel de la Hoya, Laura Fachal, Jon Zugazagoitia, Pilar Garre, Vicente Garcés, Alex Teulé, Eduardo Díaz-Rubio, Pedro Pérez-Segura, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Xunta de Galicia, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer (España)
Subjects: Oncology, Cancer Research, Receptor, ErbB-2, Triple Negative Breast Neoplasms, Immunoenzyme Techniques, Prevalence, Medicine, Prospective Studies, Age of Onset, Family history, skin and connective tissue diseases, Prospective cohort study, Triple-negative breast cancer, BRCAPRO, Family Characteristics, medicine.diagnostic_test, BRCA1 Protein, Prognosis, Receptors, Estrogen, Female, Receptors, Progesterone, TNBC, Adult, BRCA-1, medicine.medical_specialty, Genetic counseling, Genetic Counseling, Breast cancer, Internal medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Neoplasm Staging, Genetic testing, BRCA2 Protein, Gynecology, business.industry, BRCA mutation, medicine.disease, BRCA2, Sporadic breast cancer, Spain, Mutation, Feasibility Studies, Age of onset, business, Family structure, Follow-Up Studies
Abstract: Early-onset diagnosis is an eligibility criterion for BRCA1 and BRCA2 (BRCA) testing in sporadic breast cancer patients. Limited family structure has been proposed as a predictor of BRCA mutation status in this group of patients. An overwhelming amount of data supports a strong association between BRCA1 mutations and triple-negative breast cancer (TNBC). Here, we analyze the feasibility of using limited family structure and TNBC as predictors of BRCA mutation status in early-onset breast cancer patients attending genetic counseling units. We have conducted the study in a cohort of sporadic early-onset (≤35 years) breast cancer patients (N = 341) previously selected for BRCA genetic testing in Academic Hereditary Cancer Clinics from Spain. A retrospective review of medical records available at the time of risk assessment allowed us classifying patients according to family structure and TNBC. In addition, BRCAPRO score was calculated for all patients. Association between categorical variables was investigated using the Fisher’s exact test. Binary Logistic Regression Analysis was used for multivariate analysis. Limited family structure (OR 3.61, p = 0.013) and TNBC (OR 3.14, p = 0.013) were independent predictors of BRCA mutation status. Mutation prevalence in the subgroup of patients with at least one positive predictor was 14 %, whereas it dropped to 3 % in non-TNBCs with adequate family history (OR 5.31, 95 % CI 1.38–23.89, p = 0.006). BRCAPRO correctly discerned between limited and adequate family structures. Limited family structure and TNBC are feasible predictors of BRCA mutation status in sporadic early-onset (≤35 years) breast cancer patients attending genetic counseling units. The low prevalence of mutations observed in non-TNBCs with adequate family structure suggests that this subgroup of patients might be excluded from genetic testing., This work was supported by research Grants (PI12/00539) to M. de la Hoya, Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation & Eurpean Regional Development Fund (ERDF) ‘‘A way to make Europe’’, research grants (RD06/0020/1051 and RD12/0036/008) from Red Temática de Investigación Cooperativa en Cáncer (RTICC) to E. Diaz-Rubio, Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation & Eurpean Regional Development Fund (ERDF) ‘‘A way to make Europe’’, research Grant (10PXIB 9101297PR), Xunta de Galicia, and research grant FMM Foundation to A. Vega.
Published: 2014
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27. Cancer risk and overall survival in mismatch repair proficient hereditary non-polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer

Author: Inmaculada Bando, Trinidad Caldés, Pilar Garre, Atocha Romero, Miguel de la Hoya, Patricia Llovet, Eduardo Díaz-Rubio, Lorena Martín, Alicia Tosar, and Julián Sanz
Subjects: Male, Proto-Oncogene Proteins B-raf, Oncology, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, medicine.medical_specialty, Colorectal cancer, Genetic counseling, medicine.disease_cause, DNA Mismatch Repair, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Internal medicine, Epidemiology, Genetics, medicine, Humans, Family, neoplasms, Genetics (clinical), Adaptor Proteins, Signal Transducing, Aged, business.industry, Incidence (epidemiology), Nuclear Proteins, nutritional and metabolic diseases, Microsatellite instability, Syndrome, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, DNA-Binding Proteins, MutS Homolog 2 Protein, Mutation, ras Proteins, Female, Microsatellite Instability, DNA mismatch repair, KRAS, Colorectal Neoplasms, MutL Protein Homolog 1, business
Abstract: Mismatch repair proficient hereditary non-polyposis colorectal cancer (MSS-HNPCC) encloses a heterogeneous group of families consisting of different unknown genetic syndromes and/or aggregations cases. The lack of information about the hereditability of cancer risk in these families makes it difficult to carry out an individualized Genetic Counseling. Therefore, deep description of such families becomes important for a better classification and search for underlying susceptibility causes. The aim of this study is to describe and compare the clinical, morphological features, tumor KRAS status and overall survival in MSS-HNPCC, Lynch and sporadic colorectal cancer. A total of 37 MSS-HNPCC families, 50 Lynch families and 612 sporadic CRC were included. Clinical and morphological data were evaluated by reviewing medical and pathology reports of 55, 69 and 102 tumors respectively. KRAS/BRAF status were detected by allele specific real-time PCR. Standardized incidence ratios (SIR) were calculated among 602 MSS-HNPCC relatives and 668 Lynch relatives. Main features distinguishing MSS-HNPCC were diagnosis age (55.1 ± 12.6), preferential distal location (76%), polyp detection (45%) and familial colorectal cancer incidence (SIR = 6.6). In addition, we found increased incidences rates for kidney, stomach and uterus tumors. KRAS mutation rates were similar in the study populations (48.8 ± 5.8) but higher than those described before by Sanger sequencing. MSS-HNPCC overall survival was similar to Lynch in B Dukes' stage tumors and between Lynch and sporadic in C stage tumors. Anatomical and morphological data of MSS-HNPCC are consistent with other described populations. Our studies disclose an increased HNPCC-extracolonic tumors incidence and improved overall survival in MSS-HNPCC families.
Published: 2013
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28. The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins

