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1. Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management

Author

Giovanni Innella, Cristina Fortuno, Laura Caleca, Bing‐Jian Feng, Courtney Carroll, Michael T. Parsons, Sara Miccoli, Marco Montagna, Daniele Calistri, Laura Cortesi, Barbara Pasini, Siranoush Manoukian, Daniela Giachino, Laura Matricardi, Maria Cristina Foti, Valentina Zampiga, Claudia Piombino, Elena Barbieri, Francesca Vignolo Lutati, Jacopo Azzolini, Rita Danesi, Valentina Arcangeli, Sandrine M. Caputo, Nadia Boutry‐Kryza, Vincent Goussot, Susan Hiraki, Marcy Richardson, Hereditary Breast/Ovarian Cancer IOV network (HBOC IOVnet), Simona Ferrari, Paolo Radice, Amanda B. Spurdle, and Daniela Turchetti

Subjects
BRCA1, breast cancer, cancer risk, classification, clinical management, ovarian cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence. Methods Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1‐ABRAXAS1 interaction was assessed using a GFP‐fragment reassembly‐based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2. Results Variant‐carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0–155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6–40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2–2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03–61.6) emerged, warranting further evaluation. Likelihood‐ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1‐ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule‐based model. Collectively, these findings allowed to classify the variant as pathogenic. Conclusion Pathogenicity of BRCA1:c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype.

Published
2024
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2. Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

Author

Ines Block, Àngels Mateu-Regué, Thi Tuyet Nhu Do, Ieva Miceikaite, Daniel Sdogati, Martin J. Larsen, Qin Hao, Henriette Roed Nielsen, Susanne E. Boonen, Anne-Bine Skytte, Uffe Birk Jensen, Louise K. Høffding, Arcangela De Nicolo, Alessandra Viel, Emma Tudini, Michael T. Parsons, Thomas V. O. Hansen, Maria Rossing, Torben A. Kruse, Amanda B. Spurdle, and Mads Thomassen

Subjects
BRCA1, Dual carrier, Fanconi Anemia, Variant classification, Exon duplication, Transcription activation domain assay, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. Methods We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. Results Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. Conclusions This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Published
2024
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3. The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants—a multi-site prospective cohort study

Author

Aimee L. Davidson, Uwe Dressel, Sarah Norris, Daffodil M. Canson, Dylan M. Glubb, Cristina Fortuno, Georgina E. Hollway, Michael T. Parsons, Miranda E. Vidgen, Oliver Holmes, Lambros T. Koufariotis, Vanessa Lakis, Conrad Leonard, Scott Wood, Qinying Xu, Amy E. McCart Reed, Hilda A. Pickett, Mohammad K. Al-Shinnag, Rachel L. Austin, Jo Burke, Elisa J. Cops, Cassandra B. Nichols, Annabel Goodwin, Marion T. Harris, Megan J. Higgins, Emilia L. Ip, Catherine Kiraly-Borri, Chiyan Lau, Julia L. Mansour, Michael W. Millward, Melissa J. Monnik, Nicholas S. Pachter, Abiramy Ragunathan, Rachel D. Susman, Sharron L. Townshend, Alison H. Trainer, Simon L. Troth, Katherine M. Tucker, Mathew J. Wallis, Maie Walsh, Rachel A. Williams, Ingrid M. Winship, Felicity Newell, Emma Tudini, John V. Pearson, Nicola K. Poplawski, Helen G. Mar Fan, Paul A. James, Amanda B. Spurdle, Nicola Waddell, and Robyn L. Ward

Subjects
Familial cancer, Genetics, Variants, Whole-genome sequencing, Diagnostic testing, Health economics, Medicine, QH426-470
Abstract

Abstract Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Published
2023
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4. PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants

Author

Taru A. Muranen, Anna Morra, Sofia Khan, Daniel R. Barnes, Manjeet K. Bolla, Joe Dennis, Renske Keeman, Goska Leslie, Michael T. Parsons, Qin Wang, Thomas U. Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Sabine Behrens, Katarzyna Bialkowska, Stig E. Bojesen, Nicola J. Camp, Jenny Chang-Claude, Kamila Czene, Peter Devilee, HEBON investigators, Susan M. Domchek, Alison M. Dunning, Christoph Engel, D. Gareth Evans, Manuela Gago-Dominguez, Montserrat García-Closas, Anne-Marie Gerdes, Gord Glendon, Pascal Guénel, Eric Hahnen, Ute Hamann, Helen Hanson, Maartje J. Hooning, Reiner Hoppe, Louise Izatt, Anna Jakubowska, Paul A. James, Vessela N. Kristensen, Fiona Lalloo, Geoffrey J. Lindeman, Arto Mannermaa, Sara Margolin, Susan L. Neuhausen, William G. Newman, Paolo Peterlongo, Kelly-Anne Phillips, Miquel Angel Pujana, Johanna Rantala, Karina Rønlund, Emmanouil Saloustros, Rita K. Schmutzler, Andreas Schneeweiss, Christian F. Singer, Maija Suvanto, Yen Yen Tan, Manuel R. Teixeira, Mads Thomassen, Marc Tischkowitz, Vishakha Tripathi, Barbara Wappenschmidt, Emily Zhao, Douglas F. Easton, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D. P. Pharoah, Marjanka K. Schmidt, Carl Blomqvist, and Heli Nevanlinna

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.

Published
2023
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5. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Christopher Hakkaart, John F. Pearson, Louise Marquart, Joe Dennis, George A. R. Wiggins, Daniel R. Barnes, Bridget A. Robinson, Peter D. Mace, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Sami Belhadj, Lieke Berger, Marinus J. Blok, Susanne E. Boonen, Julika Borde, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Wendy K. Chung, Kathleen B. M. Claes, GEMO Study Collaborators, EMBRACE Collaborators, Marie-Agnès Collonge-Rame, Jackie Cook, Casey Cosgrove, Fergus J. Couch, Mary B. Daly, Sita Dandiker, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Mallika Dhawan, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Douglas F. Easton, Hans Ehrencrona, Christoph Engel, D. Gareth Evans, Ulrike Faust, Lidia Feliubadaló, Florentia Fostira, Eitan Friedman, Megan Frone, Debra Frost, Judy Garber, Simon A. Gayther, Andrea Gehrig, Paul Gesta, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Eric Hahnen, Christopher R. Hake, Ute Hamann, Thomas V. O. Hansen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Peter J. Hulick, Evgeny N. Imyanitov, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Zoe Kemp, Judy Kirk, Irene Konstantopoulou, Marco Koudijs, Ava Kwong, Yael Laitman, Fiona Lalloo, Christine Lasset, Charlotte Lautrup, Conxi Lazaro, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, John W. M. Martens, Lesley McGuffog, Noura Mebirouk, Alfons Meindl, Austin Miller, Marco Montagna, Lidia Moserle, Emmanuelle Mouret-Fourme, Hannah Musgrave, Sophie Nambot, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Tu Nguyen-Dumont, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Pedro Perez-Segura, Paolo Peterlongo, Timea Pocza, Paolo Radice, Juliane Ramser, Johanna Rantala, Gustavo C. Rodriguez, Karina Rønlund, Efraim H. Rosenberg, Maria Rossing, Rita K. Schmutzler, Payal D. Shah, Saba Sharif, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Katie Snape, Doris Steinemann, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Alison H. Trainer, Vishakha Tripathi, Nadine Tung, Klaartje van Engelen, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Lisa Walker, Jeffrey N. Weitzel, Marike R. Wevers, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, and Logan C. Walker

Subjects
Biology (General), QH301-705.5
Abstract

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.

Published
2022
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6. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author

Leila Dorling, Sara Carvalho, Jamie Allen, Michael T. Parsons, Cristina Fortuno, Anna González-Neira, Stephan M. Heijl, Muriel A. Adank, Thomas U. Ahearn, Irene L. Andrulis, Päivi Auvinen, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Michael Bremer, Ignacio Briceno, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, NBCS Collaborators, J. Margriet Collée, Kamila Czene, Joe Dennis, Thilo Dörk, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Graham G. Giles, Gord Glendon, Pascal Guénel, Melanie Gündert, Andreas Hadjisavvas, Eric Hahnen, Per Hall, Ute Hamann, Elaine F. Harkness, Mikael Hartman, Frans B. L. Hogervorst, Antoinette Hollestelle, Reiner Hoppe, Anthony Howell, kConFab Investigators, SGBCC Investigators, Anna Jakubowska, Audrey Jung, Elza Khusnutdinova, Sung-Won Kim, Yon-Dschun Ko, Vessela N. Kristensen, Inge M. M. Lakeman, Jingmei Li, Annika Lindblom, Maria A. Loizidou, Artitaya Lophatananon, Jan Lubiński, Craig Luccarini, Michael J. Madsen, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Nur Aishah Mohd Taib, Kenneth Muir, Heli Nevanlinna, William G. Newman, Jan C. Oosterwijk, Sue K. Park, Paolo Peterlongo, Paolo Radice, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Xueling Sim, Melissa C. Southey, Harald Surowy, Maija Suvanto, Ian Tomlinson, Diana Torres, Thérèse Truong, Christi J. van Asperen, Regina Waltes, Qin Wang, Xiaohong R. Yang, Paul D. P. Pharoah, Marjanka K. Schmidt, Javier Benitez, Bas Vroling, Alison M. Dunning, Soo Hwang Teo, Anders Kvist, Miguel de la Hoya, Peter Devilee, Amanda B. Spurdle, Maaike P. G. Vreeswijk, and Douglas F. Easton

Subjects
Breast cancer, Genetic epidemiology, Risk prediction, Missense variants, Medicine, Genetics, QH426-470
Abstract

Abstract Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Published
2022
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7. Value of the loss of heterozygosity to BRCA1 variant classification

Author

Elizabeth Santana dos Santos, Amanda B. Spurdle, Dirce M. Carraro, Adrien Briaux, Melissa Southey, Giovana Torrezan, Ambre Petitalot, Raphael Leman, Philippe Lafitte, kConFab Investigators, Didier Meseure, Keltouma Driouch, Lucy Side, Carole Brewer, Sarah Beck, Athalie Melville, Alison Callaway, Françoise Revillion, Maria A. A. Koike Folgueira, Michael T. Parsons, Heather Thorne, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Ivan Bieche, Sandrine M. Caputo, and Etienne Rouleau

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract At least 10% of the BRCA1/2 tests identify variants of uncertain significance (VUS) while the distinction between pathogenic variants (PV) and benign variants (BV) remains particularly challenging. As a typical tumor suppressor gene, the inactivation of the second wild-type (WT) BRCA1 allele is expected to trigger cancer initiation. Loss of heterozygosity (LOH) of the WT allele is the most frequent mechanism for the BRCA1 biallelic inactivation. To evaluate if LOH can be an effective predictor of BRCA1 variant pathogenicity, we carried out LOH analysis on DNA extracted from 90 breast and seven ovary tumors diagnosed in 27 benign and 55 pathogenic variant carriers. Further analyses were conducted in tumors with PVs yet without loss of the WT allele: BRCA1 promoter hypermethylation, next-generation sequencing (NGS) of BRCA1/2, and BRCAness score. Ninety-seven tumor samples were analyzed from 26 different BRCA1 variants. A relatively stable pattern of LOH (65.4%) of WT allele for PV tumors was observed, while the allelic balance (63%) or loss of variant allele (15%) was generally seen for carriers of BV. LOH data is a useful complementary argument for BRCA1 variant classification.

Published
2022
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8. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou

Subjects
Science
Abstract

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Published
2021
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9. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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10. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Vijai Joseph, Beth Y. Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, and Georgia Chenevix-Trench

Subjects
Science
Abstract

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Published
2019
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11. Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Published
2019
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12. Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation

Author

Bryony A. Thompson, Rhiannon Walters, Michael T. Parsons, Troy Dumenil, Mark Drost, Yvonne Tiersma, Noralane M. Lindor, Sean V. Tavtigian, Niels de Wind, Amanda B. Spurdle, the InSiGHT Variant Interpretation Committee, Fahd Al-Mulla, Daniel Buchanan, Susan Farrington, Ian Frayling, Maurizio Genuardi, Elke Holinski-Feder, Maija R. J. Kohonen-Corish, Andreas Laner, Alexandra Martins, Finlay Macrae, Pål Møller, Monika Morak, Elisabet Ognedal, John-Paul Plazzer, Lene Juel Rasmussen, and Carli Tops

Subjects
mismatch repair genes, splicing aberrations, variant interpretation and classification, variant type, Lynch syndrome, mRNA splicing, Genetics, QH426-470
Abstract

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants.

Published
2020
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13. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls

Author

Yukihide Momozawa, Yusuke Iwasaki, Michael T. Parsons, Yoichiro Kamatani, Atsushi Takahashi, Chieko Tamura, Toyomasa Katagiri, Teruhiko Yoshida, Seigo Nakamura, Kokichi Sugano, Yoshio Miki, Makoto Hirata, Koichi Matsuda, Amanda B. Spurdle, and Michiaki Kubo

Subjects
Science
Abstract

Association between variants in 11 different genes and breast cancer risk has been established and sequencing of these genes is recommended to provide personalized diagnosis, therapy, and surveillance for the high-risk patients and their relatives. Here the authors analyse the frequency of germline pathogenic mutations in these genes specifically in a Japanese population.

