Author: "Amanda B. Spurdle" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Amanda B. Spurdle"' showing total 480 results

Start Over Author "Amanda B. Spurdle"

480 results on '"Amanda B. Spurdle"'

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
Full Text: View/download PDF

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
Full Text: View/download PDF

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
Full Text: View/download PDF

4. 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
Full Text: View/download PDF

5. Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

Author: Xuemin Wang, Pik Fang Kho, Dhanya Ramachandran, Cemsel Bafligil, Frederic Amant, Ellen L. Goode, Rodney J. Scott, Ian Tomlinson, D. Gareth Evans, Emma J. Crosbie, Thilo Dörk, Amanda B. Spurdle, Dylan M. Glubb, and Tracy A. O'Mara
Subjects: Bioinformatics, Systems biology, Cancer, Genomics, Science
Abstract: Summary: To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.
Published: 2023
Full Text: View/download PDF

6. The association between genetically elevated polyunsaturated fatty acids and risk of cancerResearch in context

Author: Philip C. Haycock, Maria Carolina Borges, Kimberley Burrows, Rozenn N. Lemaitre, Stephen Burgess, Nikhil K. Khankari, Konstantinos K. Tsilidis, Tom R. Gaunt, Gibran Hemani, Jie Zheng, Therese Truong, Brenda M. Birmann, Tracy OMara, Amanda B. Spurdle, Mark M. Iles, Matthew H. Law, Susan L. Slager, Fatemeh Saberi Hosnijeh, Daniela Mariosa, Michelle Cotterchio, James R. Cerhan, Ulrike Peters, Stefan Enroth, Puya Gharahkhani, Loic Le Marchand, Ann C. Williams, Robert C. Block, Christopher I. Amos, Rayjean J. Hung, Wei Zheng, Marc J. Gunter, George Davey Smith, Caroline Relton, Richard M. Martin, Nathan Tintle, Terri Rice, Iona Cheng, Mark Jenkins, Steve Gallinger, Alex J. Cornish, Amit Sud, Jayaram Vijayakrishnan, Margaret Wrensch, Mattias Johansson, Aaron D. Norman, Alison Klein, Alyssa Clay-Gilmour, Andre Franke, Andres V. Ardisson Korat, Bill Wheeler, Björn Nilsson, Caren Smith, Chew-Kiat Heng, Ci Song, David Riadi, Elizabeth B. Claus, Eva Ellinghaus, Evgenia Ostroumova, Hosnijeh, Florent de Vathaire, Giovanni Cugliari, Giuseppe Matullo, Irene Oi-Lin Ng, Jeanette E. Passow, Jia Nee Foo, Jiali Han, Jianjun Liu, Jill Barnholtz-Sloan, Joellen M. Schildkraut, John Maris, Joseph L. Wiemels, Kari Hemminki, Keming Yang, Lambertus A. Kiemeney, Lang Wu, Laufey Amundadottir, Marc-Henri Stern, Marie-Christine Boutron, Mark Martin Iles, Mark P. Purdue, Martin Stanulla, Melissa Bondy, Mia Gaudet, Lenha Mobuchon, Nicola J. Camp, Pak Chung Sham, Pascal Guénel, Paul Brennan, Philip R. Taylor, Quinn Ostrom, Rachael Stolzenberg-Solomon, Rajkumar Dorajoo, Richard Houlston, Robert B. Jenkins, Sharon Diskin, Sonja I. Berndt, Spiridon Tsavachidis, Stephen J. Channock, Tabitha Harrison, Tessel Galesloot, Ulf Gyllensten, Vijai Joseph, Y. Shi, Wenjian Yang, Yi Lin, and Stephen K. Van Den Eeden
Subjects: Mendelian randomization, Cancer risk, Polyunsaturated fatty acids, Omega 3, Omega 6, Delta-5 desaturase, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P
Published: 2023
Full Text: View/download PDF

7. Splicing annotation of endometrial cancer GWAS risk loci reveals potentially causal variants and supports a role for NF1 and SKAP1 as susceptibility genes

Author: Daffodil M. Canson, Tracy A. O’Mara, Amanda B. Spurdle, and Dylan M. Glubb
Subjects: endometrial cancer, GWAS, splicing, spliceogenic, sQTL, NF1, Genetics, QH426-470
Abstract: Summary: Alternative splicing contributes to cancer development. Indeed, splicing analysis of cancer genome-wide association study (GWAS) risk variants has revealed likely causal variants. To systematically assess GWAS variants for splicing effects, we developed a prioritization workflow using a combination of splicing prediction tools, alternative transcript isoforms, and splicing quantitative trait locus (sQTL) annotations. Application of this workflow to candidate causal variants from 16 endometrial cancer GWAS risk loci highlighted single-nucleotide polymorphisms (SNPs) that were predicted to upregulate alternative transcripts. For two variants, sQTL data supported the predicted impact on splicing. At the 17q11.2 locus, the protective allele for rs7502834 was associated with increased splicing of an exon in a NF1 alternative transcript encoding a truncated protein in adipose tissue and is consistent with an endometrial cancer transcriptome-wide association study (TWAS) finding in adipose tissue. Notably, NF1 haploinsufficiency is protective for obesity, a well-established risk factor for endometrial cancer. At the 17q21.32 locus, the rs2278868 risk allele was predicted to upregulate a SKAP1 transcript that is subject to nonsense-mediated decay, concordant with a corresponding sQTL in lymphocytes. This is consistent with a TWAS finding that indicates decreased SKAP1 expression in blood increases endometrial cancer risk. As SKAP1 is involved in T cell immune responses, decreased SKAP1 expression may impact endometrial tumor immunosurveillance. In summary, our analysis has identified potentially causal endometrial cancer GWAS risk variants with plausible biological mechanisms and provides a splicing annotation workflow to aid interpretation of other GWAS datasets.
Published: 2023
Full Text: View/download PDF

8. 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
Full Text: View/download PDF

9. 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
Full Text: View/download PDF

10. Author Correction: ROR1 is upregulated in endometrial cancer and represents a novel therapeutic target

Author: Dongli Liu, Kate Gunther, Luis A. Enriquez, Benjamin Daniels, Tracy A. O’Mara, Katrina Tang, Amanda B. Spurdle, and Caroline E. Ford
Subjects: Medicine, Science
Published: 2022
Full Text: View/download PDF