Author: Eva Esteban-Cardeñosa, Cristina Miner, Eva María Sánchez-Tapia, Mar Infante, Mercedes Durán, Lídia Feliubadaló, María García-González, Ana Osorio, Orland Diez, Beatriz Díez-Gómez, Cristina Martínez-Bouzas, Miguel de la Hoya, Alberto Acedo, Alicia Barroso, Rogelio González-Sarmiento, Adriana Lasa, Eladio Velasco, Javier Godino, Enrique Lastra, Alexandre Teulé, Instituto de Salud Carlos III, Junta de Castilla y León, European Commission, Generalitat de Catalunya, and Asociación Española Contra el Cáncer
Subjects: Adult, Male, Cancer Research, Genotype, Molecular Sequence Data, Breast Neoplasms, Dna variants, Biology, Germline, BRCA2 Mutation, Mutational hotspot, Humans, Family, Base Pairing, Aged, Aged, 80 and over, BRCA2 Protein, Genetics, Polymorphism, Genetic, Base Sequence, Mutagenesis, Haplotype, General Medicine, Middle Aged, Prognosis, Haplotypes, Spain, Genetic marker, Mutation, Mutation (genetic algorithm), Female, Follow-Up Studies
Abstract: Supplementary Tables S1–S3 and figures S1 and S2 can be found at: http://carcin.oxfordjournals.org/.-- et al., BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germline mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with eleven 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 (WCL), 20 (ECL) and 6 families (SoS). Mutation age was estimated with the DMLE software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G>A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923-bp fragment of BRCA2 and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G>A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin-loop of c.2808_2811del, and one affected the same position (c.2808A>G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG and BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin-loops suggesting that these structures may represent mutational hotspots., Instituto de Salud Carlos III (PI10/2910 to E.A.V., ISCIIIRETIC: RD06/0020/1051 and PI10/01422 to L.F.); Junta de Castilla y León, Consejería de Educación (CSI004A10-2 to E.A.V.); Consejería de Sanidad (BIO39/VA27/10 to E.A.V.); Cancer Prevention Program of the Regional Government of Castilla y León; The European Social Fund and Consejería de Educación de la Junta de Castilla y León under the P.O. Castilla y León 2007–13 to A.A.; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute, Government of Catalonia (2009SGR290 to L.F.); Spanish Association Against Cancer (to L.F.).
Published: 2013
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29. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, Karoline B., Lesley, Mcguffog, Daniel, Barrowdale, Andrew, Lee, Penny, Soucy, Sue, Healey, Joe, Dennis, Michael, Lush, Mark, Robson, Spurdle, Amanda B., Ramus, Susan J., Nasim, Mavaddat, Mary Beth Terry, Neuhausen, Susan L., Ute, Hamann, Melissa, Southey, John, Esther M., Chung, Wendy K., Daly, Mary B., Buys, Saundra S., Goldgar, David E., Dorfling, Cecilia M., van Rensburg, Elizabeth J., Yuan Chun Ding, Bent, Ejlertsen, Anne-Marie, Gerdes, Hansen, Thomas V. O., Susan, Slager, Emily, Hallberg, Javier, Benitez, Ana, Osorio, Nancy, Cohen, William, Lawler, Weitzel, Jeffrey N., Paolo, Peterlongo, Valeria, Pensotti, Riccardo, Dolcetti, Monica, Barile, Bernardo, Bonanni, Jacopo, Azzollini, Siranoush, Manoukian, Bernard, Peissel, Paolo, Radice, Antonella, Savarese, Papi, Laura, Giannini, Giuseppe, Florentia, Fostira, Irene, Konstantopoulou, Julian, Adlard, Carole, Brewer, Jackie, Cook, Rosemarie, Davidson, Diana, Eccles, Ros, Eeles, Steve, Ellis, Embrace, Debra, Frost, Shirley, Hodgson, Louise, Izatt, Fiona, Lalloo, Kai-ren, Ong, Godwin, Andrew K., Norbert, Arnold, Bernd, Dworniczak, Christoph, Engel, Andrea, Gehrig, Eric, Hahnen, Jan, Hauke, Karin, Kast, Alfons, Meindl, Dieter, Niederacher, Rita Katharina Schmutzler, Raymonda, Varon-Mateeva, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Laure, Barjhoux, Marie-Agne`s, Collonge-Rame, Camille, Elan, GEMO Study Collaborators, Lisa, Golmard, Emmanuelle, Barouk-Simonet, Fabienne, Lesueur, Sylvie, Mazoyer, Joanna, Sokolowska, Dominique Stoppa- Lyonnet, Claudine, Isaacs, Claes, Kathleen B. M., Bruce, Poppe, Miguel de la Hoya, Vanesa, Garcia-Barberan, Kristiina, Aittom€aki, Heli, Nevanlinna, Ausems, Margreet G. E. M., de Lange, J. L., Gomez Garcia, Encarna B., Hebon, Hogervorst, Frans B. L., Kets, Carolien M., Meijers-Heijboer, Hanne E. J., Oosterwijk, Jan C., Rookus, Matti A., van Asperen, Christi J., van den Ouweland, Ans M. W., van Doorn, Helena C., van Os, Theo A. M., Ava, Kwong, Edith, Olah, Orland, Diez, Joan, Brunet, Conxi, Lazaro, Alex, Teule´, Jacek, Gronwald, Anna, Jakubowska, Katarzyna, Kaczmarek, Jan, Lubinski, Grzegorz, Sukiennicki, Barkardottir, Rosa B., Jocelyne, Chiquette, Simona, Agata, Marco, Montagna, Teixeira, Manuel R., Kconfab, Investigators, Sue Kyung Park, Curtis, Olswold, Marc, Tischkowitz, Lenka, Foretova, Pragna, Gaddam, Joseph, Vijai, Georg, Pfeiler, Christine, Rappaport-Fuerhauser, Singer, Christian F., Tea, Muy-Kheng M., Greene, Mark H., Loud, Jennifer T., Gad, Rennert, Imyanitov, Evgeny N., Hulick, Peter J., Hays, John L., Marion, Piedmonte, Rodriguez, Gustavo C., Julie, Martyn, Gord, Glendon, Anna Marie Mulligan, Andrulis, Irene L., Amanda Ewart Toland, Uffe Birk Jensen, Kruse, Torben A., Inge Sokilde Pedersen, Mads, Thomassen, Caligo, Maria A., Soo-Hwang, Teo, Raanan, Berger, Eitan, Friedman, Yael, Laitman, Brita, Arver, Ake, Borg, Hans, Ehrencrona, Johanna, Rantala, Olopade, Olufunmilayo I., Ganz, Patricia A., Nussbaum, Robert L., Bradbury, Angela R., Domchek, Susan M., Nathanson, Katherine L., Arun, Banu K., Paul, James, Karlan, Beth Y., Jenny, Lester, Jacques, Simard, Pharoah, Paul D. P., Kenneth, Offit, Couch, Fergus J., Georgia, Chenevix-Trench, Easton, Douglas F., and Antoniou, Antonis C.
Subjects: Adult, Cancer Research, Heterozygote, Multifactorial Inheritance, Adolescent, Breast Neoplasms, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prognosis, Proportional Hazards Models, Receptors, Estrogen, Risk Assessment, Risk Factors, Young Adult, Genes, BRCA1, Genes, BRCA2, Mutation, Oncology, endocrine system diseases, SUSCEPTIBILITY ALLELES, MODIFIERS, Article, Receptors, Medicine and Health Sciences, LOCUS, COHORT, Polymorphism, FUNCTIONAL VARIANTS, skin and connective tissue diseases, EARLY BILATERAL OOPHORECTOMY, IDENTIFICATION, MORTALITY, Biology and Life Sciences, WOMEN, Single Nucleotide, BRCA1, Estrogen, BRCA2, WIDE ASSOCIATION ANALYSIS, Genes
Abstract: Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
Published: 2017

30. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author: Marco Montagna, Bruno Buecher, Goska Leslie, Daniel Barrowdale, Anita Bane, Louise Izatt, Eitan Friedman, Yosr Hamdi, Kenneth Offit, Klaartje van Engelen, Soo Hwang Teo, Frans B. L. Hogervorst, Conxi Lázaro, Sylvie Mazoyer, Diana Eccles, Yuan Chun Ding, Laura Papi, Georgia Chenevix-Trench, Katarzyna Kaczmarek, Laima Tihomirova, Jacek Gronwald, Jocelyne Chiquette, Patricia A. Ganz, Thomas P. Slavin, Kathleen Claes, Paolo Radice, Elizabeth J. van Rensburg, Adalgeir Arason, Lenka Foretova, Milena Mariani, Johanna Rantala, Pascaline Berthet, Evgeny N. Imyanitov, Claudine Isaacs, Esther M. John, Maite Laurent, Irene L. Andrulis, Juul T. Wijnen, Paolo Peterlongo, Susan M. Domchek, Banu Arun, Amanda E. Toland, Anna Marie Mulligan, Penny Soucy, Kristiina Aittomäki, Orland Diez, Heli Nevanlinna, Anne-Marie Gerdes, Austin Miller, Olufunmilayo I. Olopade, Raymonda Varon-Mateeva, Alfons Meindl, Cecilia M. Dorfling, Niklas Loman, Paul A. James, Susan L. Neuhausen, Muy Kheng Tea, Inge Søkilde Pedersen, Arnaud Droit, D. Gareth Evans, Mark E. Robson, Jennifer T. Loud, Jan C. Oosterwijk, Judy Garber, Douglas F. Easton, Jacques Simard, Mark H. Greene, Pamela S. Ganschow, Edith Olah, Audrey Lemaçon, Norbert Arnold, Catherine M. Phelan, Gad Rennert, Judy Kirk, Johanna Sokolowska, Tomi Pastinen, Robert L. Nussbaum, Simon A. Gayther, Karoline B. Kuchenbaeker, Mads Thomassen, Ros Eeles, Riccardo Dolcetti, Hanne Meijers-Heijboer, Marc Tischkowitz, George Fountzilas, Laure Barjhoux, Kristie Bobolis, Christoph Engel, Bernardo Bonanni, Sue K. Park, Beth Y. Karlan, Nicolas Sevenet, Bent Ejlertsen, Wendy K. Chung, Timothy R. Rebbeck, Amanda B. Spurdle, Peter J. Hulick, Mary B. Daly, Yen Y. Tan, Annelie Liljegren, Carolien M. Kets, Miguel de la Hoya, Gord Glendon, Mieke Kriege, Rita K. Schmutzler, Manuel R. Teixeira, Christine Rappaport-Fuerhauser, Pedro Pérez Segura, William D. Foulkes, Rosemarie Davidson, Steven N. Hart, Javier Benitez, Jenny Lester, Melissa C. Southey, Ramunas Janavicius, Uffe Birk Jensen, Zakaria Einbeigi, Christian F. Singer, Jacopo Azzollini, Alex Teulé, David E. Goldgar, Ans M.W. van den Ouweland, Anna Jakubowska, Angela R. Bradbury, Dominique Stoppa-Lyonnet, Carole Brewer, Zsofia K. Stadler, Nadine Tung, Eric Hahnen, Vijai Joseph, Grzegorz Sukiennicki, Siranoush Manoukian, Debra Frost, Maria A. Caligo, Andrew K. Godwin, Christian Sutter, Bernard Peissel, Andrea L. Richardson, Kim De Leeneer, Antonis C. Antoniou, Florentia Fostira, Lesley McGuffog, Matti A. Rookus, Mary Beth Terry, Saundra S. Buys, Fabienne Lesueur, Gustavo C. Rodriguez, Julian Adlard, Barbara Wappenschmidt, Marinus J. Blok, Yael Laitman, Rob B. van der Luijt, Thomas Hansen, Francesca Damiola, Katherine L. Nathanson, Silje Nord, Kai Ren Ong, Ana Osorio, Katie Snape, Fergus J. Couch, John L. Hays, Walter Just, Ute Hamann, Silvia Tognazzo, Payal D. Shah, Valérie Bonadona, Ida Marie Heeholm Sonderstrup, Lídia Feliubadaló, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Research Council, Cancer Research UK (Reino Unido), Post-cancer GWAS Initiative, United States Department of Defense, Research Council of Lithuania, Asociación Española Contra el Cáncer, Red Temática de Investigación Cooperativa en Cáncer (España), Fondation ARC pour la recherche sur le cancer, Canadian Institutes of Health Research, Ministère de Économie, Innovation et Exportation (Canadá), University of Kansas. Cancer Center (Estados Unidos), Deutsche Krebshilfe, Leipzig Research Centre for Civilization Diseases, Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI), Instituto de Salud Carlos III, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Transcan Grant JTC Cancer, Hungarian Research Grants, Government of Catalonia (España), Ministry of Health and Welfare (Corea del Sur), United States of Department of Health & Human Services, State Budget of the Czech Republic (RECAMO), Charles University (República Checa), Westat (Estados Unidos), Russian Foundation for Basic Research, GOG Foundation. Gynecologic Oncology Group, Italian Association for Cancer Research, Clinical Genetics, CCA - Cancer biology and immunology, Human genetics, Epidemiology and Data Science, Human Genetics, Leslie, Goska [0000-0001-5756-6222], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medicum, Clinicum, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
Subjects: 0301 basic medicine, Genetic modifiers, Cancer Research, Epidemiology, Genes, BRCA2, BRCA1 and BRCA2 mutation carriers, Genes, BRCA1, Gene Expression, Gene mutation, DISEASE, Breast cancer, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, INVESTIGATORS, mutation carriers, skin and connective tissue diseases, Genetics, 1184 Genetics, developmental biology, physiology, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Oncology, Female, Differential allelic expression, Risk, Heterozygote, 3122 Cancers, Quantitative Trait Loci, NPAT, Single-nucleotide polymorphism, Locus (genetics), Breast Neoplasms, Quantitative trait locus, Biology, OVARIAN-CANCER, 03 medical and health sciences, CYCLIN E-CDK2, SDG 3 - Good Health and Well-being, Journal Article, medicine, Genetic predisposition, Genetic susceptibility, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Allele, BRCA1 and BRCA2, Alleles, Genetic association, HUMAN-CELLS, Chromosomes, Human, Pair 11, CONSORTIUM, Genetic Variation, DNA, medicine.disease, 030104 developmental biology, Mutation, Cis-regulatory variants, 3111 Biomedicine
Abstract: PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under Grant Agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112: the GAME-ON Initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR: this work was supported by Grant UM1 CA164920 from the National Cancer Institute. BFBOCC was supported by Lithuania (BFBOCC-LT): Research Council of Lithuania Grant SEN-18/2015. BIDMC was supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by Grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CNIO: this work was partially supported by Spanish Association Against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA), and SAF2010-20493. COH-CCGCRN: patients were recruited for this study from the City of Hope Clinical Cancer Genomics Community Research Network, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONSIT Team: Associazione Italiana Ricerca sul Cancro (AIRC) to P. Peterlongo (IG 2012 Id. 12821) and P. Radice (IG 2014 Id. 15547). Funds from Italian citizens who allocated the 5 9 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional Strategic Projects '5x1000') to S. Manoukian. FiorGen Foundation for Pharmacogenomics to L. Papi. CORE: the CIMBA Data Management and Data Analysis were supported by Cancer Research: UK Grants C12292/A20861, C12292/A11174. ACA is a Cancer Research-UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. J. Lecarpentier has been financially supported by the Fondation ARC (FONDATION ARC, 9 rue Guy Moquet 94803 Villejuif: France), Grant Number SAE20131200623. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. This work was also supported by the Ministere de l'Economie, Innovation et Exportation du Quebec: Grant No. PSR-SIIRI-701. DEMOKRITOS: this research has been co-financed by the European Union (European Social Fund: ESF) and Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF): Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA. Investing in Knowledge Society through the European Social Fund. The DKFZ Study was supported by the DKFZ. EMBRACE was supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo were supported by an NIHR Grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR Grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft were supported by Cancer Research UK Grant C5047/A8385. Ros Eeles was also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: the authors acknowledge the support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) was supported by the German Cancer Aid (Grant No. 110837, Rita K. Schmutzler). This work was supported by the European Regional Development Fund and Free State of Saxony, Germany (LIFE: Leipzig Research Centre for Civilization Diseases, Project Numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: the study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program and the French National Institute of Cancer (INCa). GEORGETOWN: CI received support from the Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI Grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical GenomicsResearch, and Swing Fore the Cure. G-FAST: Bruce Poppe is a Senior Clinical Investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC was supported by a Grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER Funds. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON Study was supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, and NKI2007-3756, the Netherlands Organization of Scientific Research Grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. HEBON thanks the Registration Teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for their help in part of the data collection. HRBCP was supported by the Hong Kong Sanatorium and Hospital, Dr. Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health 1R 03CA130065, and North California Cancer Center. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: Contract Grant Sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract Grant Numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH Group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: this work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (Grant GPH-129344), the Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec, and the Quebec Breast Cancer Foundation. IOVHBOCS was supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto Grant. IPOBCS: this study was in part supported by Liga Portuguesa Contra o Cancro. kConFab was supported by a Grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. KOHBRA was supported by a Grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO was supported by NIH Grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a Grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD was supported by MH CZ: DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague Project UNCE204024 (MZ). MSKCC was supported by Grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD: 1R01 CA149429-01. NCI: the research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by Support Services Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD. NICCC was supported by Clalit Health Services in Israel. Some of its activities were supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: this work has been supported by the Russian Federation for Basic Research (Grants 15-04-01744 and 16-54-00055). NRG Oncology: this study was supported by NRG Oncology Operations Grant Number U10 CA180868 as well as NRG SDMC Grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai, and Savage were supported by Funding from the Intramural Research Program, NCI. OSUCCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS: this work was supported by the Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) Grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06), and Cancer Research Initiatives Foundation. The SMC Team was in part sponsored by a Grant from the Israeli Cancer Association to the Israeli Consortium of Hereditary Breast Cancer. SWE-BRCA Collaborators were supported by the Swedish Cancer Society. UCHICAGO was supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. OIO is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR was supported by a Project Grant from CRUK to Paul Pharoah. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Research Center for BRCA. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr. Karlan was funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. Sí
Published: 2017
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31. Mutation analysis of the SHFM1 gene in breast/ovarian cancer families