Published
2018
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14. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4

Published
2021
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15. Comprehensive Assessment of BARD1 Messenger Ribonucleic Acid Splicing With Implications for Variant Classification

Author

Logan C. Walker, Vanessa Lilian Lattimore, Anders Kvist, Petra Kleiblova, Petra Zemankova, Lucy de Jong, George A. R. Wiggins, Christopher Hakkaart, Simone L. Cree, Raquel Behar, Claude Houdayer, kConFab Investigators, Michael T. Parsons, Martin A. Kennedy, Amanda B. Spurdle, and Miguel de la Hoya

Subjects
breast cancer, mRNA splicing, nanopore sequencing, RNAseq analysis, variant classification, ACMG, Genetics, QH426-470
Abstract

Introduction: Case–control analyses have shown BARD1 variants to be associated with up to >2-fold increase in risk of breast cancer, and potentially greater risk of triple negative breast cancer. BARD1 is included in several gene sequencing panels currently marketed for the prediction of risk of cancer, however there are no gene-specific guidelines for the classification of BARD1 variants. We present the most comprehensive assessment of BARD1 messenger RNA splicing, and demonstrate the application of these data for the classification of truncating and splice site variants according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines.Methods: Nanopore sequencing, short-read RNA-seq (whole transcriptome and targeted), and capillary electrophoresis analysis were performed by four laboratories to investigate alternative BARD1 splicing in blood, breast, and fimbriae/ovary related specimens from non-cancer affected tissues. Splicing data were also collated from published studies of nine different tissues. The impact of the findings for PVS1 annotation was assessed for truncating and splice site variants.Results: We identified 62 naturally occurring alternative spliced BARD1 splicing events, including 19 novel events found by next generation sequencing and/or reverse transcription PCR analysis performed for this study. Quantitative analysis showed that naturally occurring splicing events causing loss of clinically relevant domains or nonsense mediated decay can constitute up to 11.9% of overlapping natural junctions, suggesting that aberrant splicing can be tolerated up to this level. Nanopore sequencing of whole BARD1 transcripts characterized 16 alternative isoforms from healthy controls, revealing that the most complex transcripts combined only two alternative splicing events. Bioinformatic analysis of ClinVar submitted variants at or near BARD1 splice sites suggest that all consensus splice site variants in BARD1 should be considered likely pathogenic, with the possible exception of variants at the donor site of exon 5.Conclusions: No BARD1 candidate rescue transcripts were identified in this study, indicating that all premature translation-termination codons variants can be annotated as PVS1. Furthermore, our analysis suggests that all donor and acceptor (IVS+/−1,2) variants can be considered PVS1 or PVS1_strong, with the exception of variants targeting the exon 5 donor site, that we recommend considering as PVS1_moderate.

Published
2019
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16. TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members

Author

Rachel, Delahunty, Linh, Nguyen, Stuart, Craig, Belinda, Creighton, Dinuka, Ariyaratne, Dale W, Garsed, Elizabeth, Christie, Sian, Fereday, Lesley, Andrews, Alexandra, Lewis, Sharne, Limb, Ahwan, Pandey, Joy, Hendley, Nadia, Traficante, Natalia, Carvajal, Amanda B, Spurdle, Bryony, Thompson, Michael T, Parsons, Victoria, Beshay, Mila, Volcheck, Timothy, Semple, Richard, Lupat, Kenneth, Doig, Jiaan, Yu, Xiao Qing, Chen, Anna, Marsh, Christopher, Love, Sanela, Bilic, Maria, Beilin, Cassandra B, Nichols, Christina, Greer, Yeh Chen, Lee, Susan, Gerty, Lynette, Gill, Emma, Newton, Julie, Howard, Rachel, Williams, Christie, Norris, Andrew N, Stephens, Erin, Tutty, Courtney, Smyth, Shona, O'Connell, Thomas, Jobling, Colin J R, Stewart, Adeline, Tan, Stephen B, Fox, Nicholas, Pachter, Jason, Li, Jason, Ellul, Gisela, Mir Arnau, Mary-Anne, Young, Louisa, Gordon, Laura, Forrest, Marion, Harris, Karen, Livingstone, Jane, Hill, Georgia, Chenevix-Trench, Paul A, Cohen, Penelope M, Webb, Michael, Friedlander, Paul, James, David, Bowtell, and Kathryn, Alsop

Subjects
Male, Ovarian Neoplasms, Cancer Research, Australia, Breast Neoplasms, Pilot Projects, Carcinoma, Ovarian Epithelial, Oncology, Humans, Family, Female, Genetic Predisposition to Disease, Genetic Testing, Retrospective Studies
Abstract

PURPOSE Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.

Published
2022

17. Table S8 from A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author

Jirong Long, Wei Zheng, Paul D.P. Pharoah, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Andrew Berchuck, Antonis C. Antoniou, Simon A. Gayther, Kristin K. Zorn, Drakoulis Yannoukakos, Anna H. Wu, Alicja Wolk, Emily White, Nicolas Wentzensen, Jeffrey N. Weitzel, Penelope M. Webb, Digna Velez Edwards, Ana Vega, Adriaan Vanderstichele, Elizabeth J. van Rensburg, Shelley S. Tworoger, Nadine Tung, Antonia Trichopoulou, Amanda E. Toland, Marc Tischkowitz, Mads Thomassen, Soo H. Teo, Manuel R. Teixeira, Anthony J. Swerdlow, Rebecca Sutphen, Amanda B. Spurdle, Melissa C. Southey, Honglin Song, Christian F. Singer, Jacques Simard, Weiva Sieh, Priyanka Sharma, Veronica W. Setiawan, Rita K. Schmutzler, Dale P. Sandler, Iwona K. Rzepecka, Mary Anne Rossing, Matti A. Rookus, Isabelle Romieu, Cristina Rodríguez-Antona, Gustavo C. Rodriguez, Harvey Risch, Gad Rennert, Susan J. Ramus, Miquel Angel Pujana, Catherine M. Phelan, Paolo Peterlongo, Tanja Pejovic, Petra H.M. Peeters, Michael T. Parsons, Sue K. Park, Ana Osorio, Håkan Olsson, Sara H. Olson, Olufunmilayo I. Olopade, Edith Olah, Kenneth Offit, Robert L. Nussbaum, Liene Nikitina-Zake, Finn C. Nielsen, Heli Nevanlinna, Susan L. Neuhausen, Marco Montagna, Francesmary Modugno, Melissa A. Merritt, Iain A. McNeish, Lesley McGuffog, Taymaa May, Amalia Mattiello, Douglas A. Levine, Fabienne Lesueur, Goska Leslie, Nhu D. Le, Ava Kwong, Susanne K. Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Beth Y. Karlan, Paul James, Anna Jakubowska, Claudine Isaacs, Evgeny N. Imyanitov, David G. Huntsman, Peter J. Hulick, Antoinette Hollestelle, Claus K. Høgdall, Michelle A.T. Hildebrandt, Florian Heitz, Ute Hamann, Jacek Gronwald, Mark H. Greene, Marc T. Goodman, David E. Goldgar, Andrew K. Godwin, Graham G. Giles, Judy Garber, Patricia A. Ganz, Eitan Friedman, George Fountzilas, Renée T. Fortner, Peter A. Fasching, Diana M. Eccles, Douglas F. Easton, Thilo Dörk, Susan M. Domchek, Orland Diez, Joe Dennis, Anna deFazio, Mary B. Daly, Daniel W. Cramer, Fergus J. Couch, Kathleen B.M. Claes, Jenny Chang-Claude, Ian Campbell, Maria A. Caligo, Trinidad Caldes, Ralf Butzow, James Brenton, Line Bjorge, Javier Benitez, Daniel R. Barnes, Rosa B. Barkardottir, Elisa V. Bandera, Banu K. Arun, Hoda Anton-Culver, Irene L. Andrulis, Kirsten B. Moysich, Jamie K. Teer, Brett M. Reid, Jennifer B. Permuth, Yian A. Chen, Hae Kyung Im, Joellen M. Schildkraut, Bingshan Li, Xingyi Guo, Lang Wu, Alicia Beeghly-Fadiel, and Yingchang Lu

Abstract

Association results between minor alleles of 467 variants incorportated in cross tissue gene expression prediction model for the gene of CRHR1.

Published
2023

18. Online Supplementary Materials from A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author

Jirong Long, Wei Zheng, Paul D.P. Pharoah, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Andrew Berchuck, Antonis C. Antoniou, Simon A. Gayther, Kristin K. Zorn, Drakoulis Yannoukakos, Anna H. Wu, Alicja Wolk, Emily White, Nicolas Wentzensen, Jeffrey N. Weitzel, Penelope M. Webb, Digna Velez Edwards, Ana Vega, Adriaan Vanderstichele, Elizabeth J. van Rensburg, Shelley S. Tworoger, Nadine Tung, Antonia Trichopoulou, Amanda E. Toland, Marc Tischkowitz, Mads Thomassen, Soo H. Teo, Manuel R. Teixeira, Anthony J. Swerdlow, Rebecca Sutphen, Amanda B. Spurdle, Melissa C. Southey, Honglin Song, Christian F. Singer, Jacques Simard, Weiva Sieh, Priyanka Sharma, Veronica W. Setiawan, Rita K. Schmutzler, Dale P. Sandler, Iwona K. Rzepecka, Mary Anne Rossing, Matti A. Rookus, Isabelle Romieu, Cristina Rodríguez-Antona, Gustavo C. Rodriguez, Harvey Risch, Gad Rennert, Susan J. Ramus, Miquel Angel Pujana, Catherine M. Phelan, Paolo Peterlongo, Tanja Pejovic, Petra H.M. Peeters, Michael T. Parsons, Sue K. Park, Ana Osorio, Håkan Olsson, Sara H. Olson, Olufunmilayo I. Olopade, Edith Olah, Kenneth Offit, Robert L. Nussbaum, Liene Nikitina-Zake, Finn C. Nielsen, Heli Nevanlinna, Susan L. Neuhausen, Marco Montagna, Francesmary Modugno, Melissa A. Merritt, Iain A. McNeish, Lesley McGuffog, Taymaa May, Amalia Mattiello, Douglas A. Levine, Fabienne Lesueur, Goska Leslie, Nhu D. Le, Ava Kwong, Susanne K. Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Beth Y. Karlan, Paul James, Anna Jakubowska, Claudine Isaacs, Evgeny N. Imyanitov, David G. Huntsman, Peter J. Hulick, Antoinette Hollestelle, Claus K. Høgdall, Michelle A.T. Hildebrandt, Florian Heitz, Ute Hamann, Jacek Gronwald, Mark H. Greene, Marc T. Goodman, David E. Goldgar, Andrew K. Godwin, Graham G. Giles, Judy Garber, Patricia A. Ganz, Eitan Friedman, George Fountzilas, Renée T. Fortner, Peter A. Fasching, Diana M. Eccles, Douglas F. Easton, Thilo Dörk, Susan M. Domchek, Orland Diez, Joe Dennis, Anna deFazio, Mary B. Daly, Daniel W. Cramer, Fergus J. Couch, Kathleen B.M. Claes, Jenny Chang-Claude, Ian Campbell, Maria A. Caligo, Trinidad Caldes, Ralf Butzow, James Brenton, Line Bjorge, Javier Benitez, Daniel R. Barnes, Rosa B. Barkardottir, Elisa V. Bandera, Banu K. Arun, Hoda Anton-Culver, Irene L. Andrulis, Kirsten B. Moysich, Jamie K. Teer, Brett M. Reid, Jennifer B. Permuth, Yian A. Chen, Hae Kyung Im, Joellen M. Schildkraut, Bingshan Li, Xingyi Guo, Lang Wu, Alicia Beeghly-Fadiel, and Yingchang Lu

Abstract

Online Supplementary Documents

Published
2023

19. Data from A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author

Jirong Long, Wei Zheng, Paul D.P. Pharoah, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Andrew Berchuck, Antonis C. Antoniou, Simon A. Gayther, Kristin K. Zorn, Drakoulis Yannoukakos, Anna H. Wu, Alicja Wolk, Emily White, Nicolas Wentzensen, Jeffrey N. Weitzel, Penelope M. Webb, Digna Velez Edwards, Ana Vega, Adriaan Vanderstichele, Elizabeth J. van Rensburg, Shelley S. Tworoger, Nadine Tung, Antonia Trichopoulou, Amanda E. Toland, Marc Tischkowitz, Mads Thomassen, Soo H. Teo, Manuel R. Teixeira, Anthony J. Swerdlow, Rebecca Sutphen, Amanda B. Spurdle, Melissa C. Southey, Honglin Song, Christian F. Singer, Jacques Simard, Weiva Sieh, Priyanka Sharma, Veronica W. Setiawan, Rita K. Schmutzler, Dale P. Sandler, Iwona K. Rzepecka, Mary Anne Rossing, Matti A. Rookus, Isabelle Romieu, Cristina Rodríguez-Antona, Gustavo C. Rodriguez, Harvey Risch, Gad Rennert, Susan J. Ramus, Miquel Angel Pujana, Catherine M. Phelan, Paolo Peterlongo, Tanja Pejovic, Petra H.M. Peeters, Michael T. Parsons, Sue K. Park, Ana Osorio, Håkan Olsson, Sara H. Olson, Olufunmilayo I. Olopade, Edith Olah, Kenneth Offit, Robert L. Nussbaum, Liene Nikitina-Zake, Finn C. Nielsen, Heli Nevanlinna, Susan L. Neuhausen, Marco Montagna, Francesmary Modugno, Melissa A. Merritt, Iain A. McNeish, Lesley McGuffog, Taymaa May, Amalia Mattiello, Douglas A. Levine, Fabienne Lesueur, Goska Leslie, Nhu D. Le, Ava Kwong, Susanne K. Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Beth Y. Karlan, Paul James, Anna Jakubowska, Claudine Isaacs, Evgeny N. Imyanitov, David G. Huntsman, Peter J. Hulick, Antoinette Hollestelle, Claus K. Høgdall, Michelle A.T. Hildebrandt, Florian Heitz, Ute Hamann, Jacek Gronwald, Mark H. Greene, Marc T. Goodman, David E. Goldgar, Andrew K. Godwin, Graham G. Giles, Judy Garber, Patricia A. Ganz, Eitan Friedman, George Fountzilas, Renée T. Fortner, Peter A. Fasching, Diana M. Eccles, Douglas F. Easton, Thilo Dörk, Susan M. Domchek, Orland Diez, Joe Dennis, Anna deFazio, Mary B. Daly, Daniel W. Cramer, Fergus J. Couch, Kathleen B.M. Claes, Jenny Chang-Claude, Ian Campbell, Maria A. Caligo, Trinidad Caldes, Ralf Butzow, James Brenton, Line Bjorge, Javier Benitez, Daniel R. Barnes, Rosa B. Barkardottir, Elisa V. Bandera, Banu K. Arun, Hoda Anton-Culver, Irene L. Andrulis, Kirsten B. Moysich, Jamie K. Teer, Brett M. Reid, Jennifer B. Permuth, Yian A. Chen, Hae Kyung Im, Joellen M. Schildkraut, Bingshan Li, Xingyi Guo, Lang Wu, Alicia Beeghly-Fadiel, and Yingchang Lu

Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Published
2023

20. The splicing effect of variants at branchpoint elements in cancer genes

Author

Daffodil M. Canson, Troy Dumenil, Michael T. Parsons, Tracy A. O’Mara, Aimee L. Davidson, Satomi Okano, Bethany Signal, Tim R. Mercer, Dylan M. Glubb, and Amanda B. Spurdle

Subjects
Neoplasms, RNA Splicing, Humans, Introns, Genetics (clinical), Genes, Neoplasm
Abstract

Branchpoint elements are required for intron removal, and variants at these elements can result in aberrant splicing. We aimed to assess the value of branchpoint annotations generated from recent large-scale studies to select branchpoint-abrogating variants, using hereditary cancer genes as model.We identified branchpoint elements in 119 genes associated with hereditary cancer from 3 genome-wide experimentally-inferred and 2 predicted branchpoint data sets. We then identified variants that occur within branchpoint elements from public databases. We compared conservation, unique variant observations, and population frequencies at different nucleotides within branchpoint motifs. Finally, selected minigene assays were performed to assess the splicing effect of variants at branchpoint elements within mismatch repair genes.There was poor overlap between predicted and experimentally-inferred branchpoints. Our analysis of cancer genes suggested that variants at -2 nucleotide, -1 nucleotide, and branchpoint positions in experimentally-inferred canonical motifs are more likely to be clinically relevant. Minigene assay data showed the -2 nucleotide to be more important to branchpoint motif integrity but also showed fluidity in branchpoint usage.Data from cancer gene analysis suggest that there are few high-risk alleles that severely impact function via branchpoint abrogation. Results of this study inform a general scheme to prioritize branchpoint motif variants for further study.