11. Multi-tissue transcriptome-wide association study identifies eight candidate genes and tissue-specific gene expression underlying endometrial cancer susceptibility

Author: Pik Fang Kho, Xuemin Wang, Gabriel Cuéllar-Partida, Thilo Dörk, Ellen L. Goode, Diether Lambrechts, Rodney J. Scott, Amanda B. Spurdle, Tracy A. O’Mara, and Dylan M. Glubb
Subjects: Biology (General), QH301-705.5
Abstract: Pik Fang Kho et al. conduct multi-tissue transcriptome-wide association studies of endometrial cancer risk. Their results identify potential susceptibility genes for endometrial cancer, and provide avenues for the development of future treatments for this disease.
Published: 2021
Full Text: View/download PDF

12. Federated analysis of BRCA1 and BRCA2 variation in a Japanese cohort

Author: James Casaletto, Michael Parsons, Charles Markello, Yusuke Iwasaki, Yukihide Momozawa, Amanda B. Spurdle, and Melissa Cline
Subjects: Variant of uncertain significance, federated computing, variant classification, benign, pathogenic, data privacy, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract: Summary: More than 40% of the germline variants in ClinVar today are variants of uncertain significance (VUSs). These variants remain unclassified in part because the patient-level data needed for their interpretation is siloed. Federated analysis can overcome this problem by “bringing the code to the data”: analyzing the sensitive patient-level data computationally within its secure home institution and providing researchers with valuable insights from data that would not otherwise be accessible. We tested this principle with a federated analysis of breast cancer clinical data at RIKEN, derived from the BioBank Japan repository. We were able to analyze these data within RIKEN’s secure computational framework without the need to transfer the data, gathering evidence for the interpretation of several variants. This exercise represents an approach to help realize the core charter of the Global Alliance for Genomics and Health (GA4GH): to responsibly share genomic data for the benefit of human health.
Published: 2022
Full Text: View/download PDF

13. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas
Subjects: Science
Abstract: In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
Full Text: View/download PDF

14. Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants

Author: Raphaël Leman, Hélène Tubeuf, Sabine Raad, Isabelle Tournier, Céline Derambure, Raphaël Lanos, Pascaline Gaildrat, Gaia Castelain, Julie Hauchard, Audrey Killian, Stéphanie Baert-Desurmont, Angelina Legros, Nicolas Goardon, Céline Quesnelle, Agathe Ricou, Laurent Castera, Dominique Vaur, Gérald Le Gac, Chandran Ka, Yann Fichou, Françoise Bonnet-Dorion, Nicolas Sevenet, Marine Guillaud-Bataille, Nadia Boutry-Kryza, Inès Schultz, Virginie Caux-Moncoutier, Maria Rossing, Logan C. Walker, Amanda B. Spurdle, Claude Houdayer, Alexandra Martins, and Sophie Krieger
Subjects: Branch point, Prediction, RNA, Benchmark, HSF, SVM-BPfinder, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background Branch points (BPs) map within short motifs upstream of acceptor splice sites (3’ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3’ss. Results We used a large set of constitutive and alternative human 3’ss collected from Ensembl (n = 264,787 3’ss) and from in-house RNAseq experiments (n = 51,986 3’ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3’ss (99.48 and 65.84% accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17%. Conclusions Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3’ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area.
Published: 2020
Full Text: View/download PDF

15. GA4GH: International policies and standards for data sharing across genomic research and healthcare

Author: Heidi L. Rehm, Angela J.H. Page, Lindsay Smith, Jeremy B. Adams, Gil Alterovitz, Lawrence J. Babb, Maxmillian P. Barkley, Michael Baudis, Michael J.S. Beauvais, Tim Beck, Jacques S. Beckmann, Sergi Beltran, David Bernick, Alexander Bernier, James K. Bonfield, Tiffany F. Boughtwood, Guillaume Bourque, Sarion R. Bowers, Anthony J. Brookes, Michael Brudno, Matthew H. Brush, David Bujold, Tony Burdett, Orion J. Buske, Moran N. Cabili, Daniel L. Cameron, Robert J. Carroll, Esmeralda Casas-Silva, Debyani Chakravarty, Bimal P. Chaudhari, Shu Hui Chen, J. Michael Cherry, Justina Chung, Melissa Cline, Hayley L. Clissold, Robert M. Cook-Deegan, Mélanie Courtot, Fiona Cunningham, Miro Cupak, Robert M. Davies, Danielle Denisko, Megan J. Doerr, Lena I. Dolman, Edward S. Dove, L. Jonathan Dursi, Stephanie O.M. Dyke, James A. Eddy, Karen Eilbeck, Kyle P. Ellrott, Susan Fairley, Khalid A. Fakhro, Helen V. Firth, Michael S. Fitzsimons, Marc Fiume, Paul Flicek, Ian M. Fore, Mallory A. Freeberg, Robert R. Freimuth, Lauren A. Fromont, Jonathan Fuerth, Clara L. Gaff, Weiniu Gan, Elena M. Ghanaim, David Glazer, Robert C. Green, Malachi Griffith, Obi L. Griffith, Robert L. Grossman, Tudor Groza, Jaime M. Guidry Auvil, Roderic Guigó, Dipayan Gupta, Melissa A. Haendel, Ada Hamosh, David P. Hansen, Reece K. Hart, Dean Mitchell Hartley, David Haussler, Rachele M. Hendricks-Sturrup, Calvin W.L. Ho, Ashley E. Hobb, Michael M. Hoffman, Oliver M. Hofmann, Petr Holub, Jacob Shujui Hsu, Jean-Pierre Hubaux, Sarah E. Hunt, Ammar Husami, Julius O. Jacobsen, Saumya S. Jamuar, Elizabeth L. Janes, Francis Jeanson, Aina Jené, Amber L. Johns, Yann Joly, Steven J.M. Jones, Alexander Kanitz, Kazuto Kato, Thomas M. Keane, Kristina Kekesi-Lafrance, Jerome Kelleher, Giselle Kerry, Seik-Soon Khor, Bartha M. Knoppers, Melissa A. Konopko, Kenjiro Kosaki, Martin Kuba, Jonathan Lawson, Rasko Leinonen, Stephanie Li, Michael F. Lin, Mikael Linden, Xianglin Liu, Isuru Udara Liyanage, Javier Lopez, Anneke M. Lucassen, Michael Lukowski, Alice L. Mann, John Marshall, Michele Mattioni, Alejandro Metke-Jimenez, Anna Middleton, Richard J. Milne, Fruzsina Molnár-Gábor, Nicola Mulder, Monica C. Munoz-Torres, Rishi Nag, Hidewaki Nakagawa, Jamal Nasir, Arcadi Navarro, Tristan H. Nelson, Ania Niewielska, Amy Nisselle, Jeffrey Niu, Tommi H. Nyrönen, Brian D. O’Connor, Sabine Oesterle, Soichi Ogishima, Vivian Ota Wang, Laura A.D. Paglione, Emilio Palumbo, Helen E. Parkinson, Anthony A. Philippakis, Angel D. Pizarro, Andreas Prlic, Jordi Rambla, Augusto Rendon, Renee A. Rider, Peter N. Robinson, Kurt W. Rodarmer, Laura Lyman Rodriguez, Alan F. Rubin, Manuel Rueda, Gregory A. Rushton, Rosalyn S. Ryan, Gary I. Saunders, Helen Schuilenburg, Torsten Schwede, Serena Scollen, Alexander Senf, Nathan C. Sheffield, Neerjah Skantharajah, Albert V. Smith, Heidi J. Sofia, Dylan Spalding, Amanda B. Spurdle, Zornitza Stark, Lincoln D. Stein, Makoto Suematsu, Patrick Tan, Jonathan A. Tedds, Alastair A. Thomson, Adrian Thorogood, Timothy L. Tickle, Katsushi Tokunaga, Juha Törnroos, David Torrents, Sean Upchurch, Alfonso Valencia, Roman Valls Guimera, Jessica Vamathevan, Susheel Varma, Danya F. Vears, Coby Viner, Craig Voisin, Alex H. Wagner, Susan E. Wallace, Brian P. Walsh, Marc S. Williams, Eva C. Winkler, Barbara J. Wold, Grant M. Wood, J. Patrick Woolley, Chisato Yamasaki, Andrew D. Yates, Christina K. Yung, Lyndon J. Zass, Ksenia Zaytseva, Junjun Zhang, Peter Goodhand, Kathryn North, and Ewan Birney
Subjects: data sharing, data access, precision medicine, learning health system, genomics, standards, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract: Summary: The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.
Published: 2021
Full Text: View/download PDF

16. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Hongjie Chen, Arunabha Majumdar, Lu Wang, Siddhartha Kar, Kevin M. Brown, Helian Feng, Constance Turman, Joe Dennis, Douglas Easton, Kyriaki Michailidou, Jacques Simard, Timothy Bishop, Iona C. Cheng, Jeroen R. Huyghe, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Puya Gharahkhani, Johannes Schumacher, Janusz Jankowski, Ines Gockel, Melissa L. Bondy, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Corina Lesseur, Andy R. Ness, Brenda Diergaarde, Andrew F. Olshan, Christopher I. Amos, David C. Christiani, Maria T. Landi, James D. McKay, Myriam Brossard, Mark M. Iles, Matthew H. Law, Stuart MacGregor, Jonathan Beesley, Michelle R. Jones, Jonathan Tyrer, Stacey J. Winham, Alison P. Klein, Gloria Petersen, Donghui Li, Brian M. Wolpin, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Paul Brennan, Stephen J. Chanock, Valerie Gaborieau, Mark P. Purdue, Paul Pharoah, Rayjean J. Hung, Laufey T. Amundadottir, Peter Kraft, Bogdan Pasaniuc, and Sara Lindström
Subjects: cancer, pleiotropy, fine-mapping, 5p15.33 region, TERT, CLPTM1L, Genetics, QH426-470
Abstract: Summary: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
Full Text: View/download PDF

17. 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
Full Text: View/download PDF

18. 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
Full Text: View/download PDF

19. 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
Full Text: View/download PDF

20. Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes

Author: Keijiro Mizukami, Yusuke Iwasaki, Eiryo Kawakami, Makoto Hirata, Yoichiro Kamatani, Koichi Matsuda, Mikiko Endo, Kokichi Sugano, Teruhiko Yoshida, Yoshinori Murakami, Hidewaki Nakagawa, Amanda B. Spurdle, and Yukihide Momozawa
Subjects: Pancreatic cancer, Pathogenic variants, Universal screening for patients, Machine learning, BRCA, ATM, Medicine, Medicine (General), R5-920
Abstract: Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable. Funding: AMED under Grant Number JP19kk0305010 and Australian National Health and Medical Research funding (ID177524)
Published: 2020
Full Text: View/download PDF

21. 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
Full Text: View/download PDF

22. 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
Full Text: View/download PDF