Author: Miriam Masas, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Sandra Bonache, Judith Balmaña, Anna Tenés, and Orland Diez
Subjects: Male, Proteasome Endopeptidase Complex, Cancer Research, Ectrodactyly, endocrine system diseases, DNA Mutational Analysis, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Breast Neoplasms, Male, Neoplasms, Multiple Primary, Breast cancer, Genetic predisposition, medicine, Humans, Family, Genetic Predisposition to Disease, skin and connective tissue diseases, Gene, Ovarian Neoplasms, Genetics, Carcinoma, Family aggregation, General Medicine, medicine.disease, BRCA2 Protein, Oncology, Mutation testing, Female, Homologous recombination
Abstract: About 5-10 % of breast cancer is due to inherited disease predisposition. Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25 % of familial aggregation of breast cancer, which suggests the involvement of additional genetic susceptibility. The SHFM1 [split hand/foot malformation (ectrodactyly) type 1] gene plays an important role in the regulation of gene transcription and cell proliferation and may be involved in the maintenance of genomic integrity. It is a potential candidate for being involved in heritable cancer susceptibility due to its biological function. The SHFM1 protein binds in mammalian cells to the longest conserved region of the BRCA2 protein and is required for BRCA2 stability and function, making a critical contribution to the BRCA2 function in mediating homologous recombination. Therefore, variants in the SHFM1 gene could affect the BRCA2 functionality and be associated with the familial breast/ovarian carcinogenesis.We have screened the entire coding region and splice junctions of SHFM1 in affected index cases from 369 Spanish breast/ovarian cancer families for germ line defects, using direct sequencing.Mutation analysis revealed seven different sequence changes. Based on the in silico analyses of these sequence alterations, as well as their occurrence in cases and controls, none of them, however, were predicted to be pathogenic or associated with cancer susceptibility.To our knowledge, this is the most comprehensive study reporting the mutation screening of the SHFM1 gene in familial breast/ovarian cancer cases. No evidence for the association with breast/ovarian cancer was observed.
Published: 2013
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32. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology
Subjects: 0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract: Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed
Published: 2016
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33. Combined genetic and splicing analysis of BRCA1 c.[594-2A > C; 641A > G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