Published
2022

21. APPLICATION OF THE ACMG/AMP FRAMEWORK TO CAPTURE EVIDENCE RELEVANT TO PREDICTED AND OBSERVED IMPACT ON SPLICING: RECOMMENDATIONS FROM THE CLINGEN SVI SPLICING SUBGROUP

Author

Logan C. Walker, Miguel de la Hoya, George A.R. Wiggins, Amanda Lindy, Lisa M. Vincent, Michael T Parsons, Daffodil M Canson, Dana Bis-Brewer, Ashley Cass, Alexander Tchourbanov, Heather Zimmermann, Alicia B Byrne, Tina Pesaran, Rachid Karam, Steven Harrison, and Amanda B Spurdle

Subjects
Article
Abstract

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1 (null variant in a gene where loss-of-function is the mechanism of disease), PS3 (functional assays show damaging effect on splicing), PP3 (computational evidence supports a splicing effect), BS3 (functional assays show no damaging effect on splicing), BP4 (computational evidence suggests no splicing impact), and BP7 (silent change with no predicted impact on splicing). However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation (SVI) Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. Our study utilised empirically derived splicing evidence to: 1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, 2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and 3) exemplify methodology to calibrate bioinformatic splice prediction tools. We propose repurposing of the PVS1_Strength code to capture splicing assay data that provide experimental evidence for variants resulting in RNA transcript(s) with loss of function. Conversely BP7 may be used to capture RNA results demonstrating no impact on splicing for both intronic and synonymous variants, and for missense variants if protein functional impact has been excluded. Furthermore, we propose that the PS3 and BS3 codes are applied only for well-established assays that measure functional impact that is not directly captured by RNA splicing assays. We recommend the application of PS1 based on similarity of predicted RNA splicing effects for a variant under assessment in comparison to a known Pathogenic variant. The recommendations and approaches for consideration and evaluation of RNA assay evidence described aim to help standardise variant pathogenicity classification processes and result in greater consistency when interpreting splicing-based evidence.

Published
2023

22. SPiP: Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing

Author

Raphaël Leman, Béatrice Parfait, Dominique Vidaud, Emmanuelle Girodon, Laurence Pacot, Gérald Le Gac, Chandran Ka, Claude Ferec, Yann Fichou, Céline Quesnelle, Camille Aucouturier, Etienne Muller, Dominique Vaur, Laurent Castera, Flavie Boulouard, Agathe Ricou, Hélène Tubeuf, Omar Soukarieh, Pascaline Gaildrat, Florence Riant, Marine Guillaud‐Bataille, Sandrine M. Caputo, Virginie Caux‐Moncoutier, Nadia Boutry‐Kryza, Françoise Bonnet‐Dorion, Ines Schultz, Maria Rossing, Olivier Quenez, Louis Goldenberg, Valentin Harter, Michael T. Parsons, Amanda B. Spurdle, Thierry Frébourg, Alexandra Martins, Claude Houdayer, and Sophie Krieger

Subjects
sequence variants, machine learning, SPiP, Genetics, RNA, splicing predictions, Genetics (clinical)
Abstract

Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5’/3’ splice sites, branch sites or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on machine learning approach, comprehensive assessment of variant effect on different splicing motifs. We gathered a curated set of 4,616 variants scattered all along the sequence of 227 genes, with their corresponding splicing studies. Bayesian analysis provided us the number of control variants, i.e. variants without impact on splicing, to mimic the deluge of variants from high throughput sequencing data. Results show that SPiP can deal with the diversity of splicing alterations, with 83.13% sensitivity and 99% specificity to detect spliceogenic variants. Overall performance as measured by area under the receiving operator curve was 0.986, significantly better than 0.965 spliceAI for the same dataset. SPiP lends itself to a unique suite for comprehensive prediction of spliceogenicity in the genomic medicine era. SPiP is available at: [https://sourceforge.net/projects/splicing-prediction-pipeline/](https://sourceforge.net/projects/splicing-prediction-pipeline/)

Published
2022

23. SpliceAI-10k calculator for the prediction of pseudoexonization, intron retention, and exon deletion

Author

Daffodil M. Canson, Aimee L. Davidson, Miguel de la Hoya, Michael T. Parsons, Dylan M. Glubb, Olga Kondrashova, and Amanda B. Spurdle

Subjects
Statistics and Probability, Computational Mathematics, Computational Theory and Mathematics, Molecular Biology, Biochemistry, Computer Science Applications
Abstract

SummarySpliceAI is a widely used splicing prediction tool and its most common application relies on the maximum delta score to assign variant impact on splicing. We developed the SpliceAI-10k calculator (SAI-10k-calc) to extend use of this tool to predict: the splicing aberration type including pseudoexonization, intron retention, partial exon deletion, and (multi)exon skipping using a 10 kb analysis window; the size of inserted or deleted sequence; the effect on reading frame; and the altered amino acid sequence.SAI-10k-calc has 95% sensitivity and 96% specificity for predicting variants that impact splicing, computed from a control dataset of 1,212 single nucleotide variants (SNVs) with curated splicing assay results. Notably, it has high performance (≥84% accuracy) for predicting pseudoexon and partial intron retention. The automated amino acid sequence prediction allows for efficient identification of variants that are expected to result in mRNA nonsense-mediated decay or translation of truncated proteins.Availability and implementationSAI-10k-calc is implemented in R (https://github.com/adavi4/SAI-10k-calc) and also available as a Microsoft Excel spreadsheet. Users can adjust the default thresholds to suit their target performance values.Supplementary informationSupplementary data are available online.

Published
2022

24. Considerations for using population frequency data in germline variant interpretation: Cancer syndrome genes as a model

Author

John V. Pearson, Georgina E Hollway, Nicola Waddell, Felicity Newell, Aimee L Davidson, Lambros T. Koufariotis, Michael T. Parsons, Conrad Leonard, and Amanda B. Spurdle

Subjects
Population, Computational biology, Biology, Germline, Cancer syndrome, Population genomics, 03 medical and health sciences, Gene Frequency, Neoplasms, Genetics, medicine, Humans, Genetic Testing, education, Gene, Allele frequency, Genetics (clinical), 030304 developmental biology, Whole genome sequencing, 0303 health sciences, education.field_of_study, Genome, Human, 030305 genetics & heredity, Genetic Variation, Genomics, medicine.disease, Germ Cells, Precision and recall
Abstract

Aggregate population genomics data from large cohorts are vital for assessing germline variant pathogenicity. However, there are no specifications on how sequencing quality metrics should be considered, and whether exome-derived and genome-derived allele frequencies should be considered in isolation. Germline genome sequence data were simulated for nine read-depths to identify a minimum acceptable read-depth for detecting variants. gnomAD exome-derived and genome-derived datasets were assessed for read-depth, for six key cancer genes selected for variant curation by ClinGen expert panels. Non-Finnish European allele frequency (AF) or filter AF of coding variants in these genes, assigned into frequency bins using modified ACMG-AMP criteria, was compared between exome-derived and genome-derived datasets. A 30X read-depth achieved acceptable precision and recall for detection of substitutions, but poor recall for small insertions/deletions. Exome-derived and genome-derived datasets exhibited low read-depth for different gene exons. Individual variants were mostly assigned to non-divergent AF bins (>95%) or filter AF bins (>97%). Two major bin divergences were resolved by applying the minimal acceptable read-depth threshold. These findings show the importance of assessing read-depth separately for population datasets sourced from different short-read sequencing technologies before assigning a frequency-based ACMG-AMP classification code for variant interpretation.

Published
2021

25. Considerations in assessing germline variant pathogenicity using cosegregation analysis

Author

David E. Goldgar, Sophie Belman, Bing Jian Feng, Amanda B. Spurdle, and Michael T. Parsons

Subjects
0301 basic medicine, education.field_of_study, medicine.medical_specialty, medicine.diagnostic_test, Cosegregation, Computer science, Population, Genomics, Bayes factor, Computational biology, 030105 genetics & heredity, Penetrance, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, medicine, Mendelian inheritance, symbols, Medical genetics, education, Genetics (clinical), Genetic testing
Abstract

Purpose The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have developed guidelines for classifying germline variants as pathogenic or benign to interpret genetic testing results. Cosegregation analysis is an important component of the guidelines. There are two main approaches for cosegregation analysis: meiosis counting and Bayes factor–based quantitative methods. Of these, the ACMG/AMP guidelines employ only meiosis counting. The accuracy of either approach has not been sufficiently addressed in previous works. Methods We analyzed hypothetical, simulated, and real-life data to evaluate the accuracy of each approach for cancer-associated genes. Results We demonstrate that meiosis counting can provide incorrect classifications when the underlying genetic basis of the disease departs from simple Mendelian situations. Some Bayes factor approaches are currently implemented with inappropriate penetrance. We propose an improved penetrance model and describe several critical considerations, including the accuracy of cosegregation for moderate-risk genes and the impact of pleiotropy, population, and birth year. We highlight a webserver, COOL (Co-segregation Online, http://BJFengLab.org/), that implements an accurate Bayes factor cosegregation analysis. Conclusion An appropriate penetrance model improves the accuracy of Bayes factor cosegregation analysis for high-penetrant variants, and is a better choice than meiosis counting whenever feasible.