23. Identification of nine new susceptibility loci for endometrial cancer

Author: Tracy A. O’Mara, Dylan M. Glubb, Frederic Amant, Daniela Annibali, Katie Ashton, John Attia, Paul L. Auer, Matthias W. Beckmann, Amanda Black, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Daniel D. Buchanan, Barbara Burwinkel, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, Maxine M. Chen, Timothy H. T. Cheng, Christine L. Clarke, Mark Clendenning, Linda S. Cook, Fergus J. Couch, Angela Cox, Marta Crous-Bous, Kamila Czene, Felix Day, Joe Dennis, Jeroen Depreeuw, Jennifer Anne Doherty, Thilo Dörk, Sean C. Dowdy, Matthias Dürst, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Christine M. Friedenreich, Lin Fritschi, Jenny Fung, Montserrat García-Closas, Mia M. Gaudet, Graham G. Giles, Ellen L. Goode, Maggie Gorman, Christopher A. Haiman, Per Hall, Susan E. Hankison, Catherine S. Healey, Alexander Hein, Peter Hillemanns, Shirley Hodgson, Erling A. Hoivik, Elizabeth G. Holliday, John L. Hopper, David J. Hunter, Angela Jones, Camilla Krakstad, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Xiaolin Liang, Annika Lindblom, Jolanta Lissowska, Jirong Long, Lingeng Lu, Anthony M. Magliocco, Lynn Martin, Mark McEvoy, Alfons Meindl, Kyriaki Michailidou, Roger L. Milne, Miriam Mints, Grant W. Montgomery, Rami Nassir, Håkan Olsson, Irene Orlow, Geoffrey Otton, Claire Palles, John R. B. Perry, Julian Peto, Loreall Pooler, Jennifer Prescott, Tony Proietto, Timothy R. Rebbeck, Harvey A. Risch, Peter A. W. Rogers, Matthias Rübner, Ingo Runnebaum, Carlotta Sacerdote, Gloria E. Sarto, Fredrick Schumacher, Rodney J. Scott, V. Wendy Setiawan, Mitul Shah, Xin Sheng, Xiao-Ou Shu, Melissa C. Southey, Anthony J. Swerdlow, Emma Tham, Jone Trovik, Constance Turman, Jonathan P. Tyrer, Celine Vachon, David VanDen Berg, Adriaan Vanderstichele, Zhaoming Wang, Penelope M. Webb, Nicolas Wentzensen, Henrica M. J. Werner, Stacey J. Winham, Alicja Wolk, Lucy Xia, Yong-Bing Xiang, Hannah P. Yang, Herbert Yu, Wei Zheng, Paul D. P. Pharoah, Alison M. Dunning, Peter Kraft, Immaculata De Vivo, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, and Deborah J. Thompson
Subjects: Science
Abstract: Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
Published: 2018
Full Text: View/download PDF

24. Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Author: Jodie N. Painter, Tracy A. O'Mara, Andrew P. Morris, Timothy H. T. Cheng, Maggie Gorman, Lynn Martin, Shirley Hodson, Angela Jones, Nicholas G. Martin, Scott Gordon, Anjali K. Henders, John Attia, Mark McEvoy, Elizabeth G. Holliday, Rodney J. Scott, Penelope M. Webb, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Matthias Rübner, Per Hall, Kamila Czene, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo Runnebaum, Diether Lambrechts, Frederic Amant, Daniela Annibali, Jeroen Depreeuw, Adriaan Vanderstichele, Ellen L. Goode, Julie M. Cunningham, Sean C. Dowdy, Stacey J. Winham, Jone Trovik, Erling Hoivik, Henrica M. J. Werner, Camilla Krakstad, Katie Ashton, Geoffrey Otton, Tony Proietto, Emma Tham, Miriam Mints, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Paul D. P. Pharoah, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang‐Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Krina T. Zondervan, Dale R. Nyholt, Stuart MacGregor, Grant W. Montgomery, Ian Tomlinson, Douglas F. Easton, Deborah J. Thompson, and Amanda B. Spurdle
Subjects: Cross‐disease analysis, endometrial cancer, endometriosis, genome‐wide association study, genetic correlation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
Published: 2018
Full Text: View/download PDF

25. Nanopore sequencing of full-length BRCA1 mRNA transcripts reveals co-occurrence of known exon skipping events

Author: Lucy C. de Jong, Simone Cree, Vanessa Lattimore, George A. R. Wiggins, Amanda B. Spurdle, kConFab Investigators, Allison Miller, Martin A. Kennedy, and Logan C. Walker
Subjects: BRCA1, Splicing, MinION, Nanopore sequencing, Full-length transcript, Exon skipping, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Laboratory assays evaluating the effect of DNA sequence variants on BRCA1 mRNA splicing may contribute to classification by providing molecular evidence. However, our knowledge of normal and aberrant BRCA1 splicing events to date has been limited to data derived from assays targeting partial transcript sequences. This study explored the utility of nanopore sequencing to examine whole BRCA1 mRNA transcripts and to provide accurate categorisation of in-frame and out-of-frame splicing events. Methods The exon structure of BRCA1 transcripts from a previously studied control lymphoblastoid cell line were assessed using MinION nanopore sequencing of long-range reverse transcriptase-PCR amplicons. Results Our study identified and characterised 32 complete BRCA1 isoforms, including 18 novel isoforms which showed skipping of multiple contiguous and/or non-contiguous exons. Furthermore, we show that known BRCA1 exon skipping events, such as Δ(9,10) and Δ21, can co-occur in a single transcript, with some isoforms containing four or more alternative splice junctions. Fourteen novel isoforms were formed entirely from a combination of previously identified alternative splice junctions, suggesting that the total number of BRCA1 isoforms might be lower than the number of splicing events reported previously. Conclusions Our results highlight complexity in BRCA1 transcript structure that has not been described previously. This finding has key implications for predicting the translation frame of splicing transcripts, important for interpreting the clinical significance of spliceogenic variants. Future research is warranted to quantitatively assess full-length BRCA1 transcript levels, and to assess the application of nanopore sequencing for routine evaluation of potential spliceogenic variants.
Published: 2017
Full Text: View/download PDF

26. 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
Full Text: View/download PDF

27. Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study

Author: Pik Fang Kho, Dylan M. Glubb, Deborah J. Thompson, Amanda B. Spurdle, and Tracy A. O'Mara
Subjects: Mendelian randomization, endometrial cancer, toenail selenium, circulating selenium, genome-wide association study, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P < 5 × 10−8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87–1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89–1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53–1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer.
Published: 2019
Full Text: View/download PDF

28. Investigation of Experimental Factors That Underlie BRCA1/2 mRNA Isoform Expression Variation: Recommendations for Utilizing Targeted RNA Sequencing to Evaluate Potential Spliceogenic Variants