Author: Barbara Wappenschmidt, Fergus J. Couch, Norbert Arnold, Claude Houdayer, Manjeet K. Bolla, Omar Soukarieh, Sean V. Tavtigian, Irene L. Andrulis, Alexandra Becker, Alexandra Martins, Qin Wang, Sara Margolin, Paolo Radice, Janet E. Olson, Mitul Shah, Juul T. Wijnen, Amanda B. Spurdle, Nichola Johnson, Carole Brewer, Harald Surowy, Graham G. Giles, Ana Blanco, Kamila Czene, Thomas Hansen, Wendy S. Rubinstein, Anja Rudolph, Christian F. Singer, Antonis C. Antoniou, Douglas F. Easton, Fiona M. Blows, Michael T. Parsons, kConFab Investigators, Annika Lindblom, Nicola K. Poplawski, Melissa C. Southey, Emily Hallberg, Vanessa Lattimore, Yvette van Ierland, Logan C. Walker, Joe Dennis, Gord Glendon, Ana Vega, Diether Niederacher, Laurent Castera, David E. Goldgar, Ulrike Faust, Roger L. Milne, Marta Santamariña, Lesley McGuffog, Jan Hauke, Christi J. van Asperen, Michela Raponi, Irene López-Perolio, Diana Baralle, Tina Pesaran, Huong Meeks, Peter J. Hulick, Miguel de la Hoya, Philip Whiley, Raquel Behar, Jenny Chang-Claude, Elizabeth C. Chao, Henrik Flyger, Doris Steinemann, Pham Phuong Mai, Stig E. Bojesen, Maaike P.G. Vreeswijk, Sandrine M. Caputo, Jan Sullivan, Julian Peto, Barbara Burwinkel, Laura Galastri, Per Hall, Kyriaki Michailidou, Bernd Dworniczak, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Fundación Pública Galega Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica--USC, CIBER de Enfermedades Raras (CIBERER), Division of Genetics and Population Health, Queensland Institute of Medical Research, Genetics, University of Southampton, University of Otago [Dunedin, Nouvelle-Zélande], Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, Human Genetics Division [Southampton], Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Institut Laue-Langevin (ILL), University of Melbourne, Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig–Holstein, Institute of Cell and Molecular Pathology, Medizinische Hochschule Hannover (MHH), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), DIEP/DSV (DIEP/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Ambry Genetics [Aliso Viejo, CA, USA], Department of Clinical Genetics, Royal Devon & Exeter Hospital, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Metabolic Unit, Dept Clinical Chemistry, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine (LSHTM), Molecular Epidemiology Research Group, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Breast Surgery, Herlev and Gentofte Hospital, Karolinska University Hospital [Stockholm], Division of Cancer Epidemiology, Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medici, Cancer Epidemiology Centre, Cancer Council Victoria, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Ontario Cancer Genetics Network, Cancer Care Ontario, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Science and Technology Beijing [Beijing] (USTB), Strangeways Research Laboratory, University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Cancer Research U.K. Genetic Epidemiology Unit, Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Oncological Sciences, University of Utah-Huntsman Cancer Institute, Center for Human and Clinical Genetics, Université de Pau et des Pays de l'Adour (UPPA), International Agency for Cancer Research (IACR), ILL, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Adult, RNA Splicing, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Breast Neoplasms, Biology, 03 medical and health sciences, Exon, Genetics, Humans, Allele, Molecular Biology, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Aged, Ovarian Neoplasms, Messenger RNA, BRCA1 Protein, Tumor Suppressor Proteins, Alternative splicing, RNA, General Medicine, Articles, Exons, Middle Aged, Splicing regulatory element, 3. Good health, Gene Expression Regulation, Neoplastic, Alternative Splicing, 030104 developmental biology, RNA splicing, Mutation, Female, RNA Splice Sites
Abstract: A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A>C (IVS9-2A>C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A>C. The combined odds for causality considering case-control, segregation, and breast tumor pathology information was 3.23x10-8. Our data indicate that c.594-2A>C is always in cis with c.641A>G.The spliceogenic effect of c.[594-2A>C;641A>G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A>C; 641A>G] caused exon 10 skipping, albeit not due to c.594-2A>C impairing the acceptor site but rather by c.641A>G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile comprised of ?70-80% truncating transcripts, and ?20-30% of in-frame ?9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A>C;641A>G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
Published: 2016
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34. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author: Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany [ 58 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 59 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Basis Genet Risk & Genet Testing, Milan, Italy [ 60 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 61 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 62 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 63 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 64 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia [ 65 ] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia [ 66 ] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 67 ] Univ Oslo, Inst Clin Med, Oslo, Norway [ 68 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 69 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA [ 70 ] Univ Oulu, NordLab Oulu Univ Hosp, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 71 ] Univ Oulu, NordLab Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland [ 72 ] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 73 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 74 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 75 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 76 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 77 ] Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands [ 78 ] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands [ 79 ] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands [ 80 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 81 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 82 ] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands [ 83 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 84 ] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England [ 85 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 86 ] Int Epidemiol Inst, Rockville, MD USA [ 87 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 88 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 89 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 90 ] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore [ 91 ] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore [ 92 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 93 ] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore [ 94 ] Pontificia Univ Javerianar, Inst Human Genet, Bogota, Colombia [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France [ 97 ] Natl Canc Inst, Bangkok, Thailand [ 98 ] Roswell Pk Canc Inst, Buffalo, NY 14263 USA [ 99 ] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 100 ] China Med Univ, Sch Publ Hlth, Taichung, Taiwan [ 101 ] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan [ 102 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England [ 103 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 104 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 105 ] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 106 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 107 ] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA [ 108 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 109 ] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA [ 110 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 111 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 112 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 113 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 114 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 115 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 116 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 117 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 118 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain [ 119 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 120 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain [ 121 ] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA [ 122 ] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA [ 123 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 124 ] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy [ 125 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 126 ] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy [ 127 ] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece [ 128 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 129 ] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan [ 130 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England [ 131 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 132 ] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany [ 133 ] Univ Dusseldorf, Dusseldorf, Germany [ 134 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 135 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany [ 136 ] Univ Munster, Inst Human Genet, D-48149 Munster, Germany [ 137 ] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France [ 138 ] Inst Curie, Dept Tumour Biol, Paris, France [ 139 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 140 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France [ 141 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 142 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 143 ] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain [ 144 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 145 ] Univ Helsinki, Cent Hosp, Helsinki, Finland [ 146 ] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands [ 147 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands [ 148 ] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands [ 149 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 150 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 151 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 152 ] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain [ 153 ] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 154 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain [ 155 ] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital University of Iceland [ 156 ] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland [ 157 ] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada [ 158 ] Univ Laval, Quebec City, PQ, Canada [ 159 ] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada [ 160 ] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy [ 161 ] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal [ 162 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 163 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 164 ] McGill Univ, Program Canc Genet, Montreal, PQ, Canada [ 165 ] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic [ 166 ] Masaryk Univ, Fac Med, Brno, Czech Republic [ 167 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 168 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria [ 169 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 170 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA [ 171 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 172 ] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel [ 173 ] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 174 ] NN Petrov Oncol Res Inst, St Petersburg, Russia [ 175 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 176 ] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia [ 177 ] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA [ 178 ] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada [ 179 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada [ 180 ] Vejle Hosp, Dept Clin Genet, Vejle, Denmark [ 181 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark [ 182 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 183 ] Univ Hosp Pisa, Pisa, Italy [ 184 ] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia [ 185 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 186 ] Lund Univ, Dept Oncol, Lund, Sweden [ 187 ] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden [ 188 ] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden [ 189 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 190 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 191 ] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 192 ] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 193 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 194 ] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA [ 195 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 196 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 197 ] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia [ 198 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 199 ] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA [ 200 ] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada [ 201 ] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia [ 202 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 203 ] Harvard Univ, Sch Med, Boston, MA USA [ 204 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 205 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA [ 206 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England
Subjects: 0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund
Published: 2016
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35. Study of KRAS new predictive marker in a clinical laboratory

Author: Eduardo Díaz Rubio García, Julian Sanz-Ortega, Paula Pescador, Inmaculada Bando, Trinidad Caldés, Lourdes Cillero, Patricia Llovet, M. Ferrer, Miguel de la Hoya, and Javier Sastre
Subjects: Cancer Research, Colorectal cancer, medicine.disease_cause, Proto-Oncogene Proteins p21(ras), Exon, Sequence Analysis, Protein, Proto-Oncogene Proteins, Biomarkers, Tumor, medicine, Humans, Panitumumab, Epidermal growth factor receptor, Codon, neoplasms, Genetics, Mutation, Predictive marker, Cetuximab, biology, business.industry, General Medicine, medicine.disease, digestive system diseases, ErbB Receptors, Oncology, ras Proteins, Cancer research, biology.protein, KRAS, Colorectal Neoplasms, business, medicine.drug
Abstract: The presence of somatic mutations in the KRAS gene has been identified as a reliable strong negative predictor for the response to targeting the epidermal growth factor receptor (EGFR), in patients with metastatic colorectal cancer and the use of anti-EGFR monoclonal antibodies such as Cetuximab and Panitumumab is now restricted to patients with no detectable KRAS mutations. Between 30 and 40 % of colorectal cancers contain a mutated KRAS oncogene. The aim of this study was to evaluate concordance between three methods to analyze KRAS mutational status in regard to clinical testing. We analyzed KRAS mutations in codons 12 and 13 of exon 2 in one hundred formalin-fixed paraffin-embedded (FFPE) colorectal cancer samples by three different methods: Direct Sequencing and two commercial kits on allele-specific oligonucleotide hybridization (KRAS StripAssay, Vienna Lab.) and Amplification Refractory Mutation System/Scorpions (ARMS/S; TheraScreen KRAS Mutation kit DxS) based on q-PCR. We have found similar frequencies of KRAS mutations by TheraScreen and Strip-Assay (44 and 48 %), with a κ value of 0.90, indicating almost perfect agreement between methods. The frequency by direct sequencing was much lower (26 %) and the κ values were 0.67 (compared to TheraScreen) and 0.57 (compared to Strip-Assay) indicating low sensitivity. On analyzing KRAS mutation in FFPE tumor samples, direct sequencing sensitivity is too low to be used in a clinical setting. Choosing between ARMS/S; TheraScreen KRAS Mutation kit DxS and KRAS StripAssay, Vienna Lab, will depend on laboratory facilities and expertise.
Published: 2012
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36. Assessment of Topoisomerase II α Status in Breast Cancer by Quantitative PCR, Gene Expression Microarrays, Immunohistochemistry, and Fluorescence in Situ Hybridization

Author: Atocha Romero, Xiaping He, Manuel Arroyo Fernández, José Ángel García Sáenz, Eduardo Diaz Rubio, Miguel Martín, Belén Oliva, Miguel de la Hoya, Charles M. Perou, Trinidad Caldés Llopis, Maggie C.U. Cheang, and José Antonio López García-Asenjo
Subjects: Adult, Adolescent, Anthracycline, Receptor, ErbB-2, Biopsy, Breast Neoplasms, In situ hybridization, Biology, Polymerase Chain Reaction, Gene Expression Regulation, Enzymologic, Pathology and Forensic Medicine, Breast cancer, Antigens, Neoplasm, medicine, Humans, Poly-ADP-Ribose Binding Proteins, In Situ Hybridization, Fluorescence, Aged, Cell Proliferation, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Regular Article, Middle Aged, medicine.disease, Immunohistochemistry, Molecular biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, DNA Topoisomerases, Type II, Real-time polymerase chain reaction, Cancer research, Female, DNA microarray, Fluorescence in situ hybridization
Abstract: Anthracyclines are frequently used for the treatment of breast cancer and topoisomerase II alpha (TOP2A) is considered to be the molecular target. Numerous studies have evaluated the predictive value of TOP2A using different methodological approaches and inconsistent results have been reported. Indeed, the correlation between techniques for the assessment of TOP2A status has not been well evaluated. In this study, we determined TOP2A status in 61 breast tumor samples by real-time PCR, DNA microarrays, immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH), and then evaluated these results with clinical-pathological features and breast cancer intrinsic subtypes. First, we observed a statistical significant correlation of TOP2A gene expression between real-time PCR and microarrays (Pearson coefficient, 0.816; P < 0.001), and both predicted TOP2A IHC results fairly well (area under the curve > 0.74). In contrast, poor agreement between FISH and IHC data was observed (k: 0.134). Secondly, TOP2A expression was found significantly associated with cell proliferation, and with the highly proliferative Luminal B, Her2-enriched and Basal-like intrinsic subtypes. In conclusion, TOP2A expression in breast cancer was associated with high proliferation and aggressive tumor subtypes and appears to be independent of its amplification status. All of these features should be taken into consideration when assessing the predictive value of TOP2A for anthracycline-based chemotherapy.
Published: 2011
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37. Analysis of the Oxidative Damage Repair Genes NUDT1, OGG1, and MUTYH in Patients from Mismatch Repair Proficient HNPCC Families (MSS-HNPCC)