Published
2020

26. Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Author

V. Wendy Setiawan, Ana Osorio, Liv Cecilie Vestrheim Thomsen, Francesca Gensini, Harsha Pathak, Barbara Wappenschmidt, Ingo B. Runnebaum, Javier Benitez, Rita K. Schmutzler, Jeffrey N. Weitzel, Yin Ling Woo, Kenneth Offit, Anthony N. Karnezis, Eitan Friedman, Jacques Simard, James M. Flanagan, Pedro Pérez-Segura, Siranoush Manoukian, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Graham G. Giles, Usha Menon, Ava Kwong, Anna H. Wu, Thomas Hansen, Cristina Rodríguez-Antona, Maria A. Caligo, Argyrios Ziogas, Allison DePersia, Anna P. Sokolenko, Clarice R. Weinberg, Hoda Anton-Culver, Digna R. Velez Edwards, Jennifer B. Permuth, Patricia A. Ganz, Ana Vega, Keitaro Matsuo, Heli Nevanlinna, Frances Wang, Natalia Antonenkova, Claudine Isaacs, Conxi Lázaro, Melissa C. Larson, Henriette Roed Nielsen, Byoung-Gie Kim, Andreas du Bois, Dale P. Sandler, Anna Jakubowska, Paul D.P. Pharoah, Jenny Lester, Paolo Radice, Natalia Bogdanova, Lambertus A. Kiemeney, Mary Anne Rossing, Thilo Dörk, Ruea-Yea Huang, Judy Garber, Taymaa May, Diana Eccles, Mary Beth Terry, Jenny Chang-Claude, Jeffrey R. Marks, Dominique Stoppa-Lyonnet, Heather Eliassen, Douglas A. Levine, Phuong L. Mai, Gerasimos Aravantinos, Hui Cai, Britton Trabert, Amanda Black, Noura Mebirouk, Robin de Putter, Rayna K. Matsuno, Ralf Bützow, Joanne Ngeow Yuen Yie, James D. Brenton, Nadine Tung, Drakoulis Yannoukakos, Jonathan Tyrer, L Yan, Yen Y. Tan, Ian Komenaka, Simona Agata, Honglin Song, Tanja Pejovic, Marjorie J. Riggan, Antonis C. Antoniou, Katja K.H. Aben, Goska Leslie, Eric A. Ross, Estrid Høgdall, Kang Shan, Holly R. Harris, Eleanor Davies, Liene Nikitina-Zake, Florian Heitz, Stephen J. Chanock, Matthew Jones, Beth Y. Karlan, Matthias W. Beckmann, Penelope M. Webb, John L. Hopper, Peter A. Fasching, Jacek Gronwald, kConFab Investigators, Ana Peixoto, Joellen M. Schildkraut, Renée T. Fortner, Susan L. Neuhausen, Daehee Kang, Anthony J. Swerdlow, Lesley McGuffog, Marco Montagna, Paolo Peterlongo, Daniel R. Barnes, Marina Bermisheva, Alicja Wolk, Yuan Chun Ding, Marc Tischkowitz, Gord Glendon, Elza Khusnutdinova, Julie M. Cunningham, Saundra S. Buys, Albina N. Minlikeeva, Jennifer A. Doherty, Annemieke H. van der Hout, Austin Miller, Fergus J. Couch, Fabienne Lesueur, Peter Devilee, Kristin K. Zorn, Daniel Barrowdale, Christian F. Singer, Line Bjørge, Åke Borg, Diether Lambrechts, Shelley S. Tworoger, Allan Jensen, Ute Hamann, Douglas F. Easton, Bernardo Bonanni, Alvaro N.A. Monteiro, Johanna Rantala, Marc T. Goodman, Ellen Valen, Wei Zheng, Thomas A. Sellers, Marcus Q. Bernardini, Alice S. Whittemore, Kunle Odunsi, Inge Søkilde Pedersen, Laura Papi, Mads Thomassen, Allison W. Kurian, Emily White, Penny Soucy, D. Gareth Evans, Lenka Foretova, Kathryn L. Terry, Ruth C. Travis, Claus Høgdall, Hebon Investigators, Darya Prokofyeva, Stacey J. Winham, Yoke-Eng Chiew, Eileen Dareng, Jan Lubinski, Elizabeth Munro, Oskar T. Johannsson, Linda E. Kelemen, Kexin Chen, Xin Yang, Manuel R. Teixeira, Anna M. Piskorz, Edith Olah, Helen Steed, Beth N. Peshkin, Georgia Chenevix-Trench, Andrew K. Godwin, Pamela J. Thompson, Chad D. Huff, Rosa B. Barkardottir, Muriel A. Adank, Mikael Hartman, Linda J. Titus, Weiva Sieh, Simon A. Gayther, Peter J. Hulick, Michael T. Parsons, Elisa V. Bandera, Amanda E. Toland, Miguel de la Hoya, Orland Diez, Alicia Beeghly-Fadiel, Rebecca Sutphen, Francesmary Modugno, Judith Balmaña, Christoph Engel, Harvey A. Risch, Elizabeth J. van Rensburg, Michael Jones, Rikki Cannioto, Michelle A.T. Hildebrandt, Soo Hwang Teo, Fanny Dao, Susan J. Ramus, Sarah Colanna, Kathleen Claes, David G. Huntsman, Siel Olbrecht, Esther M. John, Robert A. Vierkant, Wendy K. Chung, Ellen L. Goode, Olufunmilayo I. Olopade, Evgeny N. Imyanitov, Joe Dennis, Andrew Berchuck, Banu Arun, Darcy L. Thull, Lian Li, Celeste Leigh Pearce, Sue K. Park, Susan M. Domchek, Agnieszka Budzilowska, Håkan Olsson, Susanne K. Kjaer, Mark H. Greene, Katia M. Zavaglia, Jolanta Kupryjanczyk, Nicolas Wentzensen, Karen H. Lu, Hayley Cassingham, Christopher A. Haiman, Eric Hahnen, Els Van Nieuwenhuysen, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Paul A. James, Sara H. Olson, Eva Machackova, Anne M. van Altena, Irene L. Andrulis, Linda S. Cook, Matthias Dürst, Mary B. Daly, John R. McLaughlin, Niclas Håkansson, Jingmei Li, Diana Torres, Iain A. McNeish, Jennifer T. Loud, Roger L. Milne, Marta Santamariña, Annelie Augustinsson, Nhu D. Le, Kate Lawrenson, Kirsten B. Moysich, Dareng, Eileen O [0000-0003-0802-419X], Tyrer, Jonathan [0000-0003-3724-4757], Barnes, Daniel [0000-0002-3781-7570], Jones, Michelle R [0000-0001-5466-3844], Agata, Simona [0000-0002-6329-0768], Anton-Culver, Hoda [0000-0002-9603-0110], Augustinsson, Annelie [0000-0003-3415-0536], Bandera, Elisa V [0000-0002-8789-2755], Barkardottir, Rosa B [0000-0003-0629-2772], Brenton, James [0000-0002-5738-6683], Campbell, Ian [0000-0002-7773-4155], Chen, Kexin [0000-0003-1010-8093], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Devilee, Peter [0000-0002-8023-2009], Diez, Orland [0000-0001-7339-0570], Bois, Andreas du [0000-0002-8477-506X], Eccles, Diana M [0000-0002-9935-3169], Eliassen, Heather A [0000-0002-3961-6609], Ganz, Patricia A [0000-0002-1841-4143], Giles, Graham G [0000-0003-4946-9099], Glendon, Gord [0000-0001-8630-6673], Greene, Mark H [0000-0003-1852-9239], Hartman, Mikael [0000-0001-5726-9965], Heitz, Florian [0000-0002-2412-0352], Isaacs, Claudine [0000-0002-9646-1260], Janavicius, Ramunas [0000-0002-3773-8485], John, Esther M [0000-0003-3259-8003], Kang, Daehee [0000-0003-4031-5878], Karlan, Beth Y [0000-0002-9451-2933], Khusnutdinova, Elza [0000-0003-2987-3334], Kjaer, Susanne K [0000-0002-8347-1398], Manoukian, Siranoush [0000-0002-6034-7562], Matsuo, Keitaro [0000-0003-1761-6314], Menon, Usha [0000-0003-3708-1732], Miller, Austin [0000-0001-9739-8462], Nikitina-Zake, Liene [0000-0003-2491-5187], Olbrecht, Siel [0000-0001-9452-5905], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Sara H [0000-0003-0182-2754], Papi, Laura [0000-0003-4552-9517], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Permuth, Jennifer B [0000-0002-4726-9264], Peterlongo, Paolo [0000-0001-6951-6855], Radice, Paolo [0000-0001-6298-4111], Swerdlow, Anthony J [0000-0001-5550-4159], Toland, Amanda E [0000-0002-0271-1792], Webb, Penelope M [0000-0003-0733-5930], Weinberg, Clarice R [0000-0002-7713-8556], Weitzel, Jeffrey N [0000-0001-6714-092X], Winham, Stacey J [0000-0002-8492-9102], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Easton, Douglas [0000-0003-2444-3247], Ramus, Susan J [0000-0003-0005-7798], Chenevix-Trench, Georgia [0000-0002-1878-2587], and Apollo - University of Cambridge Repository

Subjects
Oncology, medicine.medical_specialty, 45/61, 45/43, Single-nucleotide polymorphism, Logistic regression, 631/208/2489, 03 medical and health sciences, 0302 clinical medicine, Lasso (statistics), Internal medicine, Genotype, medicine, SNP, 030304 developmental biology, 0303 health sciences, business.industry, Hazard ratio, article, Odds ratio, 631/208/721, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, business, Ovarian cancer, 692/499
Abstract

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Published
2022
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27. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Ana Peixoto, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Michael Untch, Susan J. Ramus, Kenneth Offit, John J. Spinelli, Clarice R. Weinberg, Kyriaki Michailidou, Javier Benitez, Rita K. Schmutzler, Lizet E. van der Kolk, Heli Nevanlinna, Annika Lindblom, Sara Margolin, Stella Koutros, Elza Khusnutdinova, Diana Eccles, Lenka Foretova, Wolfgang Janni, Jennifer T. Loud, Roger L. Milne, Patrick Neven, Thomas U. Ahearn, Hedy S. Rennert, Karolina Prajzendanc, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Pascal Guénel, Antoinette Hollestelle, Jolanta Lissowska, Ni Zhao, Melissa Christiaens, Hoda Anton-Culver, Ans M.W. van den Ouweland, Christopher A. Haiman, Debra Frost, Vessela N. Kristensen, Bernard Peissel, Muhammad Usman Rashid, Noura Mebirouk, Claudine Isaacs, Matthias W. Beckmann, Sofia Khan, Xia Jiang, Jack A. Taylor, Peter Hillemanns, Robert Winqvist, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Katherine L. Nathanson, Judy Garber, Siranoush Manoukian, Simon S. Cross, Flavio Lejbkowicz, Manjeet K. Bolla, Goska Leslie, Saundra S. Buys, Banu Arun, Xiaohong R. Yang, Peter Schürmann, Irene Konstantopoulou, Mia M. Gaudet, Rob A. E. M. Tollenaar, Joe Dennis, Louise Izatt, David E. Goldgar, Anna Jakubowska, Alicja Lukomska, Fabienne Lesueur, Susanna C. Larsson, Peter Devilee, Helen Byers, Bernd Holleczek, Marc Tischkowitz, Arif B. Ekici, Austin Miller, Carl Blomqvist, Christopher R. Hake, Paul D.P. Pharoah, Harvey A. Risch, Kristin K. Zorn, Mehdi Manoochehri, Kamila Czene, Peter A. Fasching, Trinidad Caldés, Hanna Huebner, Agnes Jager, William G. Newman, Lesley McGuffog, Maren T. Scheuner, Nick Orr, Susan M. Domchek, Antonis C. Antoniou, Peter Kraft, Pooja Middha Kapoor, Daniel R. Barnes, Christine L. Clarke, Douglas F. Easton, Bernadette A M Heemskerk-Gerritsen, Ross L. Prentice, Mark E. Sherman, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Diether Lambrechts, Mark H. Greene, Mark S. Goldberg, Peter J. Hulick, Maria Elena Martinez, Arto Mannermaa, Frans B. L. Hogervorst, Christian F. Singer, Johanna Rantala, Esther M. John, Jesse Nodora, Wendy K. Chung, Csilla Szabo, Mads Thomassen, Tracy A. O'Mara, Kelly-Anne Phillips, Manuela Gago-Dominguez, Jacques Simard, John L. Hopper, Jacopo Azzollini, Rudolf Kaaks, Haoyu Zhang, Eitan Friedman, Heiko Becher, János Papp, Thomas Rüdiger, Alison M. Dunning, Daniele Campa, Alfons Meindl, Lothar Häberle, Ana Blanco, Eric Hahnen, Barbara Wappenschmidt, Elaine F. Harkness, Audrey Y. Jung, Guanghao Qi, Zumuruda Abu Ful, Maria A. Caligo, Priyanka Sharma, Håkan Olsson, Elke M van Veen, Marion Piedmonte, Linetta B. Koppert, Usha Menon, Laura Matricardi, Jonine D. Figueroa, Wei Zheng, Milena Jakimovska, Katarzyna Białkowska, Renske Keeman, Matti A. Rookus, William J. Tapper, J. Peto, Paul L. Auer, Andreas Schneeweiss, Xiao-Ou Shu, Miriam Dwek, Elvira Mingazheva, Hermann Brenner, Emilija Lazarova, Atocha Romero, Rulla M. Tamimi, Laura Papi, Hans Wildiers, Catriona McLean, Montserrat Garcia-Closas, Matthias Rübner, Thomas Brüning, Graham G. Giles, Robert J. MacInnis, Hans Christiansen, Sten Cornelissen, Paul A. James, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Nilanjan Chatterjee, D. Gareth Evans, Ignacio Briceño, Mary B. Daly, Annegien Broeks, Evgeny N. Imyanitov, Jonathan Beesley, Snezhana Smichkoska, Thilo Dörk, Yon-Dschun Ko, Paolo Peterlongo, Celine M. Vachon, Claire Mulot, Kristiina Aittomäki, Liene Nikitina-Zake, Manuel R. Teixeira, Edith Olah, Florentia Fostira, Beth N. Peshkin, Pierre Laurent-Puig, M. B. Terry, Michael T. Parsons, Anna González-Neira, Julie Lecarpentier, Jacek Gronwald, Fergus J. Couch, Mariarosaria Calvello, Leigha Senter, Ute Hamann, Brigitte Rack, Marco Montagna, Simon A. Gayther, Barbara Burwinkel, Anne-Vibeke Lænkholm, Irene L. Andrulis, Sabine Behrens, Beth Y. Karlan, Anthony J. Swerdlow, Marjanka K. Schmidt, Cari M. Kitahara, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Melissa A. Troester, Diana Torres, Daniel Barrowdale, Elinor J. Sawyer, Hiltrud Brauch, Minouk J. Schoemaker, Dale P. Sandler, José A. García-Sáenz, Jennifer Stone, Qin Wang, Conxi Lázaro, Paolo Radice, Jan Lubinski, Jose E. Castelao, Natalia Bogdanova, Drakoulis Yannoukakos, Davide Bondavalli, Kristan J. Aronson, Gad Rennert, Wing-Yee Lo, Robert N. Hoover, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Andrew K. Godwin, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Penny Soucy, Jenny Chang-Claude, Kathleen Claes, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Stig E. Bojesen, Sara Y Brucker, Darcy L. Thull, Darya Prokofyeva, Taru A. Muranen, Ben Schöttker, Orland Diez, Susan M. Gapstur, Sarah Sampson, Bernardo Bonanni, Per Hall, Ana Vega, Medical Oncology, Surgery, and Clinical Genetics

Subjects
Oncology, medicine.medical_specialty, Linkage disequilibrium, Carcinogenesis, Estrogen receptor, Genome-wide association study, Breast Neoplasms, Triple Negative Breast Neoplasms, Biology, Gene mutation, Linkage Disequilibrium, Càncer de mama, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Carcinogènesi, Triple-negative breast cancer, 030304 developmental biology, Medicinsk genetik, 0303 health sciences, Genetic heterogeneity, BRCA1 Protein, medicine.disease, 3. Good health, Case-Control Studies, Female, Mutation, Genome-Wide Association Study, Medical Genetics, 030217 neurology & neurosurgery
Abstract

Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Published
2020

28. 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

29. 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

30. 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

31. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author

Douglas F. Easton, Manuela Gago-Dominguez, Marina Bermisheva, Marike Gabrielson, Michael J. Madsen, Antoinette Hollestelle, Joe Dennis, Roger L. Milne, Per Hall, Andreas Hadjisavvas, Muriel A. Adank, Melissa C. Southey, Anthony Howell, Qin Wang, Thilo Dörk, Elza Khusnutdinova, Nicola J. Camp, Miguel de la Hoya, Pascal Guénel, Archie Campbell, Gord Glendon, Javier Benitez, Sgbcc Investigators, Manjeet K. Bolla, Jonine D. Figueroa, Paolo Radice, Maaike P.G. Vreeswijk, William G. Newman, Soo Hwang Teo, Anna Jakubowska, Paul D.P. Pharoah, Sara Margolin, Thomas U. Ahearn, Mitul Shah, Eric Hahnen, Matthias W. Beckmann, Dimitrios Mavroudis, Elinor J. Sawyer, Paolo Peterlongo, Artitaya Lophatananon, Melanie Gündert, Maria A. Loizidou, Xueling Sim, Irene L. Andrulis, Ignacio Briceño, Mehdi Manoochehri, Rita K. Schmutzler, Maija Suvanto, Sara Carvalho, Amanda B. Spurdle, Georgia Chenevix-Trench, Marjanka K. Schmidt, Graham G. Giles, Peter A. Fasching, Inge M. M. Lakeman, Vessela N. Kristensen, Leila Dorling, Annika Lindblom, Harald Surowy, Jan C. Oosterwijk, Diana Torres, Nur Aishah Taib, Xiaohong R. Yang, D. Gareth Evans, Päivi Auvinen, Heli Nevanlinna, Sabine Behrens, Arto Mannermaa, Christi J. van Asperen, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Heiko Becher, J. Margriet Collée, Jenny Chang-Claude, Mikael Hartman, Michael T. Parsons, Jamie Allen, Henrik Flyger, Sue K. Park, Craig Luccarini, Sung-Won Kim, Stephan M. Heijl, Montserrat Garcia-Closas, Cristina Fortuno, Jingmei Li, Peter Devilee, Yon-Dschun Ko, Reiner Hoppe, Stig E. Bojesen, Regina Waltes, Frans B. L. Hogervorst, Alison M. Dunning, Kenneth Muir, Mikael Eriksson, Bas Vroling, Jan Lubinski, Jose E. Castelao, Stephen J. Chanock, Natalia Bogdanova, Anders Kvist, Michael Bremer, Emmanouil Saloustros, Kamila Czene, kConFab Investigators, Elaine F. Harkness, Audrey Y. Jung, and Ute Hamann