Author: Vanessa L. Lattimore, John F. Pearson, Margaret J. Currie, Amanda B. Spurdle, kConFab Investigators, Bridget A. Robinson, and Logan C. Walker
Subjects: BRCA1, BRCA2, mRNA, quantitative, splicing, next-generation sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: PCR-based RNA splicing assays are commonly used in diagnostic and research settings to assess the potential effects of variants of uncertain clinical significance in BRCA1 and BRCA2. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium completed a multicentre investigation to evaluate differences in assay design and the integrity of published data, raising a number of methodological questions associated with cell culture conditions and PCR-based protocols. We utilized targeted RNA-seq to re-assess BRCA1 and BRCA2 mRNA isoform expression patterns in lymphoblastoid cell lines (LCLs) previously used in the multicentre ENIGMA study. Capture of the targeted cDNA sequences was carried out using 34 BRCA1 and 28 BRCA2 oligonucleotides from the Illumina Truseq Targeted RNA Expression platform. Our results show that targeted RNA-seq analysis of LCLs overcomes many of the methodology limitations associated with PCR-based assays leading us to make the following observations and recommendations: (1) technical replicates (n > 2) of variant carriers to capture methodology induced variability associated with RNA-seq assays, (2) LCLs can undergo multiple freeze/thaw cycles and can be cultured up to 2 weeks without noticeably influencing isoform expression levels, (3) nonsense-mediated decay inhibitors are essential prior to splicing assays for comprehensive mRNA isoform detection, (4) quantitative assessment of exon:exon junction levels across BRCA1 and BRCA2 can help distinguish between normal and aberrant isoform expression patterns. Experimentally derived recommendations from this study will facilitate the application of targeted RNA-seq platforms for the quantitation of BRCA1 and BRCA2 mRNA aberrations associated with sequence variants of uncertain clinical significance.
Published: 2018
Full Text: View/download PDF

29. The Association of CYP19A1 Variation with Circulating Estradiol and Aromatase Inhibitor Outcome: Can CYP19A1 Variants Be Used to Predict Treatment Efficacy?

Author: Dylan M. Glubb, Tracy A. O'Mara, Jannah Shamsani, and Amanda B. Spurdle
Subjects: CYP19A1, estradiol, genetic variation, aromatase inhibitors, patient outcome, breast cancer, Therapeutics. Pharmacology, RM1-950
Abstract: After menopause, estradiol is primarily synthesized in peripheral tissues by the enzyme aromatase, encoded by CYP19A1. CYP19A1 variation associates with circulating estradiol in postmenopausal women and this variation is best represented by the intronic variant rs727479. This variation appears to have pleiotropic effects as it also associates with endometrial cancer risk. Indeed, estradiol plays an important role in the development of breast and endometrial cancer. Aromatase inhibitor (AI) drugs are used in the treatment of both diseases, however, response rates for AIs are low and there is currently no way to identify breast or endometrial cancer patients who are more likely to receive a clinical benefit. Multiple studies have proposed that genetic variation in CYP19A1 will have effects on AI efficacy: eight candidate variant studies of sample size greater than 50 describe associations between CYP19A1 variation and the outcome of patients treated with AIs. Nominally significant associations with patient outcome were reported for several variants, including rs727479. However, only an association between rs4646 and time to progression was replicated in an independent study. Moreover, rs4646 is also the only variant that has an association with patient outcome that passes a multiple testing threshold and this variant is in linkage disequilibrium with rs727479, supporting the hypothesis that associations with patient outcome may be driven through the effects on circulating estradiol. Despite this preliminary evidence, well phenotyped and comprehensively genotyped patient sets need to be studied before conclusions can be drawn about the effects of CYP19A1 variation on AI efficacy.
Published: 2017
Full Text: View/download PDF

30. Quantifying BRCA1 and BRCA2 mRNA Isoform Expression Levels in Single Cells

Author: Vanessa L. Lattimore, John F. Pearson, Arthur E. Morley-Bunker, kConFab Investigators, Amanda B. Spurdle, Bridget A. Robinson, Margaret J. Currie, and Logan C. Walker
Subjects: splicing, single cell, mRNA expression, BRCA1, BRCA2, RNAscope, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: BRCA1 and BRCA2 spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of BRCA1 and BRCA2 splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may be present between individual cells. This novel proof of concept study utilises RNA in situ hybridisation to measure the absolute expression of BRCA1 and BRCA2 mRNA splicing events in single lymphoblastoid cells containing known spliceogenic variants (BRCA1c.671-2 A>G or BRCA2c.7988 A>T). We observed a large proportion of cells (>42%) in each sample that did not express mRNA for the targeted gene. Increased levels (average mRNA molecules per cell) of BRCA2 ∆17_18 were observed in the cells containing the known spliceogenic variant BRCA2c.7988 A>T, but cells containing BRCA1c.671-2 A>G were not found to express significantly increased levels of BRCA1 ∆11, as had been shown previously. Instead, we show for each variant carrier sample that a higher proportion of cells expressed the targeted splicing event compared to control cells. These results indicate that BRCA1/2 mRNA is expressed stochastically, suggesting that previously reported results using RT-PCR may have been influenced by the number of cells with BRCA1/2 mRNA expression and may not represent an elevation of constitutive mRNA expression. Detection of mRNA expression in single cells allows for a more comprehensive understanding of how spliceogenic variants influence the expression of mRNA isoforms. However, further research is required to assess the utility of this technology to measure the expression of predicted spliceogenic BRCA1 and BRCA2 variants in a diagnostic setting.
Published: 2019
Full Text: View/download PDF

31. Correction: Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer.

Author: Mia M. Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M. Korn, Candace Guiducci, Ayellet V. Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B. L. Hogervorst, Matti A. Rookus, J. Margriet Collée, Nicoline Hoogerbrugge, Kees E. P. van Roozendaal, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V. Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T. Johannsson, Rosa B. Barkardottir, Peter Devilee, Olofunmilayo I. Olopade, Susan L. Neuhausen, Xianshu Wang, Zachary S. Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M. Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Amanda E. Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Tim Rebbeck, Amanda B. Spurdle, Xiaoqing Chen, Helene Holland, Esther M. John, John L. Hopper, Saundra S. Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V. Overeem Hansen, Finn C. Nielsen, Mark H. Greene, Phuong L. Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N. Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J. Klein, Fergus J. Couch, Georgia Chenevix-Trench, Douglas F. Easton, Mark J. Daly, Antonis C. Antoniou, David M. Altshuler, and Kenneth Offit
Subjects: Genetics, QH426-470
Published: 2010
Full Text: View/download PDF

32. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer

Author: Yoshiaki Usui, Yukari Taniyama, Mikiko Endo, Yuriko N. Koyanagi, Yumiko Kasugai, Isao Oze, Hidemi Ito, Issei Imoto, Tsutomu Tanaka, Masahiro Tajika, Yasumasa Niwa, Yusuke Iwasaki, Tomomi Aoi, Nozomi Hakozaki, Sadaaki Takata, Kunihiko Suzuki, Chikashi Terao, Masanori Hatakeyama, Makoto Hirata, Kokichi Sugano, Teruhiko Yoshida, Yoichiro Kamatani, Hidewaki Nakagawa, Koichi Matsuda, Yoshinori Murakami, Amanda B. Spurdle, Keitaro Matsuo, and Yukihide Momozawa
Subjects: General Medicine
Published: 2023

33. Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare

Author: Zornitza Stark, Tiffany Boughtwood, Matilda Haas, Jeffrey Braithwaite, Clara L. Gaff, Ilias Goranitis, Amanda B. Spurdle, David P. Hansen, Oliver Hofmann, Nigel Laing, Sylvia Metcalfe, Ainsley J. Newson, Hamish S. Scott, Natalie Thorne, Robyn L. Ward, Marcel E. Dinger, Stephanie Best, Janet C. Long, Sean M. Grimmond, John Pearson, Nicola Waddell, Christopher P. Barnett, Matthew Cook, Michael Field, David Fielding, Stephen B. Fox, Jozef Gecz, Adam Jaffe, Richard J. Leventer, Paul J. Lockhart, Sebastian Lunke, Andrew J. Mallett, Julie McGaughran, Linda Mileshkin, Katia Nones, Tony Roscioli, Ingrid E. Scheffer, Christopher Semsarian, Cas Simons, David M. Thomas, David R. Thorburn, Richard Tothill, Deborah White, Sally Dunwoodie, Peter T. Simpson, Peta Phillips, Marie-Jo Brion, Keri Finlay, Michael CJ. Quinn, Tessa Mattiske, Emma Tudini, Kirsten Boggs, Sean Murray, Kathy Wells, John Cannings, Andrew H. Sinclair, John Christodoulou, Kathryn N. North, Stark, Zornitza, Boughtwood, Tiffany, Haas, Matilda, Braithwaite, Jeffrey, Scott, Hamish S, and North, Kathryn N
Subjects: Genetics, Genetics (clinical)
Abstract: Refereed/Peer-reviewed Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.
Published: 2023

34. Risk prediction models for endometrial cancer: development and validation in an international consortium

Author: Joy Shi, Peter Kraft, Bernard A Rosner, Yolanda Benavente, Amanda Black, Louise A Brinton, Chu Chen, Megan A Clarke, Linda S Cook, Laura Costas, Luigino Dal Maso, Jo L Freudenheim, Jon Frias-Gomez, Christine M Friedenreich, Montserrat Garcia-Closas, Marc T Goodman, Lisa Johnson, Carlo La Vecchia, Fabio Levi, Jolanta Lissowska, Lingeng Lu, Susan E McCann, Kirsten B Moysich, Eva Negri, Kelli O'Connell, Fabio Parazzini, Stacey Petruzella, Jerry Polesel, Jeanette Ponte, Timothy R Rebbeck, Peggy Reynolds, Fulvio Ricceri, Harvey A Risch, Carlotta Sacerdote, Veronica W Setiawan, Xiao-Ou Shu, Amanda B Spurdle, Britton Trabert, Penelope M Webb, Nicolas Wentzensen, Lynne R Wilkens, Wang Hong Xu, Hannah P Yang, Herbert Yu, Mengmeng Du, and Immaculata De Vivo
Subjects: prediction model, Cancer Research, Oncology, Settore MED/06 - Oncologia Medica, Settore MED/42 - Igiene Generale e Applicata, endometrial cancer, endometrium, cancer risk, Settore MED/40 - Ginecologia e Ostetricia, Settore MED/01 - Statistica Medica
Abstract: Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.
Published: 2023

35. Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines

Author: Xi Luo, Jamie L Maciaszek, Bryony A Thompson, Huei San Leong, Katherine Dixon, Sónia Sousa, Michael Anderson, Maegan E Roberts, Kristy Lee, Amanda B Spurdle, Arjen R Mensenkamp, Terra Brannan, Carolina Pardo, Liying Zhang, Tina Pesaran, Sainan Wei, Grace-Ann Fasaye, Chimene Kesserwan, Brian H Shirts, Jeremy L Davis, Carla Oliveira, Sharon E Plon, Kasmintan A Schrader, and Rachid Karam
Subjects: All institutes and research themes of the Radboud University Medical Center, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Genetics, Genetics (clinical)
Abstract: BackgroundGermline pathogenic variants inCDH1are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germlineCDH1variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen)CDH1Variant Curation Expert Panel (VCEP) developed specifications forCDH1variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.MethodsCDH1variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoingCDH1variant curations. TheCDH1VCEP reviewed 273 variants using updatedCDH1specifications and incorporated published and unpublished data provided by diagnostic laboratories.ResultsUpdatedCDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.ConclusionsThe development and evolution ofCDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.
Published: 2023

36. Predictive functional assay-based classification of PMS2 variants in Lynch syndrome

Author: Emily Rayner, Yvonne Tiersma, Cristina Fortuno, Sandrine van Hees‐Stuivenberg, Mark Drost, Bryony Thompson, Amanda B. Spurdle, Niels de Wind, and Clinical Genetics
Subjects: variants of uncertain significance, DNA mismatch repair, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA-Binding Proteins, MutS Homolog 2 Protein, Lynch syndrome, PMS2, SDG 3 - Good Health and Well-being, Genetics, Humans, Genetic Testing, MutL Protein Homolog 1, diagnostic assessment, functional analysis-based classification, Genetics (clinical), Mismatch Repair Endonuclease PMS2
Abstract: The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch syndrome, represent variants of uncertain significance (VUS). The inability to classify most VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based quantitative tool to improve the classification of VUS in MMR proteins. To derive a formula that translates CIMRA assay results into the odds of pathogenicity (OddsPath) for VUS in PMS2 we used a set of clinically classified PMS2 variants supplemented by inactivating variants that were generated by an in cellulo genetic screen, as proxies for cancer-predisposing variants. Validation of this OddsPath revealed high predictive values for benign and predisposing PMS2 VUS. We conclude that the OddsPath provides an integral metric that, following the other, higher penetrance, MMR proteins MSH2, MSH6 and MLH1 can be incorporated as strong evidence type into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).
Published: 2022