Author: Patricia Llovet, Pilar Garre, Verónica Briceño, Rosa M. Xicola, Miguel de la Hoya, Xavier Llor, Paula Pescador, Trinidad Caldés, Javier Puente, Brian J. Doyle, Eduardo Díaz-Rubio, and Julián Sanz
Subjects: Male, Cancer Research, Genotype, DNA damage, Restriction Mapping, Gene Dosage, Mutation, Missense, Biology, DNA Mismatch Repair, Disease-Free Survival, DNA Glycosylases, Gene Frequency, MUTYH, medicine, Humans, Point Mutation, Genetic Association Studies, Genetics, Point mutation, Sequence Analysis, DNA, Base excision repair, DNA Repair Pathway, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Phosphoric Monoester Hydrolases, digestive system diseases, Lynch syndrome, DNA Repair Enzymes, Oncology, Case-Control Studies, Female, DNA mismatch repair, Oxidation-Reduction, DNA Damage
Abstract: Purpose: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1. Experimental Design: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families. Results: Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1. Conclusions: Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases. Clin Cancer Res; 17(7); 1701–12. ©2011 AACR.
Published: 2011
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38. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

Author: Maria J. Soares, Mauricio Magalhaes Costa, Ingrid Petroni Ewald, Rachel Kyle, Nelly Sabbaghian, Torben A Kruse, Leonor Gusmão, Mads Thomassen, Silvia Casadei, Annemarie H. van der Hout, Marc Tischkowitz, Patrícia Rocha, Ana Vega, Miguel de la Hoya, Patricia Ashton-Prolla, Lone Sunde, Sara Gutiérrez-Enríquez, Dirce Maria Carraro, Conxi Lázaro, Philippe Maillet, Maroulio Pertesi, Cindy Benson, Pedro Pinto, Alberto Gulino, Nancy Uhrhammer, Drakoulis Yannoukakos, William D. Foulkes, Lucie Cornil, Etienne Rouleau, Ana Peixoto, Ignacio Blanco, Gaelle Benais-Pont, Robert Royer, Mary Claire King, Montserrat Baiget, Thangarajan Rajkumar, María Dolores Miramar, Ana Rodriguez Valle, Maria Teresa Calvo, Judith Balmaña, Anne-Marie Gerdes, Rosette Lidereau, Giuseppe Giannini, Catarina Santos, Eladio Velasco, Maria Isabel Achatz, Dorthe G. Crüger, Luisa Mota-Vieira, Carmen Alonso, Orland Diez, Eitan Friedman, Manuela Pinheiro, Brigitte Bressac-de Paillerets, Yael Laitman, Steven A. Narod, Teresa Ramón y Cajal, Begoña Graña, António Amorim, Trinidad Caldés, Lídia Feliubadaló, Mercedes Durán, Bruno Pardo, Erik Teugels, Audrey Remenieras, Manuel R. Teixeira, Yves-Jean Bignon, and Ana Blanco
Subjects: Proband, Reading Frames, Cancer Research, Genes, BRCA2, Polymerase Chain Reaction, DISEASE, 0302 clinical medicine, BREAST/OVARIAN CANCER FAMILIES, skin and connective tissue diseases, Predictive testing, Sequence Deletion, founder mutation, c.156_157insalu brca2 mutation, hereditary breast/ovarian cancer, age estimation, c.156-157insalu brca2 mutation, Ovarian Neoplasms, Genetics, 0303 health sciences, education.field_of_study, medicine.diagnostic_test, REARRANGEMENT, Founder Effect, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), GENETIC-HETEROGENEITY, Female, Population, Breast Neoplasms, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, medicine, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Genetic Testing, RNA, Messenger, Founder mutation, education, 030304 developmental biology, Genetic testing, Portugal, business.industry, Haplotype, medicine.disease, Genetics, Population, Mutation, Age estimation, c.156_157insAlu BRCA2 mutation, business, Hereditary breast/ovarian cancer, Microsatellite Repeats, Founder effect
Abstract: 9 páginas, 4 figuras, 1 tabla.-- El pdf del artículo es la versión pre-print.-- et al., The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement., This study was supported by Ministério da Saúde (Project N8 15/2007) and Liga Portuguesa Contra o Cancro. IPATIMUP was funded by Fundaçáo para a Ciência e Tecnologia, through POCI (Programa Operacional Ciència e Inovaçáo 2010). MT and WDF are supported by the Susan G. Komen Foundation for the Cure, the Jewish General Hospital Weekend to End Breast Cancer and the Fonds de la Recherche en Santé du Québec. EAV and MD are supported by grants PI061102 (Ministerio de Ciencia e Innovación) and 200820I135 (CSIC).
Published: 2010
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39. Alternative Splicing and Molecular Characterization of Splice Site Variants: BRCA1 c.591C>T as a Case Study

Author: Alicia Tosar, Miguel de la Hoya, Pedro Pérez-Segura, Trinidad Caldés, Carmen Cañadas, Eduardo Díaz-Rubio, and Vanesa Dosil
Subjects: Genetics, Gene isoform, Genotype, Biochemistry (medical), Clinical Biochemistry, Alternative splicing, Genes, BRCA1, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Molecular biology, Alternative Splicing, Exon, RNA splicing, Humans, Female, Allele, Gene
Abstract: Background: Deleterious mutations in BRCA1 (breast cancer 1, early onset; MIM 113705) increase breast and ovarian cancer [B(O)C] risk; however, many variants cannot be readily classified as deleterious or neutral. Unclassified variants (UVs) pose serious problems in genetic counseling. RNA-splicing analysis is essential for the assessment of many UVs. Methods: Denaturing gradient gel electrophoresis was used to genotype the BRCA1 c.591C>T variant in 685 index cases of B(O)C families, 326 sporadic breast cancer cases, and 450 healthy controls from Spain. In silico tools were used to predict the effect of the c.591C>T variant on splicing. In vitro splicing analysis was performed in 7 c.591C>T carriers and 10 noncarriers. cDNAs were PCR-amplified with primers designed to detect BRCA1 alternative splicing isoforms. The products were analyzed by capillary electrophoresis. Peak areas were used to quantify the relative abundance of each isoform. Sequencing through exonic single-nucleotide polymorphisms (SNPs) enabled us to discriminate wild-type and variant transcripts. Results: c.591C>T was detected in B(O)C families (1.5%), breast cancer cases (0.3%), and controls (0.9%). c.591C>T induced BRCA1 exon 9 skipping and modified the relative expression of Δ(9,10), Δ(9,10,11B), Δ11B, and full-length isoforms. The mean ratio of Δ(9,10) to the full-length isoform increased from 0.25 in noncarriers to 1.5 in carriers. The mean Δ(9,10,11B)/Δ11B ratio increased from 0.2 to 4. Overall expression levels of c.591C>T and wild-type alleles were similar. Conclusions: Our data support a nonpathogenic role for the BRCA1 c.591C>T variant. Naturally occurring alternative splicing isoforms need to be considered when assessing the role of BRCA1 UVs on splicing.
Published: 2010
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40. Genome-wide Linkage Scan Reveals Three Putative Breast-Cancer-Susceptibility Loci

Author: Orland Diez, Conxi Lázaro, Teresa Ramón y Cajal, Trinidad Caldés, Ignacio Blanco, Gemma Llort, Anna González-Neira, Guillermo Pita, Joan Brunet, Maria-Isabel Tejada, Miguel de la Hoya, Miguel Urioste, Juan Manuel Rosa-Rosa, and Javier Benitez
Subjects: Genetic Markers, Male, Chromosomes, Human, Pair 21, Genes, BRCA2, Population, Genes, BRCA1, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Functional Laterality, Article, Breast cancer, Germline mutation, Genetic linkage, Genetics, medicine, Humans, Genetics(clinical), Family, Genetic Predisposition to Disease, skin and connective tissue diseases, education, Germ-Line Mutation, Genetics (clinical), education.field_of_study, Genome, Human, Genetic heterogeneity, Chromosome Mapping, Cancer, Middle Aged, medicine.disease, Pedigree, Chromosomes, Human, Pair 6, Female, Chromosomes, Human, Pair 3, Breast disease
Abstract: Despite all the research efforts made during the last few decades, most of the cases of families with breast cancer remain unexplained. Mutations in BRCA1 and BRCA2, and in other breast-cancer-susceptibility genes, account for about 25% of familial breast cancer. Linkage studies have failed to identify other breast-cancer-susceptibility genes. The selection criteria of the families, differences in the population background, or clinical and genetic heterogeneity, among other factors, might determine the power to detect the linkage signal. We have performed a SNP-based linkage scan with a total of 6000 SNP markers across the genome in 41 breast-cancer Spanish families, with an average of four breast-cancer cases per family not associated with BRCA1 or BRCA2 germline mutations. In addition, we have included three BRCA-positive families to test the power in linkage detection from a low-complexity family in which a high-penetrance mutation segregates. We have identified three regions of interest, located on 3q25, 6q24, and 21q22. The two former regions showed a suggestive linkage signal (HLOD scores 3.01 and 2.26, respectively), and the latter region showed a significant linkage signal (HLOD score 3.55). Moreover, we found that a subset of 13 families with bilateral breast cancer presented a HLOD of 3.13 on the 3q25 region. Our results suggest that several variables must be taken into account before performing a linkage study in familial breast cancer because of the high heterogeneity within non-BRCA1/2 families. Phenotypic and geographic homogeneity could be the most important factors.
Published: 2009
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41. Risk-reduction surgery in BRCA mutation carriers in a Spanish population: adherence and results