Subjects
Genetics, 0303 health sciences, PALB2, Biology, medicine.disease, Logistic regression, Lower risk, Breast cancer susceptibility genes, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, medicine, Missense mutation, CHEK2, Gene, 030304 developmental biology
Abstract

BACKGROUNDProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.METHODSCombining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.RESULTSThe most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.CONCLUSIONSThese results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Published
2021

32. BRCA1andBRCA2pathogenic sequence variants in women of African origin or ancestry

Author

Tara Maga, Fabienne Lesueur, Edenir Inêz Palmero, Susan M. Domchek, Tara M. Friebel, Kent Hoskins, Elizabeth J. van Rensburg, Priyanka Sharma, Ava Kwong, Olufunmilayo I. Olopade, Nadine Tung, Georgia Chenevix-Trench, Karen H. Lu, Mark H. Greene, Judy Garber, Mary B. Daly, Irene L. Andrulis, Timothy R. Rebbeck, Ana Vega, Fergus J. Couch, Gord Glendon, Katherine L. Nathanson, Amie Blanco, Jeffrey N. Weitzel, Marc Tischkowitz, William D. Foulkes, Lesley McGuffog, Douglas F. Easton, Annette Lee, Judith Balmaña, Rachel C. Jankowitz, Patricia A. Ganz, Susan L. Neuhausen, Antonis C. Antoniou, Peter J. Hulick, Judy Kirk, Michael T. Parsons, Claudine Isaacs, Dezheng Huo, Beth Y. Karlan, Amanda E. Toland, and Kenneth Offit

Subjects
European community, Black People, Library science, Biology, African origin, Article, 03 medical and health sciences, Breast cancer, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, BRCA2 Protein, 0303 health sciences, Clinical genomics, BRCA1 Protein, 030305 genetics & heredity, Genetic Variation, Cancer, Subject (documents), medicine.disease, Population Surveillance, Mutation, Female, Hereditary Cancer, Research center
Abstract

GEMO: Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons‐en!” Award, Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and French National Institute of Cancer (INCa). Cancer Research UK Grants. Grant Numbers: C1287/A11990, C1287/A10118. University of California Los Angeles: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. Mayo Clinic: NIH, NCI Specialized Program of Research Excellence (SPORE), and a grant from the Breast Cancer Research Foundation. Grant Numbers: CA176785, CA192393, CA116201, CA116167. NCI: Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2‐CP‐11019‐50, N02‐CP‐21013‐63 and N02‐CP‐65504 with Westat, Inc, Rockville, MD. Grant Numbers: N02‐CP‐21013‐63, N02‐CP‐65504, NO2‐CP‐11019‐50. National Cancer Institute. Grant Numbers: RC4CA153828, 5U54CA156732‐07, R25CA112486. FPGMX: Mutua Madrilena Foundation (FMMA). Grant Number: FISPI05/2275. Memorial Sloane Kettering Cancer Center: Breast Cancer Research Foundation, Robert and Kate Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Grant Number: P30 CA008748. Fox Chase Cancer Center: University of Kansas Cancer Center and Kansas Bioscience Authority Eminent Scholar Program and by Chancellors Distinguished Chair in Biomedical Sciences Professorship. Grant Numbers: R01 CA214545, P30 CA168524, R0 1CA140323. BCFR ‐ all: CA164920 from National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. University of Pennsylvania: 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. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Grant Numbers: R01‐CA102776, R01‐CA083855. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Grant Number: 03CA130065. BMBSA is supported by Cancer Association of South Africa. University California San Francisco: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. CIMBA: 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 and ABS are NHMRC Research Fellows. iCOGS: European Community's Seventh Framework Programme under grant agreement n° 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), National Beth Israel Deaconess Medical Center is supported by Breast Cancer Research Foundation. UKFOCR: Cancer Research UK. GEORGETOWN: Non‐Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30‐CA051008), Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Grant Number: P30‐CA051008.

Published
2019

33. Abstract P5-10-01: Using whole genome sequencing and somatic mutation signatures to unravel insight into familial breast cancer aetiology

Author

Heather Thorne, A-M Patch, John F. Pearson, F Newell, Georgia Chenevix-Trench, Sriganesh Srihari, Vanessa Lakis, Katia Nones, Conrad Leonard, Sunil R. Lakhani, J Beasley, Peter T. Simpson, Michael T. Parsons, Mark A. Ragan, Aimee L Davidson, Amanda B. Spurdle, Andrea Degasperi, K. K. Khanna, Oliver Holmes, Julie K. Johnson, Kaltin Ferguson, Stephen H. Kazakoff, Serena Nik-Zainal, Scott Wood, Nick Waddell, Pamela Mukhopadhyay, Qinying Xu, X. M. De Luca, A.E. McCart Reed, and Lynne Reid

Subjects
Genetics, Whole genome sequencing, Cancer Research, Mutation, endocrine system diseases, PALB2, Cancer, Single-nucleotide polymorphism, Biology, medicine.disease, medicine.disease_cause, Germline mutation, Breast cancer, Oncology, medicine, skin and connective tissue diseases, CHEK2
Abstract

Approximately 10-15% of breast cancers are associated with a strong family history of disease. Pathogenic variants in BRCA1, BRCA2 or other moderate to highly penetrant susceptibility genes (e.g. TP53, ATM, CHEK2, PALB2 and PTEN) account for a number of breast cancer families. However, for over 50% of families the underlying genetic contribution to their risk remains unknown (termed here as non-BRCA1/2). This has a profound impact for how individuals and their families are managed in the clinic. We applied whole genome sequencing (WGS) to determine whether somatic mutation analysis can reveal insight into the aetiology of familial breast cancer. The full repertoire of somatic mutations was evaluated in 26 BRCA1, 22 BRCA2 and 32 non-BRCA1/2 tumours; including SNPs, indels, copy number changes and structural rearrangements, and mutational signatures. Genomes were also analysed using the HRD Index and HRDetect, as predictors of homologous recombination deficiency. BRCA1, BRCA2 and non-BRCA1/2 tumours exhibited a different burden of mutations, a different spectrum of mutational signatures and different telomere length. Based on collective patterns of mutation signatures, tumours were classified as 'BRCA1-like', 'BRCA2-like' or 'non-BRCA1/2-like' with a 15% rate of tumour re-classification from their original clinical BRCA status. The results demonstrate the power of WGS to differentiate between BRCA1 and BRCA2 driven tumours; in the identification of double-pathogenic germline mutation carriers based on the resulting somatic mutation signature; and in the interpretation of BRCA unclassified variants. WGS of tumour genomes reveals fascinating insights into tumour aetiology and could compliment current genetic testing of breast cancer families. Citation Format: Simpson P, Nones K, Johnson J, Newell F, Patch A-M, Thorne H, Kazakoff S, De Luca X, Parsons M, Ferguson K, Reid L, McCart Reed A, Srihari S, Lakis V, Davidson A, Mukhopadhyay P, Holmes O, Xu Q, Wood S, Leonard C, Beasley J, Degasperi A, Nik-Zainal S, Ragan M, Spurdle A, Khanna KK, Lakhani S, Pearson J, Chenevix-Trench G, Waddell N. Using whole genome sequencing and somatic mutation signatures to unravel insight into familial breast cancer aetiology [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-01.

Published
2019

34. Contributors

Author

Ana Catarina Alves, Christina Anne Austin-Tse, Mafalda Bourbon, Marcelo A. Carvalho, Ozge Ceyhan-Birsoy, George S. Charames, Joana Rita Chora, Mara Colombo, Xavier de la Cruz, Johan T. den Dunnen, Niels de Wind, Orland Diez, Anna B.R. Elias, D Gareth Evans, Lidia Feliubadaló, Vanessa C. Fernandes, Ivo F.A.C. Fokkema, Cristina Fortuno, Alice Garrett, Paolo Gasparini, Giorgia Girotto, Anna González-Neira, Karen W. Gripp, Sara Gutiérrez-Enríquez, Steven M. Harrison, Miguel de la Hoya, Jodie Ingles, Renee Johnson, Jordan Lerner-Ellis, Harvey Levy, Conxi Lázaro, Heather Mason-Suares, Ana Margarida Medeiros, Jessica L. Mester, Alejandro Moles-Fernández, Alvaro N.A. Monteiro, Anna Morgan, Thales C. Nepomuceno, Rocío Núñez-Torres, Selen Özkan, Natàlia Padilla, Michael T. Parsons, Tina F. Pesaran, Marta Pineda, Paolo Radice, Farrah Rajabi, Ebony Richardson, Peter Sabatini, Stephanie Sacharow, Amanda Spurdle, Bryony A. Thompson, Emma Tudini, Clare Turnbull, Lisa M. Vincent, Michael F. Walsh, and Nicholas Watkins

Published
2021

35. The Impact of Variants at Branchpoint Splicing Elements in Cancer Genes

Author

Satomi Okano, Michael T. Parsons, Troy Dumenil, Bethany Signal, Amanda B. Spurdle, Aimee L Davidson, Tracy A. O'Mara, Tim R. Mercer, Daffodil Canson, and Dylan M. Glubb

Subjects
History, education.field_of_study, Polymers and Plastics, Population, Intron, Computational biology, Biology, Industrial and Manufacturing Engineering, RNA splicing, DNA mismatch repair, Business and International Management, Allele, education, Gene, Function (biology), Minigene
Abstract

Purpose: Branchpoint elements are required for intron removal, and variations at these elements can result in aberrant splicing. We aimed to assess the value of branchpoint annotations generated from recent large-scale studies to select branchpoint-abrogating variants, using hereditary cancer genes as model.Methods: We identified branchpoint elements in 119 genes associated with hereditary cancer from three genome-wide experimentally-inferred and two predicted branchpoint datasets. We then identified variants from public databases that occur within branchpoint elements. We compared conservation, unique variant observations, and population frequencies at different nucleotides within branchpoint motifs. Finally, selected minigene assays were performed to assess the functional impact of variants in branchpoint elements within mismatch repair genes.Results: There was poor overlap between predicted and experimentally-inferred branchpoints. Our analysis of cancer genes suggested that variants at -2nt, -1nt, and branchpoint positions in experimentally-inferred canonical motifs are more likely to be clinically relevant. Minigene assay data showed the -2nt to be more important to branchpoint motif integrity, but also demonstrated fluidity in branchpoint usage.Conclusion: Data from cancer gene analysis suggests that there will be few high-risk alleles that severely impact function via branchpoint abrogation. Results inform a general scheme to prioritize branchpoint motif variants for further study.

Published
2021

36. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Pascal Guénel, John J. Spinelli, Hoda Anton-Culver, Veli-Matti Kosma, Beth Y. Karlan, Antonis C. Antoniou, Brian D. Carter, Drakoulis Yannoukakos, Orland Diez, Montserrat Garcia-Closas, Uffe Birk Jensen, Susan M. Gapstur, Christine L. Clarke, Florentia Fostira, Trinidad Caldés, Wei Zheng, Diana Eccles, Don M. Conroy, Kristan J. Aronson, Sara Margolin, Thomas U. Ahearn, Hedy S. Rennert, Evgeny N. Imyanitov, Rulla M. Tamimi, Mary Beth Terry, Jenny Chang-Claude, Per Hall, Daniel R. Barnes, Alex Teulé, D. Gareth Evans, Åke Borg, Frans B. L. Hogervorst, Yon-Dschun Ko, Celine M. Vachon, Graham G. Giles, Simona Agata, Gad Rennert, Yuan Chun Ding, J. Margriet Collée, Alison M. Dunning, Regina M. Santella, Banu Arun, William J. Tapper, Melissa C. Southey, Finn Cilius Nielsen, Michael T. Parsons, Marjanka K. Schmidt, Alfons Meindl, Vassilios Georgoulias, Simon A. Gayther, Debra Frost, Noura Mebirouk, Hebon Investigators, Austin Miller, Sue K. Park, Anthony J Swerdlow, Emmanouil Saloustros, Isabel dos-Santos-Silva, Laura Ottini, Jack A. Taylor, Siranoush Manoukian, Maria A. Caligo, Douglas F. Easton, Christoph Engel, Antoinette Hollestelle, Ana Vega, Muriel A. Adank, Mia M. Gaudet, Heko Becher, Lothar Haeberle, Priyanka Sharma, Katherine L. Nathanson, Mads Thomassen, Miriam Dwek, Manuela Gago-Dominguez, Hiltrud Brauch, Kamila Czene, Peter A. Fasching, Peter J. Hulick, David E. Goldgar, Lesley McGuffog, Anna Jakubowska, Paul D.P. Pharoah, Adrià López-Fernández, Bruce Poppe, Volker Arndt, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Jennifer Stone, Wendy K. Chung, Joseph Vijai, Qin Wang, Penny Soucy, Miquel Angel Pujana, Diether Lambrechts, Vanesa García-Barberán, Andrea Gehrig, Anna González-Neira, Thérèse Truong, Jenny Lester, Wei He, Dale P. Sandler, Rita K. Schmutzler, Julian Peto, A. Heather Eliassen, Paolo Radice, Yael Laitman, Johanna Rantala, Kelly-Anne Phillips, Amanda E. Toland, Bernardo Bonanni, Muhammad Usman Rashid, Heli Nevanlinna, John L. Hopper, Kevin Punie, kConFab Investigators, Thilo Dörk, Judy Garber, Alison H. Trainer, Irene L. Andrulis, Jeffrey N. Weitzel, Michael Jones, Caroline Baynes, David J. Hunter, Mark S. Goldberg, Kristiina Aittomäki, Barbara Burwinkel, Jonathan Beesley, Maria Rossing, Norbert Arnold, Kathleen Claes, Renske Keeman, Esther M. John, John W.M. Martens, Katie M. O'Brien, Paolo Peterlongo, Mark H. Greene, Tracy A. O'Mara, Saundra S. Buys, Craig Luccarini, Atocha Romero, Paul A. James, Siddhartha Yadav, Zoe Steinsnyder, Diana Torres, Rudolf Kaaks, Camilla Wendt, Fabienne Lesueur, Ana Osorio, Olufunmilayo I. Olopade, Christopher A. Haiman, Agnes Jager, Tricia Lindstrom, Peter Devilee, Kristin K. Zorn, Loic Le Marchand, Darling J. Horcasitas, Michael Lush, Mark E. Robson, Jennifer T. Loud, Roger L. Milne, Lin Fritschi, Johanna I. Kiiski, Eric Hahnen, Jacques Simard, Annelie Augustinsson, Stig E. Bojesen, Kenneth Offit, Nadine Andrieu, Xiaohong R. Yang, Pooja Middha Kapoor, Joe Dennis, Beth N. Peshkin, Nadege Presneau, Darcy L. Thull, Fergus J. Couch, Gunnar Schmidt, Ute Hamann, Susan M. Domchek, Henrik Flyger, Mary B. Daly, Håkan Olsson, Clarice R. Weinberg, Niclas Håkansson, Elza Khusnutdinova, Inge Søkilde Pedersen, Manjeet K. Bolla, Steven N. Hart, Carl Blomqvist, Janet E. Olson, Maren T. Scheuner, Barbara Wappenschmidt, Marc Tischkowitz, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Leslie Bernstein, Mikael Eriksson, José A. García-Sáenz, Jonathan Tyrer, Jose E. Castelao, Peter Kraft, Goska Leslie, Arto Mannermaa, Christopher G. Scott, Jacopo Azzollini, Eitan Friedman, Allison W. Kurian, Katarzyna Białkowska, Argyrios Ziogas, Hermann Brenner, Andrew K. Godwin, Patricia Harrington, Juliette Coignard, Daniele Campa, Susan L. Neuhausen, Marco Montagna, Marina Bermisheva, Alicja Wolk, Eric C. Polley, Abctb Investigators, and Daniel Barrowdale