37. Coffee consumption and risk of endometrial cancer: a pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Author: Marta Crous-Bou, Mengmeng Du, Marc J Gunter, Veronica W Setiawan, Leo J Schouten, Xiao-ou Shu, Nicolas Wentzensen, Kimberly A Bertrand, Linda S Cook, Christine M Friedenreich, Susan M Gapstur, Marc T Goodman, Torukiri I Ibiebele, Carlo La Vecchia, Fabio Levi, Linda M Liao, Eva Negri, Susan E McCann, Kelly O’Connell, Julie R Palmer, Alpa V Patel, Jeanette Ponte, Peggy Reynolds, Carlotta Sacerdote, Rashmi Sinha, Amanda B Spurdle, Britton Trabert, Piet A van den Brandt, Penelope M Webb, Stacey Petruzella, Sara H Olson, Immaculata De Vivo, Epidemiologie, and RS: GROW - R1 - Prevention
Subjects: Nutrition and Dietetics, Medicine (miscellaneous)
Abstract: BACKGROUND: Epidemiological studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating levels of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund concluded that consumption of coffee probably protects against EC.OBJECTIVE: Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors of EC.PATIENTS AND METHODS: We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 endometrial cancer cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate odds ratios (OR) and their corresponding 95% confidence intervals (CI). All models were adjusted for potential confounders including age, race, body mass index, smoking status, diabetes status, study design and study site.RESULTS: Coffee drinkers had a lower risk of EC compared to non-coffee drinkers (multi-adjusted OR = 0.87, 95% CI = 0.79,0.95). There was a dose-response relationship between higher coffee consumption and lower risk of EC: compared to non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3 and more than 4 cups/day were 0.90 (95% CI = 0.82,1.00), 0.86 (95% CI = 0.78,0.95), and 0.76 (95% CI = 0.66,0.87), respectively (p for trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with body mass index (BMI) over 25 kg/m2.CONCLUSION: The results of the largest analysis to date pooling individual-level data further support the potentially beneficial health effects of coffee consumption in relation to EC, especially among females with higher BMI.
Published: 2023

38. 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

39. The association between genetically elevated polyunsaturated fatty acids and risk of cancer

Author: Philip C. Haycock, Maria Carolina Borges, Kimberley Burrows, Rozenn N. Lemaitre, Stephen Burgess, Nikhil K. Khankari, Konstantinos K. Tsilidis, Tom R. Gaunt, Gibran Hemani, Jie Zheng, Therese Truong, Brenda M. Birmann, Tracy OMara, Amanda B. Spurdle, Mark M. Iles, Matthew H. Law, Susan L. Slager, Fatemeh Saberi Hosnijeh, Daniela Mariosa, Michelle Cotterchio, James R. Cerhan, Ulrike Peters, Stefan Enroth, Puya Gharahkhani, Loic Le Marchand, Ann C. Williams, Robert C. Block, Christopher I. Amos, Rayjean J. Hung, Wei Zheng, Marc J. Gunter, George Davey Smith, Caroline Relton, Richard M. Martin, Nathan Tintle, Terri Rice, Iona Cheng, Mark Jenkins, Steve Gallinger, Alex J. Cornish, Amit Sud, Jayaram Vijayakrishnan, Margaret Wrensch, Mattias Johansson, Aaron D. Norman, Alison Klein, Alyssa Clay-Gilmour, Andre Franke, Andres V. Ardisson Korat, Bill Wheeler, Björn Nilsson, Caren Smith, Chew-Kiat Heng, Ci Song, David Riadi, Elizabeth B. Claus, Eva Ellinghaus, Evgenia Ostroumova, null Hosnijeh, Florent de Vathaire, Giovanni Cugliari, Giuseppe Matullo, Irene Oi-Lin Ng, Jeanette E. Passow, Jia Nee Foo, Jiali Han, Jianjun Liu, Jill Barnholtz-Sloan, Joellen M. Schildkraut, John Maris, Joseph L. Wiemels, Kari Hemminki, Keming Yang, Lambertus A. Kiemeney, Lang Wu, Laufey Amundadottir, Marc-Henri Stern, Marie-Christine Boutron, Mark Martin Iles, Mark P. Purdue, Martin Stanulla, Melissa Bondy, Mia Gaudet, Lenha Mobuchon, Nicola J. Camp, Pak Chung Sham, Pascal Guénel, Paul Brennan, Philip R. Taylor, Quinn Ostrom, Rachael Stolzenberg-Solomon, Rajkumar Dorajoo, Richard Houlston, Robert B. Jenkins, Sharon Diskin, Sonja I. Berndt, Spiridon Tsavachidis, Stephen J. Channock, Tabitha Harrison, Tessel Galesloot, Ulf Gyllensten, Vijai Joseph, Y. Shi, Wenjian Yang, Yi Lin, and Stephen K. Van Den Eeden
Subjects: Cancer och onkologi, General Practice, Delta-5 desaturase, General Medicine, General Biochemistry, Genetics and Molecular Biology, Omega 6, Allmänmedicin, Cancer risk, Omega 3, Cancer and Oncology, Mendelian randomization, Delta-6 desaturase, Polyunsaturated fatty acids, Bristol Population Health Science Institute
Abstract: BackgroundThe causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.MethodsUsing a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures.FindingsGenetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07–1.11]), esophageal squamous cell carcinoma (1.16 [1.06–1.26]), lung cancer (1.06 [1.03–1.08]) and basal cell carcinoma (1.05 [1.02–1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99–1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99–1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95–1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98–1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding.InterpretationThe PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease.FundingCancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).
Published: 2023

40. Exploring the impact of the reclassification of a hereditary cancer syndrome gene variant: emerging themes from a qualitative study