Author: Javier Puente, Miguel de la Hoya, Trinidad Caldés, Pedro Pérez Segura, Helena Olivera, Raquel Andrés Conejero, Arancha Moreno, Eduardo Díaz-Rubio, J.M. Roman, and Paula Jiménez
Subjects: Adult, Heterozygote, Cancer Research, medicine.medical_specialty, Genetic counseling, Genes, BRCA2, Population, Genes, BRCA1, Breast Neoplasms, Genetic Counseling, Papillary adenocarcinoma, medicine, Humans, Family, education, Genetic testing, Ovarian Neoplasms, education.field_of_study, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Carcinoma, BRCA mutation, General Medicine, medicine.disease, Prophylactic Surgery, Surgery, Oncology, Spain, Mutation, Patient Compliance, Female, Preventive Medicine, business, Ovarian cancer
Abstract: To analyse the level of adherence to prophylactic surgery of breast and/or ovarian cancer in female carriers of the BRCA1 or BRCA2 mutation in a referential genetic counselling unit in Spain. Between January 1998 and November 2006, a total of 684 families with several cases of breast and/or ovarian cancer were selected by the Genetic Counselling Unit at the Hospital Clinico Universitario San Carlos. Some of them opted for prophylactic surgery after genetic counselling and genetic testing. The pathogenic mutation was found in 57 families out of a total of 449 families who fulfilled the hereditary breast/ovarian cancer criteria. Out of a total of 238 individuals who were carriers of the mutation, 136 (57%) were offered risk-reducing prophylactic surgery. Prophylactic surgery was chosen by 58 (43%) women out of a total of 136 who were offered this possibility; the histological findings observed 7% malignant lesions in the breast and, in the ovarian-fallopian complex, 2 cases (8%) of a borderline tumour and one case (4%) of papillary adenocarcinoma. This is the first study published on the role of prophylactic surgery in BRCA mutation carriers in the Spanish population. The incidence of occult carcinoma in these cases is lower than in other series.
Published: 2008
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42. Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

Author: Lara Lipton, Amy Price, Enric Domingo, Trinidad Caldés, Gianluca Severi, Emma Jaeger, Sarah Fielding, Auli Karhu, José M. Ladero, Alan M. Pittman, David J. Kerr, Axel Walther, Mobshra Qureshi, Ian Tomlinson, Sergi Castellví-Bel, King Yip Cheng, Miguel de la Hoya, Wendy Wood, Emily L. Webb, John M. Luk, G Evans, Philip Twiss, Timothy Bishop, Hans Morreau, Steven Penegar, Pak C. Sham, Angel Carracedo, Melissa C. Southey, Eamonn R. Maher, Maria Chiara Di Bernardo, Sarah L. Spain, Julian Peto, Anneke Lucassen, Kari Hemminki, Lynn Martin, Richard Gray, Ian Chandler, Luis G. Carvajal-Carmona, Jean-Baptiste Cazier, Steven J. Lubbe, Kimberley Howarth, Richard S. Houlston, Graham G. Giles, Maggie Gorman, Kate Sullivan, Zoe Kemp, Pavel Vodicka, Judy W. C. Ho, Lauri A. Aaltonen, Clara Ruiz-Ponte, Jayaram Vijayakrishnan, Asta Försti, Huw Thomas, Alessio Naccarati, Peter Broderick, Juul T. Wijnen, Antoni Castells, Tom van Wezel, John L. Hopper, Iina Niittymäki, José A. G. Agúndez, Sari Tuupanen, Andrew Rowan, and Ella Barclay
Subjects: Adult, Male, Genotype, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, Humans, SNP, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Aged, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, Pair 11, Case-control study, Genetic Variation, General Medicine, Middle Aged, 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Mutation, Female, Colorectal Neoplasms, Imputation (genetics)
Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
Published: 2008
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43. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

Author: Sari Tuupanen, Melissa C. Southey, Ian Chandler, Enric Domingo, Paul D.P. Pharoah, Luis G. Carvajal-Carmona, D. Gareth Evans, Malcolm G. Dunlop, Trinidad Caldés, Graham G. Giles, Zoe Kemp, Harry Campbell, David J. Kerr, Alan M. Pittman, Eamonn R. Maher, D. Timothy Bishop, Jayaram Vijayakrishnan, Hans Morreau, Albert Tenesa, Asta Försti, Jean-Baptiste Cazier, Kimberley Howarth, Ella Barclay, Rebecca A. Barnetson, Tom van Wezel, Juul T. Wijnen, James G. D. Prendergast, Maggie Gorman, Julian Peto, Anneke Lucassen, Antoni Castells, Jochen Hampe, José A. G. Agúndez, Susan M. Farrington, Kate Sullivan, Henry Völzke, Richard Gray, Ulrich John, King Yip Cheng, Pavel Vodicka, Emma Jaeger, Peter Broderick, Judy W. C. Ho, Mobshra Qureshi, Lauri A. Aaltonen, Stephan Buch, Sarah Fielding, Sarah L. Spain, Lynn Martin, Andrew Rowan, Wendy Wood, Emily L. Webb, John M. Luk, Angel Carracedo, Clara Ruiz-Ponte, Alessio Naccarati, Steven J. Lubbe, Ian Tomlinson, Lara Lipton, John L. Hopper, Iina Niittymäki, Axel Walther, José M. Ladero, Pak C. Sham, Stefan Schreiber, Sergi Castellví-Bel, Miguel de la Hoya, Clemens Schafmayer, Gianluca Severi, Auli Karhu, Steven Penegar, Thibaud Koessler, Kari Hemminki, Richard S. Houlston, and Huw Thomas
Subjects: Adult, Male, Genetic Linkage, Colorectal cancer, Eukaryotic Initiation Factor-3, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Alleles, Aged, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, Pair 10, Genome, Human, Cancer, Middle Aged, medicine.disease, Pedigree, 3. Good health, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, Chromosomes, Human, Pair 8
Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Published: 2008
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44. Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC)

Author: Sneha Bontu, Esther Lee, Francesc Balaguer, Pilar Garre, Brian J. Doyle, John A. Baron, Xavier Bessa, Nathan A. Ellis, Luis Bujanda, Jamie Rawson, Sergi Castellví-Bel, Miguel de la Hoya, Trinidad Caldés, Montserrat Andreu, Polly A. Newcomb, Joan Clofent, Xavier Llor, John D. Potter, Sapna Syngal, Clara Ruiz-Ponte, Antoni Castells, Rosa M. Xicola, Angel Carracedo, Cristina Alenda, Noralane M. Lindor, and Rodrigo Jover
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Candidate gene, Genotype, Colorectal cancer, Receptor, Transforming Growth Factor-beta Type I, Original Manuscript, Single-nucleotide polymorphism, MiRNA binding, Protein Serine-Threonine Kinases, Biology, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Axin Protein, medicine, Humans, SNP, DNA Modification Methylases, neoplasms, Alleles, beta Catenin, Aged, Genetics, Binding Sites, Tumor Suppressor Proteins, Receptor, Transforming Growth Factor-beta Type II, Microsatellite instability, General Medicine, Middle Aged, Protein-Serine-Threonine Kinases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Gene Expression Regulation, Neoplastic, DNA Repair Enzymes, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, DNA mismatch repair, Receptors, Transforming Growth Factor beta
Abstract: We describe an association between TGFBR1 polymorphism rs868 and mismatch repair proficient hereditary colorectal cancers. This polymorphism results in more binding of TGFBR1 to let-7b-5p miRNA, which would result in lower expression of TGFBR1 and thus higher colorectal cancer risk.The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.
Published: 2016

45. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Author: Kenneth Offit, D. Gareth Evans, Dominique Stoppa-Lyonnet, Edith Olah, Nadine Tung, Andrew K. Godwin, Irene L. Andrulis, Jeffrey N. Weitzel, Eitan Friedman, Gord Glendon, Mary B. Daly, Kathleen Claes, Laima Tihomirova, Bella Kaufman, kConFab Investigators, Aleksandra Tołoczko-Grabarek, Katarzyna Jaworska-Bieniek, Fergus J. Couch, Jonathan Carter, Ute Hamann, Embrace, Emily Hallberg, Olufunmilayo I. Olopade, Niklas Loman, Claudine Isaacs, Raanan Berger, Caroline Seynaeve, Patricia A. Ganz, Trinidad Caldés, Jenny Lester, Steve Ellis, Fei Wan, Stephanie Chen, Cezary Cybulski, Saundra S. Buys, Åke Borg, Jamal Zidan, Matti A. Rookus, Javier Benitez, Csilla Szabo, Gillian Mitchell, Douglas F. Easton, Jocelyne Chiquette, Katherine L. Nathanson, Mary Beth Terry, Kristin K. Zorn, Danylo Villano, Mads Thomassen, Nandita Mitra, Mariella Tancredi, Conxi Lázaro, Hebon, Jacek Gronwald, Paolo Radice, Katarzyna Durda, Pascaline Berthet, Shan Wang-Gohrke, Orland Diez, Siranoush Manoukian, Amanda E. Toland, Ava Kwong, Barbara Wappenschmidt, Tara M. Friebel, Lenka Foretova, Beth Y. Karlan, Marco Montagna, Yael Laitman, Georgia Chenevix-Trench, Antonis C. Antoniou, Paraskevi Apostolou, Susan J. Ramus, Jacques Simard, Daniel Barrowdale, Timothy R. Rebbeck, Thomas Hansen, Jan Lubinski, Manuel R. Teixeira, Eric Hahnen, Grzegorz Sukiennicki, Christine Lasset, Sue K. Park, Christian F. Singer, Debra Frost, Elizabeth J. van Rensburg, Esther M. John, Susan L. Neuhausen, Lesley McGuffog, Dieter Niederacher, Penny Soucy, Heli Nevanlinna, Judy Garber, Norbert Arnold, Robert L. Nussbaum, Susan M. Domchek, Melissa C. Southey, Ramunas Janavicius, Mark H. Greene, Anna Jakubowska, Marc Tischkowitz, Christine Rappaport-Fuerhauser, Marion Piedmonte, Miguel de la Hoya, Soo Hwang Teo, Evgeny N. Imyanitov, Banu Arun, Hematology, Medical Oncology, Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Department of Obstetrics and Gynecology, and Clinicum
Subjects: DOUBLE HETEROZYGOSITY, 0301 basic medicine, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, CANCER SUSCEPTIBILITY GENE, Loss of Heterozygosity, Estrogen receptor, medicine.disease_cause, Loss of heterozygosity, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, Medicine, Promoter Regions, Genetic, skin and connective tissue diseases, SPORADIC BREAST-CANCER, Medicine(all), Mutation, UNKNOWN CLINICAL-SIGNIFICANCE, Exons, GERMLINE MUTATIONS, female genital diseases and pregnancy complications, transheterozygosity, 3. Good health, Phenotype, Population Surveillance, WILD-TYPE CHROMOSOME, 030220 oncology & carcinogenesis, Female, Transheterozygosity, Research Article, Heterozygote, medicine.medical_specialty, 3122 Cancers, Hereditary breast and ovarian cancer, Breast Neoplasms, DNA-SEQUENCE VARIANTS, hereditary breast and ovarian cancer, OVARIAN-CANCER, Càncer de mama, SPORADIC, 03 medical and health sciences, Germline mutation, GERMLINE, Progesterone receptor, Humans, BREAST-CANCER, Allele, neoplasms, Alleles, Germ-Line Mutation, Gynecology, MUTATIONS, business.industry, Biology and Life Sciences, medicine.disease, BRCA1, BRCA2, HETEROGENIC LOSS, 030104 developmental biology, FANCONI-ANEMIA, business, Ovarian cancer
Abstract: BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). 'Cases' were defined as TH, and 'controls' were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 'controls' carried a BRCA1 mutation found in the TH 'case'. Matched SH2 'controls' carried a BRCA2 mutation found in the TH 'case'. After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p, published_or_final_version
Published: 2016
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46. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Kenneth Offit, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Christine Maugard, Marco Montagna, Annette Fontaine, Janusz Menkiszak, Robert Winqvist, Pascal Guénel, Rosalind Glasspool, Usha Menon, Daniel Barrowdale, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Martha J. Shrubsole, Lambertus A. Kiemeney, Camilla Krakstad, Dong Liang, Minouk J. Schoemaker, Judith S. Brand, Joseph Vijai, Marc T. Goodman, Thomas A. Sellers, David Van Den Berg, Celeste Leigh Pearce, Alice S. Whittemore, Irene L. Andrulis, Radka Platte, Kunle Odunsi, Orland Diez, Estrid Høgdall, Brooke L. Fridley, C. J. van Asperen, Mary Anne Rossing, Vessela N. Kristensen, Jonathan Tyrer, Tara M. Friebel, Douglas F. Easton, Per Hall, Mads Thomassen, Christine Walsh, Thilo Dörk, Louise A. Brinton, Keith Humphreys, Douglas A. Levine, Allison F. Vitonis, Anna H. Wu, Hermann Brenner, Maria Bisogna, Joellen M. Schildkraut, Maria A. Caligo, Jonine D. Figueroa, Lynne R. Wilkens, Grace Friel, Michael G. Schrauder, Evgeny N. Imyanitov, Sune F. Nielsen, Sylvie Mazoyer, Diana Eccles, Andrew Berchuck, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, Gad Rennert, Arif B. Ekici, Elisa Alducci, Bjarni A. Agnarsson, Linda S. Cook, Javier Benitez, Paolo Peterlongo, Natalia Antonenkova, Annika Lindblom, Patrick Neven, Julia A. Knight, Alan Ashworth, Matti A. Rookus, Frans B. L. Hogervorst, Daniela Zaffaroni, Banu Arun, Sue Healey, Robert P. Edwards, Susanne K. Kjaer, Laura J. van't Veer, John W.M. Martens, Christa Stegmaier, Claudine Isaacs, Daniel W. Cramer, Lars Beckmann, Liisa M. Pelttari, Dieter Flesch-Janys, Irene Orlow, Atocha Romero, Diana Torres, Marjanka K. Schmidt, Simon S. Cross, Alison M. Dunning, Rosemary L. Balleine, Sandra L. Halverson, Benoit Beuselinck, Melissa C. Larson, Senno Verhoef, Jirong Long, Angela Cox, Maartje J. Hooning, Bruce Poppe, Katarzyna Jaworska, Jolanta Kupryjanczyk, Nicolas Wentzensen, Gustavo C. Rodriguez, Tanja Pejovic, Roberta B. Ness, James Paul, Dominique Stoppa-Lyonnet, Nadine Tung, Gianluca Severi, Malcolm C. Pike, Hoda Anton-Culver, Ans M.W. van den Ouweland, Mark E. Robson, Roger L. Milne, Jan C. Oosterwijk, Laima Tihomirova, Helen Tsimiklis, Pierre Laurent-Puig, Florian Heitz, Beth Y. Karlan, Ian Tomlinson, Thérèse Truong, Bernardo Bonanni, Frederik Marmé, Qin Wang, Conxi Lázaro, Volker Arndt, Antoinette Hollestelle, Jacek Gronwald, M. Pilar Zamora, Barbara Wappenschmidt, Maren Weischer, Veli-Matti Kosma, Giulietta Scuvera, Jenny Lester, Andreas Berger, Stephen J. Chanock, Line Bjørge, Anthony J. Swerdlow, Andrew K. Godwin, Mervi Grip, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Paolo Radice, Bent Ejlertsen, Frederieke H. van der Baan, Lothar Haeberle, Valerie McGuire, Kamila Czene, Rob A. E. M. Tollenaar, Maria Soller, Katherine L. Nathanson, Sandrina Lambrechts, Susan J. Ramus, Anja Rudolph, Penny Soucy, Caroline Weltens, Hiltrud Brauch, Olivia Fletcher, Sara H. Olson, Yael Laitman, Marion Piedmonte, Arto Mannermaa, Agnieszka Budzilowska, Olga M. Sinilnikova, Christian F. Singer, Cezary Cybulski, Weiva Sieh, Ed Dicks, Elizabeth J. van Rensburg, Isabel dos Santos Silva, Hans Ehrencrona, Timothy R. Rebbeck, Jaana M. Hartikainen, Sandra Orsulic, Jingmei Li, Carmel Apicella, Anna deFazio, Ian G. Campbell, Ignace Vergote, Rita K. Schmutzler, Fredrick R. Schumacher, Julian Peto, Nadeem Siddiqui, Brian E. Henderson, Starr R. Guzman, Maria Kabisch, John L. Hopper, Arto Leminen, Jeffrey N. Weitzel, Honglin Song, J. Margriet Collée, Ingvild L. Tangen, Børge G. Nordestgaard, Antonis C. Antoniou, Lara Sucheston, Helena C. van Doorn, Lídia Feliubadaló, Leon F.A.G. Massuger, Iain A. McNeish, Nichola Johnson, Simon A. Gayther, Jennifer A. Doherty, Anders Bojesen, Gord Glendon, Yukie Bean, Celine M. Vachon, Barbara Burwinkel, Edith Olah, Shan Wang-Gohrke, Brita Arver, Marc Tischkowitz, Arja Jukkola-Vuorinen, Martin Gore, Vesa Kataja, Nicola Miller, Pamela J. Thompson, Malcolm W.R. Reed, Michelle A.T. Hildebrandt, Ritu Salani, Janet E. Olson, Catriona McLean, Cecilia M. Dorfling, Georgia Chenevix-Trench, Frederique Mariette, Laura Ottini, Fergus J. Couch, Linda E. Kelemen, Nhu D. Le, Michael J. Kerin, Claus Høgdall, Miguel de la Hoya, Jonathan Carter, Mercedes Durán, Inge Søkilde Pedersen, Julie M. Cunningham, Manjeet K. Bolla, Galina Lurie, Loic Le Marchand, Ute Hamann, Muy-Kheng Tea, Karoline Kuchenbaecker, Irene Konstantopoulou, Thomas Hansen, Francesca Damiola, Stefano Fortuzzi, Shelley S. Tworoger, Mikael Eriksson, Carl Blomqvist, Joan Brunet, Allan Jensen, Karen Lu, Elisa V. Bandera, Anne M. van Altena, Anne-Marie Gerdes, Lene Lundvall, Susan L. Neuhausen, Wei Zheng, Ana Osorio, Fiona Bruinsma, Hannah P. Yang, Graham G. Giles, Christoph Engel, Nick Orr, Harvey A. Risch, Jan Lubinski, Jacoba P. Knol-Bout, Phuong L. Mai, Martine Dumont, Xifeng Wu, Christof Sohn, Noah D. Kauff, Kristiina Aittomäki, Natalia Bogdanova, Alexander Hein, Francesmary Modugno, Heli Nevanlinna, Helga B. Salvesen, Adriana Lasa, Daphne Gschwantler Kaulich, Dominiek Smeets, Jenny Permuth-Wey, Josef Herzog, Catherine M. Phelan, Clareann H. Bunker, Steve Ellis, Christopher A. Haiman, Jolanta Lissowska, Judy Garber, Joanna Plisiecka-Halasa, Robert A. Vierkant, Steven A. Narod, Mark H. Greene, Florence Menegaux, Norbert Arnold, Primitiva Menéndez, Robert L. Nussbaum, Katja K.H. Aben, Andreas Schneeweiss, Katri Pylkäs, Els Van Nieuwenhuysen, Tomasz Huzarski, Joe Dennis, Susan M. Domchek, Andreas du Bois, Aleksandra Gentry-Maharaj, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Eitan Friedman, Argyrios Ziogas, Hatef Darabi, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Stig E. Bojesen, Jo Perkins, Raanan Berger, Sharon E. Johnatty, Taru A. Muranen, Montserrat Garcia-Closas, Uffe Birk Jensen, Thomas Brüning, Heiko Müller, Debra Frost, Peter A. Fasching, Lesley McGuffog, Diether Lambrechts, Kelly-Anne Phillips, Caroline M. Seynaeve, Kathryn L. Terry, Ira Schwaab, Ralf Bützow, Manuel R. Teixeira, Joseph H. Rothstein, Bernard Peissel, Anna von Wachenfeldt, Saundra S. Buys, Peter Devilee, Alfons Meindl, Laura Baglietto, Kirsten B. Moysich, Arjen R. Mensenkamp, Philipp Harter, Jacques Simard, Generalitat de Catalunya, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, National Institutes of Health (US), Wellcome Trust, European Commission, National Cancer Institute (US), Medical Oncology, Clinical Genetics, Erasmus MC other, Pediatric Surgery, Pathology, and Neurology
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Endometriosis, Breast cancer, Clinical outcome, Genetic association, KRAS variant, Ovarian cancer, Genome-wide association study, Carcinoma, Ovarian Epithelial, medicine.disease_cause, Prostate, Brjóstakrabbamein, Clinical outcomes, Genotype, Obstetrics and Gynaecology, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PROSTATE, Neoplasms, Glandular and Epithelial, skin and connective tissue diseases, RISK, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics and Gynecology, WOMEN, female genital diseases and pregnancy complications, 3. Good health, medicine.anatomical_structure, Treatment Outcome, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, KRAS, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Breast Neoplasms, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Carcinoma, Humans, GENOME-WIDE ASSOCIATION, Genetic Association Studies, POLYMORPHISMS, Krabbamein, MICRORNA-BINDING-SITE, IDENTIFICATION, business.industry, ENDOMETRIOSIS, Arfgengi, medicine.disease, 030104 developmental biology, PTT12, Eggjastokkar, business
Abstract: Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2: et al., [Objective]: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. [Methods]: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). [Results]: We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. [Conclusions]: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the project was provided by the Wellcome Trust under award 076113. This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285 and 2009SGR290.
Published: 2016
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47. Molecular haplotyping of tandem single nucleotide polymorphisms by allele-specific PCR

Author: Juan Manuel Fernández, Ana Sánchez-de-Abajo, Carmen Cañadas, Trinidad Caldés, Miguel Martín, Miguel de la Hoya, and Eduardo Díaz-Rubio
Subjects: Genetic Markers, Ubiquitin-Protein Ligases, Biophysics, Single-nucleotide polymorphism, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Biochemistry, Humans, SNP, Typing, Molecular Biology, Alleles, DNA Primers, Genetic association, Genetics, Genome, Human, Tumor Suppressor Proteins, Haplotype, Electrophoresis, Capillary, Nucleic Acid Hybridization, Reproducibility of Results, Sequence Analysis, DNA, Cell Biology, SNP genotyping, Haplotypes, Molecular Diagnostic Techniques, Genetic marker, Variants of PCR, Nucleic Acid Amplification Techniques
Abstract: BARD1 Val507Met (1592 A>G) is an interesting marker for association studies on cancer risk. However, studies are scarce in the literature, probably reflecting the methodological problem imposed by the fact that next to the 1592 A>G stands the 1591 C>T single nucleotide polymorphism (SNP). We have designed an allele-specific PCR method capable of molecular haplotyping tandem SNPs. In the tandem SNPs haplotyping assay (tSNPh), four reverse primers are designed to be perfect matches of each potential haplotype. The forward primer is labeled with a fluorochrome. PCR products are analyzed by capillary electrophoresis. Haplotyping is performed by size calling. To ascertain the accuracy and reproducibility of the assay, we measured the level of concordance with sequencing data in 124 samples. In vitro-generated templates have been used for further testing. We developed a novel and reliable assay that permits typing two SNPs directly adjacent to each other, avoiding mutual interferences. The method is amenable to automation and high throughput. We expect that this assay will contribute to clarifying the role of BARD1 in cancer susceptibility. In addition, we suggest that tandem SNPs are potentially interesting polymorphic markers in which molecular haplotyping can be performed easily.
Published: 2007
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48. BRCA2 gene mutations and coagulation-associated biomarkers

Author: Luis Alfonso Rico Zalba, Javier Modrego, José J. Zamorano-León, Juana María Santos-Sancho, Vicente Lahera, Pedro Pérez-Segura, Miguel de la Hoya, Natalia de las Heras, Eduardo Díaz-Rubio, Daniel Acosta, Trinidad Caldés, Isabel Díaz-Millán, Olle Melander, and Antonio López Farré
Subjects: 0301 basic medicine, Fibrinogen-gamma chain, Adult, Heterozygote, endocrine system diseases, Vitamin D-binding protein, DNA Mutational Analysis, Breast Neoplasms, Gene mutation, Biology, medicine.disease_cause, Platelet Factor 4, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Blood Coagulation, BRCA2 Protein, Mutation, Binding Sites, Haptoglobins, Transferrin, Cancer, Fibrinogen, Hematology, Middle Aged, medicine.disease, Isotype, P-Selectin, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, alpha 1-Antitrypsin, Immunology, Cancer research, Female, Rad51 Recombinase, Biomarkers
Abstract: SummaryThromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 nonmutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.
Published: 2015

49. Screening for large rearrangements of the BRCA2 gene in Spanish families with breast/ovarian cancer

Author: Gemma Llort, Ana Sánchez de Abajo, Ignacio Blanco, Elena Beristain, Cristina Martínez-Bouzas, Trinidad Caldés, Maria-Isabel Tejada, Orland Diez, Teresa Ramón y Cajal, Eduardo Díaz-Rubio, Carmen Alonso, Miguel de la Hoya, and Sara Gutiérrez-Enríquez
Subjects: Adult, Male, Cancer Research, endocrine system diseases, Genes, BRCA2, Breast Neoplasms, Biology, Breast Neoplasms, Male, Breast cancer, Gene Duplication, Gene duplication, medicine, Humans, Genetic Testing, Multiplex ligation-dependent probe amplification, skin and connective tissue diseases, Genetic testing, Family Health, Ovarian Neoplasms, Genetics, medicine.diagnostic_test, Point mutation, Gene rearrangement, Middle Aged, medicine.disease, Oncology, Spain, Male breast cancer, Mutation, Female, Chromosome Deletion, Ovarian cancer
Abstract: Germ-line mutations in BRCA1 and BRCA2 are responsible for about 30-60% of the hereditary breast and ovarian cancer (HBOC). A large number of point mutations have been described in both genes. However, large deletions and duplications that disrupt one or more exons are overlooked by point mutation detection approaches. Over the past years several rearrangements have been identified in BRCA1, while few studies have been designed to screen this type of mutations in BRCA2. Our aim was to estimate the prevalence of large genomic rearrangements in the BRCA2 gene in Spanish breast/ovarian cancer families. The multiplex ligation-dependent probe amplification (MLPA) was employed to search gross deletions or duplications of BRCA2 in 335 Spanish moderate to high-risk breast/ovarian cancer families previously screened negative for point mutations by conventional methods. Four different and novel large genomic alterations were consistently identified by MLPA in five families, respectively: deletions of exon 2, exons 10-12 and exons 15-16 and duplication of exon 20 (in two families). RT-PCR experiments confirmed the deletion of exons 15-16. All patients harbouring a genomic rearrangement were members of high-risk families, with three or more breast/ovarian cancer cases or the presence of breast cancer in males. We provide evidence that the BRCA2 rearrangements seem to account for a relatively small proportion of familial breast cancer cases in Spanish population. The screening for these alterations as part of the comprehensive genetic testing can be recommended, especially in multiple case breast/ovarian families and families with male breast cancer cases.
Published: 2006
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50. BRCA1 Alternative splicing landscape in breast tissue samples

Author: Francisco García-García, Patricia Ayllón, Joaquín Dopazo, Esperanza Benito, Miguel de la Hoya, Gorka Ruiz de Garibay, T. Caldes, Atocha Romero, Eduardo Díaz-Rubio, Pilar Garre, José A. García-Sáenz, and Irene López-Perolio
Subjects: Cancer Research, Pathology, medicine.medical_specialty, endocrine system diseases, Somatic cell, DNA repair, Biopsy, Genes, BRCA1, Breast Neoplasms, Splicing, Càncer de mama, Breast cancer, Genetics, medicine, Humans, Breast, Gene Silencing, skin and connective tissue diseases, In Situ Hybridization, Fluorescence, medicine.diagnostic_test, business.industry, Alternative splicing, Cell cycle, medicine.disease, BRCA1, Immunohistochemistry, Alternative Splicing, Genes, Oncology, RNA splicing, Cancer research, Female, Neoplasm Grading, business, Gens, Research Article
Abstract: Background BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples. Methods BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal. Results 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689). Conclusions Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1145-9) contains supplementary material, which is available to authorized users.
Published: 2015

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