Subjects
Adult, Genotype, media_common.quotation_subject, Science, Quantitative Trait Loci, General Physics and Astronomy, Breast Neoplasms, 02 engineering and technology, Brca1 brca2, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Linkage Disequilibrium, 03 medical and health sciences, Breast cancer, Cancer epidemiology, Humans, Genetic Predisposition to Disease, Author Correction, Cancer genetics, Alleles, 030304 developmental biology, media_common, BRCA2 Protein, 0303 health sciences, Multidisciplinary, BRCA1 Protein, Published Erratum, General Chemistry, Art, Middle Aged, 021001 nanoscience & nanotechnology, 3. Good health, Risk factors, Mutation, Female, 0210 nano-technology, Humanities, Genome-Wide Association Study
Abstract

Author(s): Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O'Mara, Tracy A; Dennis, Joe; Tyrer, Jonathan P; Barnes, Daniel R; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K; Adank, Muriel A; Agata, Simona; Ahearn, Thomas; Aittomaki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Arun, Banu K; Augustinsson, Annelie; Azzollini, Jacopo; Barrowdale, Daniel; Baynes, Caroline; Becher, Heko; Bermisheva, Marina; Bernstein, Leslie; Bialkowska, Katarzyna; Blomqvist, Carl; Bojesen, Stig E; Bonanni, Bernardo; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campa, Daniele; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen BM; Clarke, Christine L; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J Margriet; Conroy, Don M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M; Dork, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter A; Flyger, Henrik; Fostira, Florentia; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gago-Dominguez, Manuela; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A; Gaudet, Mia M; Gayther, Simon A; Gehrig, Andrea; Georgoulias, Vassilios; Giles, Graham G; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E | Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

Published
2021
Full Text
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37. Classification of genetic variants in hereditary cancer genes

Author

Emma Tudini, Lídia Feliubadaló, Marta Pineda, and Michael T. Parsons

Subjects
Genetics, Mechanism (biology), Genetic variants, Hereditary Cancer, Clinical case, Biology, Pathogenicity, Gene, Loss function, Associated phenotype
Abstract

Since most hereditary cancer genes are tumour suppressor genes, the mechanism of pathogenicity of their variants is the loss of function. This is the case of the 4 example variants included in this chapter. For each of the variants, the presentation of a hypothetical clinical case that support the gene test request is followed by the basic information of the gene, associated phenotype and detected variant. The pathogenicity assessment of each variant is organised according to the data types on which ACMG/AMP recommended criteria are based. If additional data not considered by the ACMG/AMP is available, it is also presented. Finally, a table summarizes the criteria met by the variant and a biological and clinical interpretation is provided.

Published
2021

38. Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Author

Douglas F. Easton, Mads Thomassen, Georgia Chenevix-Trench, Kristiina Aittomäki, Marjanka K. Schmidt, Hebon Investigators, Esther M. John, Irene L. Andrulis, Maartje J. Hooning, Antonis C. Antoniou, Swe-Brca Investigators, Caroline Maria Rossing, Penny Soucy, Jacques Simard, Michael T. Parsons, Julie M. Cunningham, Paul A. James, Joe Dennis, Gabriel Wagner, Melissa C. Southey, Susan M. Domchek, Eric Hahnen, kConFab Investigators, Goska Leslie, Sofia Khan, Katherine L. Nathanson, Rita K. Schmutzler, Anna Jakubowska, Jeffrey N. Weitzel, Taru A. Muranen, Heli Nevanlinna, Barbara Wappenschmidt, Drakoulis Yannoukakos, Judy Garber, Marc Tischkowitz, Conxi Lázaro, Inge Søkilde Pedersen, Carl Blomqvist, Amanda B. Spurdle, Christian F. Singer, Susan L. Slager, Lesley McGuffog, Rainer Fagerholm, Manuel R. Teixeira, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital Area, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Muranen, Taru A. [0000-0002-5895-1808], Cunningham, Julie M. [0000-0002-8159-3025], Dennis, Joe [0000-0003-4591-1214], Leslie, Goska [0000-0001-5756-6222], Parsons, Michael T. [0000-0003-3242-8477], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Spurdle, Amanda B. [0000-0003-1337-7897], Pedersen, Inge Sokilde [0000-0002-9902-8040], Nathanson, Katherine L. [0000-0002-6740-0901], Lazaro, Conxi [0000-0002-7198-5906], Andrulis, Irene L. [0000-0002-4226-6435], Teixeira, Manuel R. [0000-0002-4896-5982], James, Paul [0000-0002-4361-4657], Weitzel, Jeffrey N. [0000-0001-6714-092X], Jakubowska, Anna [0000-0002-5650-0501], Yannoukakos, Drakoulis [0000-0001-7509-3510], Schmidt, Marjanka K. [0000-0002-2228-429X], Nevanlinna, Heli [0000-0002-0916-2976], Apollo - University of Cambridge Repository, Muranen, Taru A [0000-0002-5895-1808], Cunningham, Julie M [0000-0002-8159-3025], Parsons, Michael T [0000-0003-3242-8477], Easton, Douglas F [0000-0003-2444-3247], Spurdle, Amanda B [0000-0003-1337-7897], Nathanson, Katherine L [0000-0002-6740-0901], Andrulis, Irene L [0000-0002-4226-6435], Teixeira, Manuel R [0000-0002-4896-5982], Weitzel, Jeffrey N [0000-0001-6714-092X], and Schmidt, Marjanka K [0000-0002-2228-429X]

Subjects
0301 basic medicine, Oncology, Etiology, Genome-wide association study, Genome-wide association studies, Germline, 0302 clinical medicine, Breast cancer, PRIMARY THERAPY, Pharmacology (medical), skin and connective tissue diseases, Cancer genetics, RISK, medicine.diagnostic_test, Hazard ratio, article, INTERNATIONAL EXPERT CONSENSUS, Tumor Pathology, OVARIAN, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, Etiologia, EXPRESSION, medicine.medical_specialty, GENES, 3122 Cancers, 631/208/205/2138, lcsh:RC254-282, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, 631/67/68, Genetic variation, REVEALS, medicine, Radiology, Nuclear Medicine and imaging, Genetic testing, IDENTIFICATION, business.industry, FALSE DISCOVERY, Cancer, medicine.disease, 030104 developmental biology, CELLS, 692/4028/67/1347, business
Abstract

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03–6.30, P = 3.1 × 10−9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

Published
2020

39. 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

40. 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

41. Considerations in assessing germline variant pathogenicity using cosegregation analysis

Author

Sophie, Belman, Michael T, Parsons, Amanda B, Spurdle, David E, Goldgar, and Bing-Jian, Feng

Subjects
Germ Cells, Virulence, Mutation, Genetic Variation, Humans, Bayes Theorem, Genetic Testing, Sequence Analysis, DNA
Abstract

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have developed guidelines for classifying germline variants as pathogenic or benign to interpret genetic testing results. Cosegregation analysis is an important component of the guidelines. There are two main approaches for cosegregation analysis: meiosis counting and Bayes factor-based quantitative methods. Of these, the ACMG/AMP guidelines employ only meiosis counting. The accuracy of either approach has not been sufficiently addressed in previous works.We analyzed hypothetical, simulated, and real-life data to evaluate the accuracy of each approach for cancer-associated genes.We demonstrate that meiosis counting can provide incorrect classifications when the underlying genetic basis of the disease departs from simple Mendelian situations. Some Bayes factor approaches are currently implemented with inappropriate penetrance. We propose an improved penetrance model and describe several critical considerations, including the accuracy of cosegregation for moderate-risk genes and the impact of pleiotropy, population, and birth year. We highlight a webserver, COOL (Co-segregation Online, http://BJFengLab.org/ ), that implements an accurate Bayes factor cosegregation analysis.An appropriate penetrance model improves the accuracy of Bayes factor cosegregation analysis for high-penetrant variants, and is a better choice than meiosis counting whenever feasible.

Published
2020

42. 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

43. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls

Author

Amanda B. Spurdle, Koichi Matsuda, Yoshio Miki, Teruhiko Yoshida, Kokichi Sugano, Atsushi Takahashi, Chieko Tamura, Yukihide Momozawa, Yusuke Iwasaki, Toyomasa Katagiri, Michael T. Parsons, Makoto Hirata, Yoichiro Kamatani, Seigo Nakamura, and Michiaki Kubo

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, PALB2, Science, General Physics and Astronomy, Breast Neoplasms, General Biochemistry, Genetics and Molecular Biology, Germline, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Breast cancer, Asian People, Internal medicine, medicine, PTEN, Humans, lcsh:Science, skin and connective tissue diseases, Gene, Germ-Line Mutation, Aged, Aged, 80 and over, Multidisciplinary, biology, business.industry, Case-control study, General Chemistry, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, biology.protein, lcsh:Q, Female, business, Hereditary Breast Cancer
Abstract

Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed, Association between variants in 11 different genes and breast cancer risk has been established and sequencing of these genes is recommended to provide personalized diagnosis, therapy, and surveillance for the high-risk patients and their relatives. Here the authors analyse the frequency of germline pathogenic mutations in these genes specifically in a Japanese population.

Published
2018

44. Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation

Author

Bryony, A Thompson 1 2, Rhiannon Walters, 3, Michael, T Parsons 3, Troy Dumenil, 3, Mark Drost, 4, Yvonne Tiersma, 4, Noralane, M Lindor 5, Sean, V Tavtigian 6, Niels de Wind, 4, Amanda, B Spurdle 3, Genuardi, Maurizio, InSiGHT Variant Interpretation Collaborators, Affiliations expand, Genuardi M. (ORCID:0000-0002-7410-8351), Bryony, A Thompson 1 2, Rhiannon Walters, 3, Michael, T Parsons 3, Troy Dumenil, 3, Mark Drost, 4, Yvonne Tiersma, 4, Noralane, M Lindor 5, Sean, V Tavtigian 6, Niels de Wind, 4, Amanda, B Spurdle 3, Genuardi, Maurizio, InSiGHT Variant Interpretation Collaborators, Affiliations expand, and Genuardi M. (ORCID:0000-0002-7410-8351)

Abstract

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants. Keywords: Lynch syndrome; mRNA splicing; mismatch repair genes; splicing aberrations; variant interpretation and classification; variant type.

Published
2020

45. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort

Author

Gérald Le Gac, Alexandra Martins, Pascaline Gaildrat, Florence Coulet, Françoise Revillon, Antoine Rousselin, Sandrine M. Caputo, Marine Guillaud-Bataille, Chandran Ka, Mélanie Léoné, Nadia Boutry-Kryza, Virginie Caux-Moncoutier, Claude Férec, Capucine Delnatte, Danielle Muller, Grégoire Davy, Amanda B. Spurdle, Maria Rossing, Raphaël Leman, Yann Fichou, Michael T. Parsons, Barbara Wappenschmidt, Violaine Bourdon, Joanna Sokolowska, Nicolas Sevenet, Claude Houdayer, M.-P. Audrézet, Brigitte Bressac-de Paillerets, Françoise Bonnet-Dorion, Sylvie Mazoyer, Gaia Castelain, Sophie Krieger, Laurent Castera, Etienne Rouleau, 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), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Institut Curie [Paris], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University Hospital of Cologne [Cologne], IT University of Copenhagen (ITU), Centre Paul Strauss, CRLCC Paul Strauss, Laboratoire d'oncogénétique moléculaire, Unite d'Oncogenese Virale, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, QIMR Berghofer Medical Research Institute, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang Bretagne, EFS, Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), COMBE, Isabelle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IT University of Copenhagen, Institut Gustave Roussy (IGR), Service d'Oncologie Génétique, de Prévention et Dépistage, Laboratoire d'Oncologie Moléculaire Humaine, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, CHU Pontchaillou [Rennes], Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre René Gauducheau, and CRLCC René Gauducheau

Subjects
0301 basic medicine, International Cooperation, RNA Splicing, In silico, Spice, Breast Neoplasms, Computational biology, Biology, Sensitivity and Specificity, Set (abstract data type), 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Consensus sequence, RNA and RNA-protein complexes, Humans, Computer Simulation, 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, Internet, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], BRCA1 Protein, Intron, Computational Biology, Genetic Variation, Reproducibility of Results, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], In vitro, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA Splice Sites, RNA characterisation and manipulation, Corrigendum, Computational Methods, Optimal decision
Abstract

Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5′ and 3′ consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).

Published
2018

46. A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author

Adriaan Vanderstichele, Kenneth Offit, Anna H. Wu, Claudine Isaacs, Mary B. Daly, Jamie K. Teer, Jacek Gronwald, Diana Eccles, Heli Nevanlinna, Javier Benitez, Dale P. Sandler, Maria A. Caligo, Priyanka Sharma, Mary Anne Rossing, Thilo Dörk, Hae Kyung Im, Hoda Anton-Culver, Fergus J. Couch, Douglas A. Levine, Judy Garber, Marc Tischkowitz, Edith Olah, Ute Hamann, Rita K. Schmutzler, Soo Hwang Teo, Ralf Bützow, Amanda E. Toland, Robert L. Nussbaum, Michael T. Parsons, Drakoulis Yannoukakos, Jeffrey N. Weitzel, Georgia Chenevix-Trench, Francesmary Modugno, Yingchang Lu, Manuel R. Teixeira, Jirong Long, Honglin Song, Antonis C. Antoniou, Susan J. Ramus, Elizabeth J. van Rensburg, Gad Rennert, Douglas F. Easton, Evgeny N. Imyanitov, Andrew Berchuck, Tanja Pejovic, Amanda B. Spurdle, Florian Heitz, Catherine M. Phelan, Nhu D. Le, Lang Wu, David G. Huntsman, Renée T. Fortner, Beth Y. Karlan, Irene L. Andrulis, Matti A. Rookus, Anthony J. Swerdlow, Miguel Angel Pujana, Christian F. Singer, Amalia Mattiello, George Fountzilas, Banu Arun, Shelley S. Tworoger, Graham G. Giles, Liene Nikitina-Zake, Kirsten B. Moysich, Nadine Tung, Mads Thomassen, Trinidad Caldés, Wei Zheng, Digna R. Velez Edwards, Kathleen Claes, Nicolas Wentzensen, Gustavo C. Rodriguez, Thomas A. Sellers, Ellen L. Goode, Daniel R. Barnes, Susan L. Neuhausen, Alicja Wolk, Andrew K. Godwin, Taymaa May, Olufunmilayo I. Olopade, Yian Ann Chen, Brett M. Reid, Line Bjørge, Fabienne Lesueur, Weiva Sieh, Kristin K. Zorn, Jacques Simard, Peter J. Hulick, Melissa C. Southey, Finn Cilius Nielsen, Ava Kwong, Sue K. Park, Joellen M. Schildkraut, Peter A. Fasching, Lesley McGuffog, Ana Vega, Antonia Trichopoulou, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Paul A. James, Claus Høgdall, Lambertus A. Kiemeney, Susanne K. Kjaer, Sara H. Olson, Ana Osorio, Jenny Chang-Claude, Cristina Rodríguez-Antona, Isabelle Romieu, Iwona K. Rzepecka, Iain A. McNeish, Xingyi Guo, Eitan Friedman, Marco Montagna, Marc T. Goodman, Goska Leslie, Melissa A. Merritt, Emily White, Penelope M. Webb, Jennifer B. Permuth, Patricia A. Ganz, Antoinette Hollestelle, Paolo Peterlongo, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Joe Dennis, Petra H.M. Peeters, Veronica Wendy Setiawan, Susan M. Domchek, Rosa B. Barkardottir, Simon A. Gayther, Mark H. Greene, Harvey A. Risch, Orland Diez, Anna deFazio, Ian G. Campbell, Daniel W. Cramer, Linda E. Kelemen, Elisa V. Bandera, Bingshan Li, Håkan Olsson, James D. Brenton, and Medical Oncology

Subjects
0301 basic medicine, Cancer Research, endocrine system diseases, Carcinogenesis, LOCI, Genome-wide association study, CORTICOTROPIN-RELEASING HORMONE, Carcinoma, Ovarian Epithelial, VARIANTS, Transcriptome, Cohort Studies, Risk Factors, MULTIPLE, GWAS, Genetics, Ovarian Neoplasms, Prognosis, female genital diseases and pregnancy complications, 3. Good health, HOXB2, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, EXPRESSION, Genotype, Quantitative Trait Loci, Locus (genetics), Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Gene, Genotyping, Genetic association, Science & Technology, IDENTIFICATION, Gene Expression Profiling, Gene expression profiling, 030104 developmental biology, IN-VITRO FERTILIZATION, Genome-Wide Association Study
Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Published
2018

47. A plugin for the Ensembl Variant Effect Predictor that uses MaxEntScan to predict variant spliceogenicity

Author

Amanda B. Spurdle, Michael T. Parsons, Stephen H. Kazakoff, Nicola Waddell, Jannah Shamsani, Bryony A. Thompson, Tracy A. O'Mara, Will McLaren, Irina M. Armean, and Sarah E. Hunt

Subjects
Statistics and Probability, Source code, Computer science, media_common.quotation_subject, RNA Splicing, Computational biology, computer.software_genre, ENCODE, Biochemistry, 03 medical and health sciences, Ensembl, Plug-in, Molecular Biology, Gene, 030304 developmental biology, media_common, 0303 health sciences, 030302 biochemistry & molecular biology, Exons, Genome Analysis, Applications Notes, Introns, Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, RNA splicing, computer, Algorithms, Software
Abstract

Summary Assessing the pathogenicity of genetic variants can be a complex and challenging task. Spliceogenic variants, which alter mRNA splicing, may yield mature transcripts that encode non-functional protein products, an important predictor of Mendelian disease risk. However, most variant annotation tools do not adequately assess spliceogenicity outside the native splice site and thus the disease-causing potential of variants in other intronic and exonic regions is often overlooked. Here, we present a plugin for the Ensembl Variant Effect Predictor that packages MaxEntScan and extends its functionality to provide splice site predictions using a maximum entropy model. The plugin incorporates a sliding window algorithm to predict splice site loss or gain for any variant that overlaps a transcript feature. We also demonstrate the utility of the plugin by comparing our predictions to two mRNA splicing datasets containing several cancer-susceptibility genes. Availability and implementation Source code is freely available under the Apache License, Version 2.0: https://github.com/Ensembl/VEP_plugins. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2018

48. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Christine L. Clarke, Pierre Laurent-Puig, Mary B. Daly, Jacek Gronwald, Douglas F. Easton, M. B. Terry, Dominique Stoppa-Lyonnet, Mads Thomassen, Fergus J. Couch, José A. García-Sáenz, Mariarosaria Calvello, Florentia Fostira, Nadine Tung, Manuela Gago-Dominguez, Gad Rennert, Ute Hamann, Brigitte Rack, Csilla Szabo, Rudolf Kaaks, Kamila Czene, Simon A. Gayther, Sabine Behrens, John L. Hopper, kConFab Investigators, Barbara Burwinkel, Anne-Vibeke Lænkholm, Elaine F. Harkness, Audrey Y. Jung, János Papp, Usha Menon, Stephen J. Chanock, Lenka Foretova, Andrew K. Godwin, Snezhana Smichkoska, William J. Tapper, Melissa Christiaens, Muhammad Usman Rashid, Per Hall, Ana Vega, Elke M van Veen, Kathleen Claes, Pascal Guénel, Jennifer T. Loud, Roger L. Milne, Vessela N. Kristensen, Katarzyna Białkowska, Xia Jiang, Manuel R. Teixeira, Antoinette Hollestelle, Debra Frost, Noura Mebirouk, Beth N. Peshkin, Olufunmilayo I. Olopade, Bernd Holleczek, Andreas Schneeweiss, Hermann Brenner, Jeffrey N. Weitzel, Goska Leslie, Stig E. Bojesen, Peter J. Hulick, Xiaohong R. Yang, Mark S. Goldberg, Ignacio Briceño, Heli Nevanlinna, Maren T. Scheuner, Thilo Dörk, John J. Spinelli, Tracy A. O'Mara, Maria A. Caligo, Claire Mulot, Nick Orr, Anna González-Neira, Sara Y Brucker, Darcy L. Thull, Darya Prokofyeva, Paul L. Auer, Hans Wildiers, Jan Lubinski, Jose E. Castelao, Diana Eccles, Priyanka Sharma, Jonine D. Figueroa, Maria Elena Martinez, Wendy K. Chung, Rulla M. Tamimi, Taru A. Muranen, Wing-Yee Lo, Rob A. E. M. Tollenaar, Thomas Rüdiger, Natalia Bogdanova, Louise Izatt, Ben Schöttker, Thomas U. Ahearn, Hedy S. Rennert, Claudine Isaacs, Embrace Study, Jennifer Stone, Jolanta Lissowska, D. Gareth Evans, Matthias W. Beckmann, Peter Schürmann, Qin Wang, Orland Diez, Christopher R. Hake, Mehdi Manoochehri, Peter A. Fasching, Lesley McGuffog, Haoyu Zhang, Joe Dennis, Hanna Huebner, Judy Garber, Drakoulis Yannoukakos, Kenneth Offit, Yon-Dschun Ko, Celine M. Vachon, Robert N. Hoover, Marc Tischkowitz, Pooja Middha Kapoor, Agnes Jager, Davide Bondavalli, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Marjanka K. Schmidt, Edith Olah, Laura Papi, Conxi Lázaro, Arif B. Ekici, Paolo Radice, Austin Miller, Kristan J. Aronson, Harvey A. Risch, Jack A. Taylor, Robert Winqvist, Jacques Simard, Catriona McLean, Michael T. Parsons, Wei Zheng, Linetta B. Koppert, Susan M. Gapstur, Georgia Chenevix-Trench, Susan M. Domchek, Tjoung-Won Park-Simon, Zumuruda Abu Ful, Javier Benitez, Clarice R. Weinberg, Kyriaki Michailidou, Alfons Meindl, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Ana Blanco, Nilanjan Chatterjee, Montserrat Garcia-Closas, Thomas Brüning, Rita K. Schmutzler, Lizet E. van der Kolk, Peter Hillemanns, Beth Y. Karlan, Hoda Anton-Culver, Ans M.W. van den Ouweland, Banu Arun, J. Peto, Anthony J. Swerdlow, Marco Montagna, Ana Peixoto, Emmanouil Saloustros, Peter Kraft, Mark H. Greene, Evgeny N. Imyanitov, Siranoush Manoukian, Diether Lambrechts, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Milena Jakimovska, Dijana Plaseska-Karanfilska, Kristiina Aittomäki, Johanna Rantala, Kelly-Anne Phillips, Melissa A. Troester, Michael Untch, Susan J. Ramus, Arto Mannermaa, Christian F. Singer, Abctb Investigators, Bernard Peissel, Daniel Barrowdale, Elinor J. Sawyer, Jacopo Azzollini, Leigha Senter, Antonis C. Antoniou, Barbara Wappenschmidt, Hiltrud Brauch, Heiko Becher, Julie Lecarpentier, Sarah Sampson, Jonathan Beesley, Eitan Friedman, Dale P. Sandler, Minouk J. Schoemaker, Irene L. Andrulis, Paolo Peterlongo, Saundra S. Buys, Stella Koutros, Lothar Häberle, Christopher A. Haiman, Fabienne Lesueur, Cari M. Kitahara, Peter Devilee, Kristin K. Zorn, Karolina Prajzendanc, Monica Zuradelli, Simon S. Cross, William G. Newman, Ni Zhao, Jesse Nodora, Susanna C. Larsson, Helen Byers, Flavio Lejbkowicz, Trinidad Caldés, Eric Hahnen, Laura Matricardi, Daniel R. Barnes, Mark E. Sherman, Åke Borg, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Diana Torres, Penny Soucy, Bernardo Bonanni, Ross L. Prentice, Marion Piedmonte, Xiao-Ou Shu, Elvira Mingazheva, Elza Khusnutdinova, Patrick Neven, Renske Keeman, Matti A. Rookus, Manjeet K. Bolla, Atocha Romero, Robert J. MacInnis, Jenny Chang-Claude, Irene Konstantopoulou, Emilija Lazarova, Annegien Broeks, Carl Blomqvist, Annika Lindblom, Bernadette A M Heemskerk-Gerritsen, Matthias Rübner, Graham G. Giles, Hans Christiansen, Liene Nikitina-Zake, Håkan Olsson, Wolfgang Janni, Sofia Khan, Katherine L. Nathanson, Alicja Lukomska, Miriam Dwek, Sara Margolin, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Elizabeth J. van Rensburg, Michael Jones, Frans B. L. Hogervorst, Esther M. John, Alison M. Dunning, Daniele Campa, Guanghao Qi, Sten Cornelissen, and Paul A. James

Subjects
0303 health sciences, Estrogen receptor, Genome-wide association study, Biology, medicine.disease, Tumor heterogeneity, 3. Good health, Tumor Subtype, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Progesterone receptor, Susceptibility locus, medicine, Cancer research, Human Epidermal Growth Factor Receptor 2, 030304 developmental biology
Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate PIn-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Published
2019
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49. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Karina Dalsgaard Sørensen, Mattias Johansson, Manjeet K. Bolla, Kay-Tee Khaw, Carl Blomqvist, Joan Brunet, Robert L. Ferris, Graham G. Giles, Ruth C. Travis, Philip Lazarus, Stephan Lam, Stella Koutros, Michael Hoffmeister, Liene Nikitina-Zake, Adonina Tardón, Christopher I. Amos, Emmanouil Saloustros, Christopher K. Edlund, Jacqueline M. Lane, Ana Osorio, Dijana Plaseska-Karanfilska, Catherine M. Tangen, Brenda Diergaarde, Mark C. Weissler, Diana Eccles, Per Hall, Mark H. Greene, Pascal Guénel, Amanda B. Spurdle, Marco Montagna, Sara Margolin, Gary E. Goodman, Irene L. Andrulis, Hongbing Shen, Barry S. Rosenstein, Hedy S. Rennert, Julie M. Cunningham, Paul Brennan, Jeroen R. Huyghe, Andrew T. Chan, Henrik Grönberg, Orland Diez, Hiltrud Brauch, Eunjung Lee, Trinidad Caldés, V. Wendy Setiawan, Matthias W. Beckmann, Angeline S. Andrew, Pooja Middha, Shelley S. Tworoger, Maria Teresa Landi, Alison M. Dunning, Jenny Lester, Angela Cox, Daniel R. Barnes, Jong Y. Park, Renée T. Fortner, Peter Kraft, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Tabea Kühl, Dale P. Sandler, Jeri Kim, Sue A. Ingles, Andy R Ness, Younghun Han, Marc Tischkowitz, Evgeny N. Imyanitov, Annika Lindblom, Ralf Bützow, Austin Miller, Kamila Czene, Jochen Hampe, Robert J. Hamilton, José A. García-Sáenz, Kenneth Muir, Wei Zheng, Gad Rennert, Johanna Schleutker, Mary Anne Rossing, Thilo Dörk, Andrew Berchuck, Angela Risch, Jyotsna Batra, Michael O. Woods, Julia A. Knight, Elinor J. Sawyer, Kim De Ruyck, Douglas F. Easton, Jeffrey N. Weitzel, Anna H. Wu, Børge G. Nordestgaard, Francesmary Modugno, Alkes L. Price, Douglas A. Levine, Lorelei A. Mucci, John L. Hopper, Davor Lessel, Javier Benitez, Richard S. Houlston, Diana Torres, Corina Lesseur, Arto Mannermaa, Daniel D. Buchanan, Mary B. Daly, Xifeng Wu, Matthew B. Schabath, Barbara Burwinkel, Bogdan Pasaniuc, Graham Casey, Peter A. Fasching, David G. Huntsman, Mads Thomassen, Manuela Gago-Dominguez, Lesley McGuffog, Christian F. Singer, Patricia A. Ganz, Manolis Kogevinas, Andrew F. Olshan, André Lopes Carvalho, Polly A. Newcomb, Banu Arun, Sonja I. Berndt, Niclas Håkansson, Leon Raskin, Marc T. Goodman, M. Dawn Teare, Hoda Anton-Culver, Fergus J. Couch, Christopher I. Li, Peter Devilee, Kristin K. Zorn, Neil E. Caporaso, Chu Chen, Kenneth Offit, Eitan Friedman, Natalia Antonenkova, Ute Hamann, Karin Sundfeldt, Stephanie A. Bien, Weiva Sieh, Rosalind A. Eeles, Claudine Isaacs, Maria A. Caligo, Nhu D. Le, Ulrike Peters, Triantafillos Liloglou, Stefania Boccia, Jacques Simard, Melissa C. Southey, Kathleen Claes, Darya Prokofyeva, Heike Bickeböller, Argyrios Ziogas, Sebastian Stintzing, Rayjean J. Hung, Carolina Ellberg, Rolando Herrero, Jennifer Stone, David C. Christiani, Mikael Johansson, Wilbert H.M. Peters, Montserrat Garcia-Closas, Jan Lubinski, Marcia Cruz Correa, Gabriella Cadoni, Rebecca Sutphen, Cornelia M. Ulrich, Paul A. Townsend, Qin Wang, Li Li, Nadine Tung, Ellen L. Goode, Silvia Franceschi, Lisa A. Cannon-Albright, Finn Cilius Nielsen, Stephanie L. Schmit, Antonis C. Antoniou, Clarice R. Weinberg, Kyriaki Michailidou, Susanne M. Arnold, Li Hsu, Natalia Bogdanova, Victor Moreno, Paolo Radice, Peter Hillemanns, Eloiza H. Tajara, Olufunmilayo I. Olopade, Stephen B. Gruber, Heli Nevanlinna, Kari Stefansson, Yun-Chul Hong, Amit Joshi, Emily White, Peter J. Hulick, Aage Haugen, Sara Benlloch, Mark A. Jenkins, Xia Jiang, Peter T. Campbell, Jack A. Taylor, Christopher A. Haiman, Jenny L Donovan, Roger L. Milne, Stephen J. Chanock, Judy Garber, Stig E. Bojesen, Taymaa May, David E. Neal, Kirsten B. Moysich, Jane C. Figueiredo, Alfons Meindl, Georgia Chenevix-Trench, Frank Claessens, Melinda C. Aldrich, Gregory Idos, Robert L. Nussbaum, Robert Winqvist, Tanja Pejovic, H-Erich Wichmann, Diether Lambrechts, Eric J. Duell, Demetrius Albanes, Drakoulis Yannoukakos, Kathryn L. Penney, Loic Le Marchand, Florian Heitz, Beth Y. Karlan, Lovise Maehle, Fotios Loupakis, Ana Vega, Zsofia Kote-Jarai, Marjorie J. Riggan, Stephen N. Thibodeau, Fredrik Wiklund, Steven Gallinger, Hans Brunnström, Geoffrey Liu, Duncan Thomas, Kathryn L. Terry, Els Van Nieuwenhuysen, Anthony J. Swerdlow, Miguel E. Aguado-Barrera, Nawaid Usmani, Mia M. Gaudet, David J. Hunter, Estrid Høgdall, Kristan J. Aronson, Vessela N. Kristensen, Line Bjørge, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Flavio Lejbkowicz, Jonathan Tyrer, James D. Brenton, Alice S. Whittemore, Catharine M L West, Goska Leslie, Jacek Gronwald, Martha L. Slattery, Christiane Maier, Radka Kaneva, Joe Dennis, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Erin M. Siegel, Paul A. James, Penella J. Woll, Catherine M. Phelan, Susan J. Ramus, Olivia Fletcher, Hermann Brenner, Geraldine Cancel-Tassin, Marjanka K. Schmidt, D. Gareth Evans, Manuel R. Teixeira, Amanda I. Phipps, Jolanta Kupryjanczyk, Penelope M. Webb, James McKay, Shanbeh Zienolddiny, Sara Lindström, Lambertus A. Kiemeney, Celine M. Vachon, Ali Amin Al Olama, Edith Olah, Andrew K. Godwin, Victoria L. Stevens, Mark N. Brook, Fredrick R. Schumacher, Digna R. Velez Edwards, Lisa F. Newcomb, Michael T. Parsons, David V. Conti, J. Margriet Collée, Rosa B. Barkardottir, Simon A. Gayther, Miranda Pring, Harvey A. Risch, Karoline Kuchenbaecker, Martin Lacko, Judith A. Clements, Mark S. Goldberg, Adam S. Kibel, Robert J. MacInnis, Richa Saxena, Heinz-Josef Lenz, Linda E. Kelemen, Stephanie J. Weinstein, Elisa V. Bandera, Freddie C. Hamdy, Håkan Olsson, Cezary Cybulski, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Nora Pashayan, Hilary K. Finucane, Hardev Pandha, Susan L. Neuhausen, Alicja Wolk, Elizabeth J. van Rensburg, Esther M. John, Daniele Campa, Kjell Grankvist, Janet L. Stanford, Miriam Dwek, Susanne K. Kjaer, Monique J. Roobol, and Elza Khusnutdinova

Subjects
Genetics, 0303 health sciences, Multidisciplinary, business.industry, Published Erratum, Science, MEDLINE, General Physics and Astronomy, General Chemistry, Heritability, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, lcsh:Q, lcsh:Science, business, solid cancers, 030304 developmental biology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

50. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Haoyu, Zhang, Thomas U, Ahearn, Julie, Lecarpentier, Daniel, Barnes, Jonathan, Beesley, Guanghao, Qi, Xia, Jiang, Tracy A, O'Mara, Ni, Zhao, Manjeet K, Bolla, Alison M, Dunning, Joe, Dennis, Qin, Wang, Zumuruda Abu, Ful, Kristiina, Aittomäki, Irene L, Andrulis, Hoda, Anton-Culver, Volker, Arndt, Kristan J, Aronson, Banu K, Arun, Paul L, Auer, Jacopo, Azzollini, Daniel, Barrowdale, Heiko, Becher, Matthias W, Beckmann, Sabine, Behrens, Javier, Benitez, Marina, Bermisheva, Katarzyna, Bialkowska, Ana, Blanco, Carl, Blomqvist, Natalia V, Bogdanova, Stig E, Bojesen, Bernardo, Bonanni, Davide, Bondavalli, Ake, Borg, Hiltrud, Brauch, Hermann, Brenner, Ignacio, Briceno, Annegien, Broeks, Sara Y, Brucker, Thomas, Brüning, Barbara, Burwinkel, Saundra S, Buys, Helen, Byers, Trinidad, Caldés, Maria A, Caligo, Mariarosaria, Calvello, Daniele, Campa, Jose E, Castelao, Jenny, Chang-Claude, Stephen J, Chanock, Melissa, Christiaens, Hans, Christiansen, Wendy K, Chung, Kathleen B M, Claes, Christine L, Clarke, Sten, Cornelissen, Fergus J, Couch, Angela, Cox, Simon S, Cross, Kamila, Czene, Mary B, Daly, Peter, Devilee, Orland, Diez, Susan M, Domchek, Thilo, Dörk, Miriam, Dwek, Diana M, Eccles, Arif B, Ekici, D Gareth, Evans, Peter A, Fasching, Jonine, Figueroa, Lenka, Foretova, Florentia, Fostira, Eitan, Friedman, Debra, Frost, Manuela, Gago-Dominguez, Susan M, Gapstur, Judy, Garber, José A, García-Sáenz, Mia M, Gaudet, Simon A, Gayther, Graham G, Giles, Andrew K, Godwin, Mark S, Goldberg, David E, Goldgar, Anna, González-Neira, Mark H, Greene, Jacek, Gronwald, Pascal, Guénel, Lothar, Häberle, Eric, Hahnen, Christopher A, Haiman, Christopher R, Hake, Per, Hall, Ute, Hamann, Elaine F, Harkness, Bernadette A M, Heemskerk-Gerritsen, Peter, Hillemanns, Frans B L, Hogervorst, Bernd, Holleczek, Antoinette, Hollestelle, Maartje J, Hooning, Robert N, Hoover, John L, Hopper, Anthony, Howell, Hanna, Huebner, Peter J, Hulick, Evgeny N, Imyanitov, Claudine, Isaacs, Louise, Izatt, Agnes, Jager, Milena, Jakimovska, Anna, Jakubowska, Paul, James, Ramunas, Janavicius, Wolfgang, Janni, Esther M, John, Michael E, Jones, Audrey, Jung, Rudolf, Kaaks, Pooja Middha, Kapoor, Beth Y, Karlan, Renske, Keeman, Sofia, Khan, Elza, Khusnutdinova, Cari M, Kitahara, Yon-Dschun, Ko, Irene, Konstantopoulou, Linetta B, Koppert, Stella, Koutros, Vessela N, Kristensen, Anne-Vibeke, Laenkholm, Diether, Lambrechts, Susanna C, Larsson, Pierre, Laurent-Puig, Conxi, Lazaro, Emilija, Lazarova, Flavio, Lejbkowicz, Goska, Leslie, Fabienne, Lesueur, Annika, Lindblom, Jolanta, Lissowska, Wing-Yee, Lo, Jennifer T, Loud, Jan, Lubinski, Alicja, Lukomska, Robert J, MacInnis, Arto, Mannermaa, Mehdi, Manoochehri, Siranoush, Manoukian, Sara, Margolin, Maria Elena, Martinez, Laura, Matricardi, Lesley, McGuffog, Catriona, McLean, Noura, Mebirouk, Alfons, Meindl, Usha, Menon, Austin, Miller, Elvira, Mingazheva, Marco, Montagna, Anna Marie, Mulligan, Claire, Mulot, Taru A, Muranen, Katherine L, Nathanson, Susan L, Neuhausen, Heli, Nevanlinna, Patrick, Neven, William G, Newman, Finn C, Nielsen, Liene, Nikitina-Zake, Jesse, Nodora, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Håkan, Olsson, Nick, Orr, Laura, Papi, Janos, Papp, Tjoung-Won, Park-Simon, Michael T, Parsons, Bernard, Peissel, Ana, Peixoto, Beth, Peshkin, Paolo, Peterlongo, Julian, Peto, Kelly-Anne, Phillips, Marion, Piedmonte, Dijana, Plaseska-Karanfilska, Karolina, Prajzendanc, Ross, Prentice, Darya, Prokofyeva, Brigitte, Rack, Paolo, Radice, Susan J, Ramus, Johanna, Rantala, Muhammad U, Rashid, Gad, Rennert, Hedy S, Rennert, Harvey A, Risch, Atocha, Romero, Matti A, Rookus, Matthias, Rübner, Thomas, Rüdiger, Emmanouil, Saloustros, Sarah, Sampson, Dale P, Sandler, Elinor J, Sawyer, Maren T, Scheuner, Rita K, Schmutzler, Andreas, Schneeweiss, Minouk J, Schoemaker, Ben, Schöttker, Peter, Schürmann, Leigha, Senter, Priyanka, Sharma, Mark E, Sherman, Xiao-Ou, Shu, Christian F, Singer, Snezhana, Smichkoska, Penny, Soucy, Melissa C, Southey, John J, Spinelli, Jennifer, Stone, Dominique, Stoppa-Lyonnet, Anthony J, Swerdlow, Csilla I, Szabo, Rulla M, Tamimi, William J, Tapper, Jack A, Taylor, Manuel R, Teixeira, MaryBeth, Terry, Mads, Thomassen, Darcy L, Thull, Marc, Tischkowitz, Amanda E, Toland, Rob A E M, Tollenaar, Ian, Tomlinson, Diana, Torres, Melissa A, Troester, Thérèse, Truong, Nadine, Tung, Michael, Untch, Celine M, Vachon, Ans M W, van den Ouweland, Lizet E, van der Kolk, Elke M, van Veen, Elizabeth J, vanRensburg, Ana, Vega, Barbara, Wappenschmidt, Clarice R, Weinberg, Jeffrey N, Weitzel, Hans, Wildiers, Robert, Winqvist, Alicja, Wolk, Xiaohong R, Yang, Drakoulis, Yannoukakos, Wei, Zheng, Kristin K, Zorn, Roger L, Milne, Peter, Kraft, Jacques, Simard, Paul D P, Pharoah, Kyriaki, Michailidou, Antonis C, Antoniou, Marjanka K, Schmidt, Georgia, Chenevix-Trench, Douglas F, Easton, Nilanjan, Chatterjee, and Montserrat, García-Closas

Subjects
BRCA1 Protein, Case-Control Studies, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Triple Negative Breast Neoplasms, Linkage Disequilibrium, Article, Genome-Wide Association Study
Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate (FDR)

Published
2019

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