Author: Laura Wedd, Margaret Gleeson, Bettina Meiser, Rosie O’Shea, Kristine Barlow-Stewart, Amanda B. Spurdle, Paul James, Jane Fleming, Cassandra Nichols, Rachel Austin, Elisa Cops, Melissa Monnik, Judy Do, and Rajneesh Kaur
Subjects: Epidemiology, Public Health, Environmental and Occupational Health, Genetics (clinical)
Abstract: The complexity of genetic variant interpretation means that a proportion of individuals who undergo genetic testing for a hereditary cancer syndrome will have their test result reclassified over time. Such a reclassification may involve a clinically significant upgrade or downgrade in pathogenicity, which may have significant implications for medical management. To date, few studies have examined the psychosocial impact of a reclassification in a hereditary cancer syndrome context. To address this gap, semi-structured telephone interviews were performed with eighteen individuals who had a BRCA1, BRCA2 or Lynch syndrome-related (MLH1, MSH2, MSH6 or PMS2) gene variant reclassified. The interviews were analysed utilising an inductive, qualitative approach and emergent themes were identified by thematic analysis. Variable levels of recall amongst participants were found. Common motivations for initial testing included a significant personal and/or family history of cancer and a desire to “find an answer”. No individual whose uncertain result was upgraded reported negative psychosocial outcomes; most reported adapting to their reclassified result and appraised their genetic testing experience positively. However, individuals whose likely pathogenic/pathogenic results were downgraded reported feelings of anger, shock and sadness post reclassification, highlighting that additional psychosocial support may be required for some. Genetic counselling issues and recommendations for clinical practice are outlined.
Published: 2023

41. Supplementary Tables 2 - 5, Figures 2 - 3 from A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

Author: Jyotsna Batra, Jong Y. Park, Judith A. Clements, Amanda B. Spurdle, Manuel R. Teixeira, Radka Kaneva, Hermann Brenner, Lisa Cannon-Albright, Cezary Cybulski, Adam S. Kibel, Christiane Maier, Stephen Thibodeau, William J. Blot, Janet L. Stanford, Kay-Tee Khaw, Paul Pharoah, David Neal, Ruth C. Travis, Børge G. Nordestgaard, Johanna Schleutker, Christopher A. Haiman, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Doug Easton, Rosalind Eeles, Srilakshmi Srinivasan, Thomas A. Sellers, Jennifer Permuth-Wey, Hui-Yi Lin, Donghwa Kim, Tracy A. O'Mara, Kerenaftali Klein, Ernest Amankwah, and Shane Stegeman
Abstract: Supplementary Table 2. Indolent versus aggressive disease analysis. Supplementary Table 3. Geometric mean PSA levels by genotype in cases and controls. Supplementary Table 4. Association of miRSNPs with prostate cancer risk in different age categories. Supplementary Table 5. Association of miRSNPs with expression of genes located in cis using TCGA SNP array and RNASeq data. Supplementary Figure 2. miRNA target reporter vector assays. Supplementary Figure 3. miR-3162-5p is expressed in prostate and prostate cancer-derived cell lines as well as in prostate cancer patient tissue samples.
Published: 2023

42. Supplementary Table 1 from A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

Author: Jyotsna Batra, Jong Y. Park, Judith A. Clements, Amanda B. Spurdle, Manuel R. Teixeira, Radka Kaneva, Hermann Brenner, Lisa Cannon-Albright, Cezary Cybulski, Adam S. Kibel, Christiane Maier, Stephen Thibodeau, William J. Blot, Janet L. Stanford, Kay-Tee Khaw, Paul Pharoah, David Neal, Ruth C. Travis, Børge G. Nordestgaard, Johanna Schleutker, Christopher A. Haiman, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Doug Easton, Rosalind Eeles, Srilakshmi Srinivasan, Thomas A. Sellers, Jennifer Permuth-Wey, Hui-Yi Lin, Donghwa Kim, Tracy A. O'Mara, Kerenaftali Klein, Ernest Amankwah, and Shane Stegeman
Abstract: Supplementary Table 1. Prostate cancer risk estimates for 2169 putative miRSNPs.
Published: 2023

43. Supplementary Figure 1 from A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer

Author: Jyotsna Batra, Jong Y. Park, Judith A. Clements, Amanda B. Spurdle, Manuel R. Teixeira, Radka Kaneva, Hermann Brenner, Lisa Cannon-Albright, Cezary Cybulski, Adam S. Kibel, Christiane Maier, Stephen Thibodeau, William J. Blot, Janet L. Stanford, Kay-Tee Khaw, Paul Pharoah, David Neal, Ruth C. Travis, Børge G. Nordestgaard, Johanna Schleutker, Christopher A. Haiman, Henrik Gronberg, Fredrik Wiklund, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Doug Easton, Rosalind Eeles, Srilakshmi Srinivasan, Thomas A. Sellers, Jennifer Permuth-Wey, Hui-Yi Lin, Donghwa Kim, Tracy A. O'Mara, Kerenaftali Klein, Ernest Amankwah, and Shane Stegeman
Abstract: Supplementary Figure 1. Forest Plot (Fixed effects model) of the 22 prostate cancer risk associated miRSNPs.
Published: 2023

44. 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

45. Supplementary Data from Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry

Author: Joanne P. Young, Michael A. McGuckin, Noralane M. Lindor, Stephen N. Thibodeau, Bharati Bapat, Loic Le Marchand, John D. Potter, John A. Baron, Robert W. Haile, Finlay A. Macrae, Susan Parry, Sonja Woodall, Michael R. Gattas, Elise Pelzer, Kathy Tucker, Amanda Muir, Jack Goldblatt, Jill George, Graeme K. Suthers, Kerry D. Phillips, Mark A. Jenkins, John L. Hopper, Amanda B. Spurdle, Diane M. McKeone, Rhiannon Walters, Mark Clendenning, Sven T. Arnold, Sally-Ann Pearson, Margaret C. Cummings, Daniel D. Buchanan, and Michael D. Walsh
Abstract: Supplementary Data from Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry
Published: 2023

46. Supplementary Table 2 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 2. Results of the statistical analyses in BRCA mutation carriers.
Published: 2023

47. Supplementary Table 1 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 1. The 3,248 SNPs included in the study
Published: 2023

48. Supplementary Tables 1-4 from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: PDF file - 90K
Published: 2023

49. Supplementary Figure 3 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author: Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama
Abstract: Supplementary Figure 3. Absolute Risk (A model with only family history of prostate cancer)
Published: 2023

50. Data from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.
Published: 2023

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

480 results on '"Amanda B. Spurdle"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources