Citations 17
Pathogenic Variants, Family History, and Cumulative Risk of Breast Cancer in US Women
Keil, Alexander P. , Taylor, Jack A. , Yadav, Siddhartha , Culver, Hoda Anton, Auer, Paul L. , Bodelón, Clara , Haiman, Christopher A., Lindströem, Sara, Martinez, Maria Elena, Nathanson, Katherine L. , Patel, Alpa V. , Penney, Kathryn L., Ruddy, Kathryn J. , Teras, Lauren R., Vachon, Celine M. , Weitzel, Jeffrey N. , Yao, Song, Weitzel, Jeffrey N , Yadav, Siddhartha , Taylor, Jack A , Nathanson, Katherine L , O’Brien, Katie M. , Weinberg, Clarice R. , Polley, Eric C. , Boddicker, Nicholas , Hu, Chunling , Ambrosone, Christine B. , Brantley, Kristen D. , Burnside, Elizabeth S. , Chen, Fei , Domchek, Susan M. , Eliassen, A. Heather , Hodge, James M. , Kraft, Peter , Lacey, James V. , Neuhausen, Susan L. , Olson, Janet E. , Palmer, Julie R. , Penney, Kathryn , Scott, Christopher G. , Teras, Lauren R. , Trentham‐Dietz, Amy , Vachon, Celine M. , Yao, Song , Zirpoli, Gary , Couch, Fergus J. , Sandler, Dale P.
JAMA Oncology | October 9, 2025 | Volume: 11 | Issue: 12 | Pages: 1458
Importance Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described. Objective To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors. Design, Setting, and Participants This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025. Exposures PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors. Main Outcomes and Measures Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated. Results A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors. Conclusions and Relevance In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.
Exogenous Hormones, Tumor Intrinsic Subtypes, and Breast Cancer
Cornet, Charlotte Le , Truong, Thérèse, Bolla, Manjeet K. , Koutros, Stella, Stone, Jennifer , Shulman, Katerina, Aronson, Kristan J. , Guénel, Pascal, Patel, Alpa V , Bodelón, Clara , Teras, Lauren R., Shahi, Shamim , Dossus, Laure, Kaaks, R., Holleczek, Bernd , Hoppe, Reiner , Czene, Kamila, Hall, P.F., Mannermaa, Arto, Wu, Anna H. , Obi, Nadia , Panayiotidis, Mihalis I. , Haiman, Christopher A., Shu, Xiao , Perou, Charles M. , Alsten, Sarah Van, Eliassen, A. Heather, Kraft, Peter, Ahearn, Thomas U., Evans, D. Gareth , Wolk, Alicja, Easton, Douglas F., Pharoah, Paul D. P., Vachon, Celine M. , Chang-Claude, Jenny, Evans, D Gareth , Perou, Charles M , Stone, Jennifer , Panayiotidis, Mihalis I , Jung, Audrey , Behrens, Sabine , Middha, Pooja , Truong, Thérèse , Jernström, Helena , Wang, Qin , Southey, Melissa C. , Freeman, Laura E. Beane , Koutros, Stella , Rennert, Gad , Murphy, Rachel A. , Guénel, Pascal , Teras, Lauren R. , Lacey, James V. , Dossus, Laure , Kaaks, Rudolf , Brenner, Hermann , Brauch, Hiltrud , Czene, Kamila, Mannermaa, Arto , Michailidou, Kyriaki , McLean, Catriona , Haiman, Christopher A., Augustinsson, Annelie , Zheng, Wei , Troester, Melissa A. , Abubakar, Mustapha , Ahearn, Thomas U., Wolk, Alicja , Milne, Roger L. , Easton, Douglas F. , Schmidt, Marjanka K. , García‐Closas, Montserrat , Vachon, Celine M. , Fortner, Renée T. , Chang‐Claude, Jenny
JAMA Network Open | July 7, 2025 | Volume: 8 | Issue: 7 | Pages: e2519236
10.1001/jamanetworkopen.2025.19236
ImportanceEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.ObjectiveTo examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.Design, Setting, and ParticipantsThis study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.ExposureMHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).Main Outcomes and MeasuresBreast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30).ResultsThis study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors.Conclusions and RelevanceIn this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.
Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma
Winden, Annemieke W. J. Opstal‐van, Haan, Hugoline G. de , Hauptmann, Michael , Schmidt, Marjanka K. , Russell, Nicola S. , Janus, Cécile P.M. , Krol, Augustinus D. G. , Baan, Frederieke H. van der , Bruin, Marie L. De , Eggermond, Anna M. van, Haiman, Christopher A., Sawyer, Elinor J. , Hooning, Maartje J. , Peto, Julian , Orr, Nick , Easton, Douglas F. , Strong, Louise C. , Cooke, Rosie, Swerdlow, Anthony J. , Leeuwen, Flora E. van , de Haan, Hugoline G , De Bruin, Marie L , Dennis, Joe , Pharoah, Paul D P , Swerdlow, Anthony J , Schmidt, Marjanka K , Broeks, Annegien , Anton‐Culver, Hoda , Cox, Angela , Devilee, Peter , Couch, Fergus J. , Pharoah, Paul D.P. , Aleman, Berthe M.P. , Bhatia, Smita , Robison, Leslie L. , Sawyer, Elinor J , Orr, Nick
Blood | December 21, 2018 | Volume: 133 | Issue: 10 | Pages: 1130-1139
AbstractFemale Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.
The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity
Colombo, Mara , López‐Perolio, Irene, Caleca, Laura , Li, Hongyan , Vecchi, Giovanna De, Tudini, Emma , Foglia, Claudia , Mondini, P, Manoukian, Siranoush , Behar, Raquel, Gómez, E. , Meindl, Alfons, Montagna, Marco , Niederacher, Dieter , Schmidt, Ane Yde , Varesco, Liliana , Wappenschmidt, Barbara , Bolla, Manjeet K. , Michailidou, Kyriaki , Wang, Qin , Aittomäki, Kristiina, Andrulis, Irene L. , Beckmann, Matthias W. , Beeghly-Fadel, Alicia, Benı́tez, Javier , Bojesen, Stig E. , Bonanni, Bernardo, Brauch, Hiltrud , Brenner, Hermann , Burwinkel, Barbara , Chang‐Claude, Jenny , Conroy, Don, Eriksson, Mikael , Fasching, Peter A. , Figueroa, Jonine D. , Fletcher, Olivia , Flyger, Henrik, Gabrielson, Marike , García‐Closas, Montserrat , González‐Neira, Anna , Guénel, Pascal , Haiman, Christopher A., Hamann, Ute , Hartman, Mikael , Hauke, Jan , Hopper, John L. , Jakubowska, Anna , Kosma, Veli‐Matti , Lambrechts, Diether , Marchand, Loid Le, Lindblom, Annika , Lubiński, Jan , Mannermaa, Arto, Margolin, Sara , Miao, Hui, Peterlongo, Paolo , Peto, Julian , Pylkäs, Katri , Sawyer, Elinor J. , Schmutzler, Rita K., Schneeweiß, Andreas , Schoemaker, Minouk J. , See, Mee‐Hoong , Southey, Melissa C. , Swerdlow, Anthony J. , Teo, Soo‐Hwang , Tomlinson, Ian , Truong, Thérèse , Ouweland, Ans M.W. van den, Kolk, Lizet E. van der, Winqvist, Robert , Zheng, Wei , Investigators, kConFab/AOCS, Easton, Douglas F. , Henderson, Alex, Hogervorst, Frans B.L., Izatt, Louise, Offitt, Kenneth, Side, Lucy, Rensburg, Elizabeth J. van , EMBRACE, Study, HEBON, Study, McGuffog, Lesley, Antoniou, Antonis C. , Chenevix‐Trench, Georgia , Goldgar, David E., Hoya, Miguel de la , Radice, Paolo , Bowtell, David D.L. , Lambrechts, Diether , Lambrechts, Diether , Peterlongo, Paolo , Teo, Soo H , van Rensburg, Elizabeth J , Swerdlow, Anthony J , de la Hoya, Miguel , Radice, Paolo , Southey, Melissa C , Jakubowska, Anna , Lambrechts, Diether , Brenner, Hermann , Guénel, Pascal , Hartman, Mikael , García-Closas, Montserrat , Michailidou, Kyriaki , Benitez, Javier , Montagna, Marco , Chenevix-Trench, Georgia , Zheng, Wei , Eriksson, Mikael , Figueroa, Jonine D , Gabrielson, Marike , Bowtell, David D , Meeks, Huong , Parsons, Michael T. , Meindl, Alfons, Dennis, Joe , Anton‐Culver, Hoda , Arndt, Volker , Boeckx, Bram , Bogdanova, Natalia , Bonanni, Bernardo , Couch, Fergus J. , Cox, Angela , Cross, Simon S. , Czene, Kamila , Devilee, Peter , Dörk, Thilo , Giles, Graham G. , Hall, Per N , Hollestelle, Antoinette , Jung, Audrey , Mannermaa, Arto , Miao, Hui, Milne, Roger L. , Neuhausen, Susan L. , Nevanlinna, Heli , Olson, Janet E. , Schmidt, Marjanka K. , Toland, Amanda Ewart , Asperen, Christi J. van , Yannoukakos, Drakoulis , Investigators, kConFab/AOCS, Dunning, Alison M. , Spurdle, Amanda B. , Goldgar, David E., Pylkäs, Katri , Gómez-García, Encarna B , Hauke, Jan , Manoukian, Siranoush , Lubinski, Jan , Fletcher, Olivia , Bojesen, Stig E , Schoemaker, Minouk J , Truong, Therese , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J
Human Mutation | February 21, 2018 | Volume: 39 | Issue: 5 | Pages: 729-741
PHIP- a novel candidate breast cancer susceptibility locus on 6q14.1
Jiao, Xiang , Collaborators, NBCS, Investigators, kConFab/AOCS, Aravidis, Christos , Marikkannu, Rajeshwari, Rantala, Johanna, Adamović, Tatjana , Maguire, Paula , Kremeyer, Bárbara , Holst, Susanna von, Kontham, Vinaykumar, Thutkawkorapin, Jessada , Margolin, Sara , Du, Quan , Lundin, Johanna , Michailidou, Kyriaki , Bolla, Manjeet K. , Wang, Qin , Andrulis, Irene L. , Antonenkova, Natalia, Beckmann, Matthias W. , Blomqvist, Carl , Blot, William J. , Bojesen, Stig E. , Brand, Judith S. , Brauch, Hiltrud , Brenner, Hermann , Brüning, Thomas , Burwinkel, Barbara , Chang‐Claude, Jenny , Couch, Fergus J. , Deming-Halverson, Sandra, Dörk, Thilo , Eriksson, Mikael , Fasching, Peter A. , Figueroa, Jonine D. , Flesch‐Janys, Dieter, Flyger, Henrik, Gabrielson, Marike , García‐Closas, Montserrat , González‐Neira, Anna , Guénel, Pascal , Guo, Qi , Gündert, Melanie , Haiman, Christopher A., Hallberg, Emily, Hamann, Ute , Harrington, Patricia, Hooning, Maartje J. , Hopper, John L. , Huang, Guanmengqian, Jakubowska, Anna , Jones, Michael E. , Kerin, Michael J. , Kosma, Veli‐Matti , Kristensen, Vessela N. , Lambrechts, Diether , Lubiński, Jan , Mannermaa, Arto, Meindl, Alfons, Mulligan, Anna Marie , Peto, Julian, Pylkäs, Katri , Radice, Paolo , Rhenius, Valerie , Sawyer, Elinor J. , Schmutzler, Rita K., Seynaeve, Caroline, Shah, Mitul , Simard, Jacques , Southey, Melissa C. , Swerdlow, Anthony J. , Truong, Thérèse , Wendt, Camilla, Winqvist, Robert , Easton, Douglas F. , Lindblom, Annika , Durocher, Francine , Bowtell, David D.L. , Lambrechts, Diether , Dörk, Thilo , Lambrechts, Diether , Swerdlow, Anthony J , Radice, Paolo , Southey, Melissa C , Jakubowska, Anna , Jones, Michael E , Lambrechts, Diether , Brenner, Hermann , Guénel, Pascal , García-Closas, Montserrat , Michailidou, Kyriaki , Simard, Jacques , Eriksson, Mikael , Figueroa, Jonine D , Gabrielson, Marike , Bowtell, David D , Collaborators, NBCS, Investigators, kConFab/AOCS, Picelli, Simone , Liu, Tao , Luo, Liping , Dennis, Joe , Lush, Michael J. , Ambrosone, Christine B. , Anton‐Culver, Hoda , Arndt, Volker , Boeckx, Bram , Bonanni, Bernardo , Broeks, Annegien , Cai, Qiuyin , Couch, Fergus J. , Cox, Angela , Cross, Simon S. , Devilee, Peter , dos‐Santos‐Silva, Isabel , Giles, Graham G. , Hooning, Maartje J. , Marchand, Loı̈c Le , Mannermaa, Arto, Martens, John W.M. , Meindl, Alfons, Milne, Roger L. , Neuhausen, Susan L. , Nevanlinna, Heli , Schmidt, Marjanka K. , Zheng, Wei , Benı́tez, Javier , Dunning, Alison M. , Pharoah, Paul D.P. , Czene, Kamila , Hall, Per N , Pylkäs, Katri , Lubinski, Jan , Bojesen, Stig E , Truong, Therese , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J
Oncotarget | December 7, 2017 | Volume: 8 | Issue: 61 | Pages: 102769-102782
Body mass index and breast cancer survival: a Mendelian randomization analysis
Guo, Qi , Burgess, Stephen , Bolla, Manjeet K. , Wang, Qin , Abraham, Jean , Aittomäki, Kristiina, Andrulis, Irene L. , Apicella, Carmel, Berg, Christine D. , Blomqvist, Carl , Bojesen, Stig E. , Brand, Judith S. , Brenner, Hermann , Burwinkel, Barbara , Caldas, Carlos , Campa, Daniele , Canzian, Federico , Chang‐Claude, Jenny , Couch, Fergus J. , Darabi, Hatef, Diver, W. Ryan , Earl, Helena , Eccles, Diana M, Ekici, Arif B. , Eriksson, Mikael , Evans, D. Gareth , Fasching, Peter A. , Figueroa, Jonine D. , Flesch‐Janys, Dieter, Flyger, Henrik, Gapstur, Susan M. , Gaudet, Mia M. , Glendon, Gord, Grip, Mervi, Haeberle, Lothar, Haiman, Christopher A., Hamann, Ute, Hankinson, Susan E. , Hein, Alexander , Hiller, Louise , Hogervorst, Frans B.L., Holleczek, Bernd , Hooning, Maartje J. , Hoover, Robert N. , Humphreys, Keith , Hunter, David J., Hüsing, Anika , Jakubowska, Anna , Jukkola‐Vuorinen, Arja , Kabisch, Maria, Investigators, kConFab/AOCS, Knight, Julia A. , Koppert, Linetta B. , Kosma, Veli‐Matti , Kristensen, Vessela N. , Lambrechts, Diether , Li, Jingmei , Lindblom, Annika , Lindström, Sara, Lissowska, Jolanta , Lubiński, Jan , Machiela, Mitchell J. , Mannermaa, Arto, Manoukian, Siranoush , Margolin, Sara , Marmé, F., McLean, Catriona , Menéndez, Primitiva, Mulligan, Anna Marie , Muranen, Taru , Neven, Patrick , Nielsen, Sune F. , Nordestgaard, Børge G. , Perez, Jose IA, Peterlongo, Paolo , Phillips, Kelly‐Anne , Poole, Christopher, Pylkäs, Katri , Radice, Paolo , Rüdiger, Thomas , Sawyer, Elinor J. , Schumacher, Fredrick R. , Seynaeve, Caroline, Shah, Mitul , Smeets, Ann , Southey, Melissa C. , Tollenaar, Rob A.�E.�M. , Tomlinson, Ian , Ulmer, Hans-Ulrich, Vachon, Celine M. , Ouweland, Ans MW van den, Veer, Laura J. van’t , Wildiers, Hans , Winqvist, Robert , Zamora, M. Pilar , Chenevix‐Trench, Georgia , Dörk, Thilo , Easton, Douglas F. , García‐Closas, Montserrat , Kraft, Peter , Hopper, John L. , Pharoah, Paul D.P., Eccles, Diana , Bowtell, David D.L. , Lambrechts, Diether , Vachon, Celine, Turman, Constance , Lush, Michael J. , Arndt, Volker , Benı́tez, Javier , Bonanni, Bernardo , Broeks, Annegien , Chanock, Stephen Jacob , Chin, Suet‐Feung , Couch, Fergus J. , Cox, Angela , Cross, Simon S. , Cybulski, Cezary , Czene, Kamila , Devilee, Peter , Dunning, Alison M. , Eriksson, Mikael , Giles, Graham G. , Gronwald, Jacek , Hall, Per N , Hankinson, Susan E. , Hartikainen, Jaana M. , Hooning, Maartje J. , Kaaks, Rudolf , Kataja, Vesa , Investigators, kConFab/AOCS, Marchand, Loı̈c Le , Mannermaa, Arto, Martens, John W.M. , Milne, Roger L. , Nevanlinna, Heli , Olson, Janet E. , Rahman, Nazneen , Rudolph, Anja , Seibold, Petra , Tsimiklis, Helen , Vachon, Celine M. , Willett, Walter C. , Zheng, Wei , Schmidt, Marjanka K. , Dörk, Thilo , Lambrechts, Diether , Peterlongo, Paolo , Hein, Alexander , Eccles, Diana , Radice, Paolo , Lissowska, Jolanta , Caldas, Carlos , Evans, D Gareth , Southey, Melissa C , Canzian, Federico , Jakubowska, Anna , Lambrechts, Diether , Brenner, Hermann , Li, Jingmei , Muranen, Taru A , García-Closas, Montserrat , Ekici, Arif B , Kraft, Peter , Chenevix-Trench, Georgia , Figueroa, Jonine D , Machiela, Mitchell J , Hüsing, Anika , Bowtell, David D , Pylkäs, Katri , Manoukian, Siranoush , Lubinski, Jan , Bojesen, Stig E , Phillips, Kelly-Anne , Wildiers, Hans , Mclean, Catriona , Lindblom, Annika , Sawyer, Elinor J
International Journal of Epidemiology | June 29, 2017 | Volume: 46 | Issue: 6 | Pages: 1814-1822
BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer
Mesman, Romy L.S. , Nicolai, Catharina Von , Ehlén, Åsa , Guidugli, Lucia, Martin, Charlotte , Calléja, Fabienne M.G.R., Hallberg, Emily, Hinton, Jamie, Lilyquist, Jenna , Hu, Chunling , Aalfs, Cora M. , Aittomäki, Kristiina, Andrulis, Irene L. , Beckmann, Matthias W. , Benı́tez, Javier , Bogdanova, Natalia , Bojesen, Stig E. , Bolla, Manjeet K. , Børresen‐Dale, Anne‐Lise , Brauch, Hiltrud , Brennan, Paul , Brenner, Hermann , Brouwers, Barbara , Brüning, Thomas , Burwinkel, Barbara , Chang‐Claude, Jenny , Chenevix‐Trench, Georgia , Cheng, Ching‐Yu , Choi, Ji‐Yeob , Collée, J. Margriet, Darabi, Hatef, Dörk, Thilo , Fasching, Peter A. , Figueroa, Jonine D. , Flyger, Henrik, García‐Closas, Montserrat , Glendon, Gord, Guénel, Pascal , Haiman, Christopher A., Hamann, Ute, Hartman, Mikael , Hogervorst, Frans B.L., Hopper, John L. , Jakubowska, Anna , Kang, Daehee , Kosma, Veli‐Matti , Kristensen, Vessela N. , Lai, Kah-Nyin, Lambrechts, Diether , Li, Jingmei , Lindblom, Annika , Lubiński, Jan , Macháčková, Eva , Mannermaa, Arto, Margolin, Sara , Matsuo, Keitaro , Miao, Hui , Michailidou, Kyriaki , Muir, Kenneth , Olswold, Curtis, Oosterwijk, Jan J.C., Osório, Ana , Peterlongo, Paolo , Peto, Julian , Pylkäs, Katri , Radice, Paolo , Rashid, Muhammad Usman , Rhenius, Valerie , Sangrajrang, Suleeporn , Sawyer, Elinor J. , Schmidt, Marjanka K. , Schoemaker, Minouk J. , Seynaeve, Caroline, Shah, Mitul , Shrubsole, Martha J. , Slager, Susan, Southey, Melissa C. , Swerdlow, Anthony J. , Teo, Soo‐Hwang , Tomlinson, Ian , Torres, Diana , Truong, Thérèse , Kolk, Lizet E. van der, Wang, Qin, Winqvist, Robert , Wu, Anna H. , Yu, Jyh‐Cherng , Zheng, Wei , Zheng, Ying , Leary, Jennifer, Walker, Logan C. , Foretová, Lenka , Claes, Kathleen , Varesco, Liliana , Moghadasi, Setareh , Easton, Douglas F. , Devilee, Peter , Vrieling, Harry , Monteiro, Álvaro N.A. , Goldgar, David E., Carreira, Aura , Vreeswijk, Maaike P.G. , Bowtell, David D.L. , Lambrechts, Diether , Shimelis, Hermela , Meeks, Huong , Anton‐Culver, Hoda , Arndt, Volker , Broeks, Annegien , Cox, Angela , Cross, Simon S. , Czene, Kamila , Dennis, Joe , dos‐Santos‐Silva, Isabel , Dunning, Alison M. , Giles, Graham G. , Hall, Per N , Hollestelle, Antoinette , Ito, Hidemi , Marchand, Loı̈c Le , Lophatananon, Artitaya , Mannermaa, Arto, Marmé, Frederik , Milne, Roger L. , Neuhausen, Susan L. , Nevanlinna, Heli , Olson, Janet E. , Pharoah, Paul D.P. , Rudolph, Anja , Shen, Chen‐Yang , Shu, Xiao‐Ou , Stram, Daniel O. , Asperen, Christi J. van , Wang, Qin, Fostira, Florentia , Spurdle, Amanda B. , Goldgar, David E., Couch, Fergus J. , Dörk, Thilo , Lambrechts, Diether , Peterlongo, Paolo , Teo, Soo H , Shrubsole, Martha J , Monteiro, Alvaro N , Swerdlow, Anthony J , Vreeswijk, Maaike P G , Radice, Paolo , Claes, Kathleen B M , Southey, Melissa C , Muir, Kenneth , Matsuo, Keitaro , Jakubowska, Anna , Lambrechts, Diether , Brenner, Hermann , Guénel, Pascal , Hartman, Mikael , Li, Jingmei , Torres, Diana , García-Closas, Montserrat , Schmidt, Marjanka K , Hu, Chunling , Michailidou, Kyriaki , Bogdanova, Natalia V , Benitez, Javier , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Bowtell, David D , Pylkäs, Katri , Rashid, Muhammad U , Devilee, Peter , Lubinski, Jan , Bojesen, Stig E , Schoemaker, Minouk J , Truong, Therese , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Kang, Daehee
Cancer Research | March 10, 2017 | Volume: 77 | Issue: 11 | Pages: 2789-2799
Abstract Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.
Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21
Hamdi, Yosr , Collaborators, NBCS, Soucy, Penny, Adoue, Véronique , Michailidou, Kyriaki , Canisius, Sander , Lemaçon, Audrey , Droit, Arnaud , Andrulis, Irene L. , Baynes, Caroline, Blomqvist, Carl , Bogdanova, Natalia , Bojesen, Stig E. , Bolla, Manjeet K. , Børresen‐Dale, Anne‐Lise , Brand, Judith S. , Brauch, Hiltrud , Brenner, Hermann , Burwinkel, Barbara , Chang‐Claude, Jenny , Darabi, Hatef, Devilee, Peter , Dörk, Thilo , Eriksson, Mikael , Fasching, Peter A. , Figueroa, Jonine D. , Flyger, Henrik, García‐Closas, Montserrat , Goldberg, Mark S. , González‐Neira, Anna , Grenaker-Alnæs, Grethe Irene, Guénel, Pascal , Haeberle, Lothar, Haiman, Christopher A., Hamann, Ute, Hallberg, Emily, Hooning, Maartje J. , Jakubowska, Anna , Jones, Michael E. , Kabisch, Maria, Kataja, Vesa , Lambrechts, Diether , Lindblom, Annika , Lubiński, Jan , Mannermaa, Arto, Maranian, Mel, Margolin, Sara , Marme, Frederik, Neven, Patrick , Olswold, Curtis, Peto, Julian, Plaseska‐Karanfilska, Dijana , Pylkäs, Katri , Radice, Paolo , Sawyer, Elinor J. , Schmidt, Marjanka K. , Shu, Xiao-Ou , Southey, Melissa C. , Swerdlow, Anthony J. , Tollenaar, Rob A.�E.�M. , Tomlinson, Ian , Torres, Diana , Truong, Thérèse , Vachon, Celine M. , Ouweland, Ans M.W. van den, Wang, Qin , Winqvist, Robert , Investigators, kConFab AOCS, Benı́tez, Javier , Chenevix‐Trench, Georgia , Dunning, Alison M. , Kristensen, Vessela N. , Easton, Douglas F. , Pastinen, Tomi , Simard, Jacques , Durocher, Francine , Zheng, Wei , Thorne, Heather , Lambrechts, Diether , Vachon, Celine, Collaborators, NBCS, Anton‐Culver, Hoda , Arndt, Volker , Bonanni, Bernardo , Broeks, Annegien , Couch, Fergus J. , Cox, Angela , Cross, Simon S. , Czene, Kamila , Dennis, Joe , dos‐Santos‐Silva, Isabel , Eriksson, Mikael , Giles, Graham G. , Hooning, Maartje J. , Hopper, John L. , Marchand, Loı̈c Le , Mannermaa, Arto , Milne, Roger L. , Neuhausen, Susan L. , Nevanlinna, Heli , Rudolph, Anja , Vachon, Celine M. , Zheng, Wei , Pharoah, Paul D.P. , Hall, Per N , Nord, Silje , Dörk, Thilo , Lambrechts, Diether , Swerdlow, Anthony J , Radice, Paolo , Southey, Melissa C , Dunning, Alison M , Jakubowska, Anna , Jones, Michael E , Lambrechts, Diether , Brenner, Hermann , Guénel, Pascal , Torres, Diana , García-Closas, Montserrat , Schmidt, Marjanka K , Michailidou, Kyriaki , Bogdanova, Natalia V , Benitez, Javier , Simard, Jacques , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Pylkäs, Katri , Devilee, Peter , Lubinski, Jan , Bojesen, Stig E , Truong, Therese , Brauch, Hiltrud , Lindblom, Annika , Plaseska-Karanfilska, Dijana , Sawyer, Elinor J , Droit, Arnaud
Oncotarget | November 28, 2016 | Volume: 7 | Issue: 49 | Pages: 80140-80163
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
Southey, Melissa C. , Goldgar, David E, Winqvist, Robert , Pylkäs, Katri , Michailidou, Kyriaki , Rensburg, Elizabeth J. van , Heikkinen, Tuomas , Hopper, John L. , Dörk, Thilo , Claes, Kathleen , Teo, Zhi L. , Radice, Paolo , Catucci, Irene, Peterlongo, Paolo , Odefrey, Fabrice, Dowty, James G., Schmidt, Marjanka K. , Hogervorst, Frans B.L., Verhoef, Senno, Carpenter, Jane, Clarke, Christine L. , Scott, Rodney J. , Fasching, Peter A. , Haeberle, Lothar, Ekici, Arif B. , Beckmann, Matthias W. , Peto, Julian , Fletcher, Olivia , Johnson, Nichola , Bolla, Manjeet K. , Sawyer, Elinor J. , Tomlinson, Ian , Kerin, Michael J. , Miller, Nicola, Marmé, F., Burwinkel, Barbara , Guénel, Pascal , Truong, Thérèse , Sanchez, Marie, Bojesen, Stig E. , Nielsen, Sune F. , Flyger, Henrik, Benı́tez, Javier , Zamora, M. Pilar , Menéndez, Primitiva, Brenner, Hermann , Stegmaier, Christa, Brauch, Hiltrud , Brüning, Thomas , Ko, Yon‐Dschun, Muranen, Taru , Aittomäki, Kristiina, Blomqvist, Carl , Bogdanova, Natalia , Antonenkova, Natalia, Lindblom, Annika , Margolin, Sara , Mannermaa, Arto, Kataja, Vesa , Kosma, Veli‐Matti , Hartikainen, Jaana M. , Investigators, kConFab, Group, Australian Ovarian Cancer Study, Wauters, Els , Smeets, Dominiek, Beuselinck, Benoit , Floris, Giuseppe , Chang‐Claude, Jenny , Flesch‐Janys, Dieter, Vachon, Celine M. , McLean, Catriona , Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick R. , Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei , Hunter, David J. , Lindström, Sara, Hankinson, Susan E. , Kraft, Peter , Andrulis, Irene L. , Knight, Julia A. , Glendon, Gord, Mulligan, Anna Marie , Jukkola‐Vuorinen, Arja , Grip, Mervi, Kauppila, Saila , Devilee, Peter , Tollenaar, Robert A.E.M., Seynaeve, Caroline, García‐Closas, Montserrat , Figueroa, Jonine D. , Lissowska, Jolanta , Darabi, Hatef, Eriksson, Mikael , Eccles, Diana M, Tapper, William , Gerty, Sue, Hooning, Maartje J. , Collée, J. Margriet, Tilanus‐Linthorst, Madeleine M.A., Li, Jingmei , Brand, Judith S. , Humphreys, Keith , Reed, Malcolm , Luccarini, Craig , Baynes, Caroline, Dunning, Alison M. , Hamann, Ute, Torres, Diana , Ulmer, Hans Ulrich, Rüdiger, Thomas , Jakubowska, Anna , Lubiński, Jan , Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Yannoukakos, Drakoulis , Swerdlow, Anthony J. , Ashworth, Alan , Orr, Nick , Jones, Michael E. , González‐Neira, Anna , Pita, Guillermo , Alonso, M. Rosario, Álvarez, Núria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel , Bacot, François, Simard, Jacques , Dumont, Martine , Soucy, Penny, Eeles, Rosalind A. , Muir, Kenneth , Grönberg, Henrik , Schleutker, Johanna , Nordestgaard, Børge G. , Weischer, Maren , Travis, Ruth C. , Neal, David E. , Donovan, Jenny , Hamdy, Freddie C. , Stanford, Janet L. , Blot, William J. , Thibodeau, Stephen N. , Schaid, Daniel J. , Kelley, Joseph L., Maier, Christiane, Kibel, Adam S. , Butterbach, Katja, Kaneva, Radka , Batra, Jyotsna , Teixeira, Manuel R. , Olama, Ali Amin Al , Benlloch, Sara, Hartmann, Arndt , Hein, Alexander , Ruebner, Matthias , Lambrechts, Diether , Nieuwenhuysen, Els Van , Vergote, Ignace , Lambretchs, Sandrina, Rossing, Mary Anne, Nickels, Stefan , Eilber, Ursula, Wang‐Gohrke, Shan , Odunsi, Kunle , Sucheston‐Campbell, Lara, Friel, Grace , Lurie, Galina, Killeen, Jeffrey , Goodman, Marc T. , Runnebaum, Ingo B., Hillemanns, Peter , Pelttari, Liisa M. , Edwards, Robert P., Ness, Roberta B., Moysich, Kirsten B., Heitz, Florian , Harter, Philipp , Kommoss, Stefan , Walsh, Christine , Lester, Jenny, Jensen, Allan , Høgdall, Estrid , Peissel, Bernard , Bernard, Loris, Goode, Ellen L. , Vierkant, Robert A. , Cunningham, Julie M. , Fogarty, Zachary C. , Kalli, Kimberly R., Liang, Dong , Lu, Karen H., Hildebrandt, Michelle A.T., Wu, Xifeng , Levine, Douglas A. , Bisogna, Maria, Iversen, Edwin S., Marks, Jeffrey R. , Akushevich, Lucy , Schildkraut, Joellen M. , Terry, Kathryn L. , Stampfer, Meir J. , Tworoger, Shelley S. , Olson, Sara H. , Salvesen, Helga B., Altena, Anne M. van , Aben, Katja K.H. , Kiemeney, Lambertus A. , Massuger, Leon F.A.G. , Bean, Yukie T., Kelemen, Linda E., Le, Nhu D. , Górski, Bohdan , Menkiszak, Janusz , Høgdall, Claus , Lundvall, Lene, Nedergaard, Lotte , Engelholm, Svend Aage, Dicks, Ed , Campbell, Ian , McNeish, Iain A. , Whittemore, Alice S. , Rothstein, Joseph H. , McGuire, Valerie, Sieh, Weiva , Cai, Hui , Teten, Rachel Threet, Sutphen, Rebecca , McLaughlin, John R, Narod, Steven A., Phelan, Catherine M., Monteiro, Álvaro N.A. , Fenstermacher, David, Lin, Hui‐Yi , Sellers, Thomas A. , Chen, Y. Ann , Chen, Zhihua , Gayther, Simon A. , Ramus, Susan J. , Menon, Usha , Wu, Anna H. , Pearce, Celeste Leigh, Pike, Malcolm C., Dansonka‐Mieszkowska, Agnieszka , Plisiecka-Hałasa, Joanna, Moes-Sosnowska, Joanna , Kupryjańczyk, Jolanta , Song, Honglin , Winship, Ingrid , Chenevix‐Trench, Georgia , Tavtigian, Sean V. , Easton, Doug , Lu, Karen H. , Durocher, Francine , Eccles, Diana , Lambrechts, Diether , Vachon, Celine, Pankratz, Vernon S, Thibodeau, Stephen, Goldgar, David E, Couch, Fergus J. , Tischkowitz, Marc D. , Foulkes, William D. , Dennis, Joe , Nevanlinna, Heli , Reis‐Filho, Jorge S. , Tsimiklis, Helen , Broeks, Annegien , dos‐Santos‐Silva, Isabel , Yang, Rongxi , Ménégaux, F. , Sanchez, Marie, Pérez, José Ignacio Arias , Anton‐Culver, Hoda , Neuhausen, Susan L. , Ziogas, Argyrios , Clarke, Christina A. , Arndt, Volker , Mannermaa, Arto, Spurdle, Amanda B. , Group, Australian Ovarian Cancer Study, Rudolph, Anja , Seibold, Petra , Olson, Janet E. , Vachon, Celine M. , Pankratz, V. Shane , Marchand, Loı̈c Le , Kristensen, Vessela N. , Hankinson, Susan E. , Hollestelle, Antoinette , Chanock, Stephen Jacob , Czene, Kamila , Eriksson, Mikael , Eccles, Diana M, Rafiq, Sajjad , Hooning, Maartje J. , Martens, John W.M. , Hall, Per N , Cox, Angela , Toland, Amanda Ewart , Ambrosone, Christine B. , Wiklund, Fredrik E. , Khaw, Kay‐Tee , Cybulski, Cezary , Cannon‐Albright, Lisa , Park, Jong, Kote‐Jarai, Zsofia , Renner, Stefan P. , Doherty, Jennifer A. , Wilkens, Lynne R. , Bützow, Ralf C. , Modugno, Francesmary , Moysich, Kirsten B., Bois, Andreas du , Karlan, Beth Y. , Kjær, Susanne K. , Bonanni, Bernardo , Fridley, Brooke L. , Larson, Melissa C. , Hildebrandt, Michelle A.T. , Dao, Fanny , Berchuck, Andrew , Cramer, Daniel W. , Poole, Elizabeth M. , Bandera, Elisa V. , Orlow, Irene , Bjørge, Line , Pejovic, Tanja B. , Brooks‐Wilson, Angela , Cook, Linda S. , Gronwald, Jacek , Tyrer, Jonathan P. , Paul, James , Siddiqui, Nadeem , Glasspool, Rosalind , Shu, Xiao‐Ou , McLaughlin, John R, Permuth, Jennifer B. , Gentry‐Maharaj, Aleksandra , Berg, David Van Den , Pharoah, Paul D.P. , Giles, Graham G. , Milne, Roger L. , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Kiemeney, Lambertus A , McNeish, Iain A , Peterlongo, Paolo , Ramus, Susan J , Teixeira, Manuel R , Tworoger, Shelley S , van Rensburg, Elizabeth J , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Monteiro, Alvaro N , Swerdlow, Anthony J , Moysich, Kirsten , Radice, Paolo , Lissowska, Jolanta , Claes, Kathleen B M , Campbell, Ian G , Eeles, Rosalind A , Southey, Melissa C , Menkiszak, Janusz , Donovan, Jenny L , Muir, Kenneth , Schleutker, Johanna , Travis, Ruth C , Lin, Hui-Yi , Fogarty, Zachary C , Dunning, Alison M , Heitz, Florian , Jakubowska, Anna , Jones, Michael E , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Brenner, Hermann , Guénel, Pascal , Li, Jingmei , Muranen, Taru A , Torres, Diana , García-Closas, Montserrat , Schmidt, Marjanka K , Winship, Ingrid M , Ekici, Arif B , Michailidou, Kyriaki , Hartikainen, Jaana M , Bogdanova, Natalia V , Kraft, Peter , Benitez, Javier , Simard, Jacques , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Høgdall, Estrid , Høgdall, Claus K , Batra, Jyotsna , Pylkäs, Katri , Yannoukakos, Drakoulis , Devilee, Peter , Lubinski, Jan , Fletcher, Olivia , Bojesen, Stig E , Goodman, Marc T , Truong, Therese , Mclean, Catriona , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Orr, Nick
Journal of Medical Genetics | September 5, 2016 | Volume: 53 | Issue: 12 | Pages: 800-811
Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing
Easton, Douglas F. , Lesueur, Fabienne , Decker, Brennan , Michailidou, Kyriaki , Li, Jun , Allen, Jamie , Luccarini, Craig , Pooley, Karen A. , Shah, Mitul , Bolla, Manjeet K. , Wang, Qin, Ahmad, Jamil , Thompson, Ella R. , Pertesi, Maroulio , Voegele, Catherine , Mebirouk, Noura, Robinot, Nivonirina , Forey, Nathalie, Luben, Robert , Aittomäki, Kristiina, Group, Australian Ovarian Cancer Study, Baynes, Caroline, Beckman, Matthias W., Benı́tez, Javier , Blot, William J. , Bogdanova, Natalia , Bojesen, Stig E. , Brenner, Hermann , Chang‐Claude, Jenny , Chia, Kee Seng , Choi, Ji‐Yeob , Conroy, Don, Darabi, Hatef, Devilee, Peter , Eriksson, Mikael , Fasching, Peter A. , Figueroa, Jonine D. , Flyger, Henrik, García‐Closas, Montserrat , Giles, Graham G. , Glendon, Gord, Guénel, Pascal , Haiman, Christopher A., Hart, Steven N. , Hartman, Mikael , Hooning, Maartje J. , Hsiung, Chia‐Ni , Jakubowska, Anna , James, Paul A. , John, Esther M. , Johnson, Nichola , Jones, Michael E. , Kabisch, Maria, Kang, Daehee , Investigators, kConFab, Kosma, Veli‐Matti , Kristensen, Vessela, Lambrechts, Diether , Li, Na , Investigators, Lifepool, Lindblom, Annika , Long, Jirong , Lophatananon, Artitaya, Lubiński, Jan , Mannermaa, Arto, Manoukian, Siranoush , Margolin, Sara , Matsuo, Keitaro , Meindl, Alfons , Mitchell, Gillian, Investigators, NBCS, Nevelsteen, Ines, Ouweland, Ans van den, Peterlongo, Paolo , Phuah, Sze Yee, Pylkäs, Katri , Rowley, Simone M. , Sangrajrang, Suleeporn , Schmutzler, Rita K., Shen, Chen‐Yang , Southey, Melissa C. , Surowy, Harald , Swerdlow, Anthony J. , Teo, Soo‐Hwang , Tollenaar, Rob A.�E.�M. , Tomlinson, Ian , Torres, Diana , Truong, Thérèse , Vachon, Celine M. , Verhoef, Senno, Wong‐Brown, Michelle W. , Zheng, Wei , Zheng, Ying , Scott, Rodney J. , Andrulis, Irene L. , Wu, Anna H. , Hopper, John L. , Winqvist, Robert , Burwinkel, Barbara , Sawyer, Elinor J. , Schmidt, Marjanka K. , Dörk, Thilo , Brauch, Hiltrud , Hamann, Ute, Fletcher, Olivia , Campbell, Ian , Dunning, Alison M. , Calvez‐Kelm, Florence Le , Goldgar, David E, Tavtigian, Sean V. , Chenevix‐Trench, Georgia , Thorne, Heather , Lambrechts, Diether , Luben, Robert N , Vachon, Celine, Decker, Brennan , Wang, Qin, Dennis, Joe , Damiola, Francesca , Durand, Geoffroy , Ahmed, Shahana , Anton‐Culver, Hoda , Arndt, Volker , Group, Australian Ovarian Cancer Study, Berg, David Van Den , Cox, Angela , Cross, Simon S. , Czene, Kamila , Eriksson, Mikael , Fostira, Florentia , González‐Neira, Anna , Hall, Per N , Hooning, Maartje J. , Ito, Hidemi , Investigators, kConFab, Kristensen, Vessela N. , Investigators, Lifepool, Mannermaa, Arto, Meindl, Alfons , Muir, Kenneth , Investigators, NBCS, Shu, Xiao‐Ou , Vachon, Celine M. , Nevanlinna, Heli , Couch, Fergus J. , Rudolph, Anja , Neuhausen, Susan L. , Milne, Roger L. , Pharoah, Paul D.P. , Goldgar, David E, Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , James, Paul , Lesueur, Fabienne , Peterlongo, Paolo , Teo, Soo H , Swerdlow, Anthony J , Campbell, Ian G , John, Esther M , Southey, Melissa C , Matsuo, Keitaro , Hart, Steven N , Dunning, Alison M , Jakubowska, Anna , Jones, Michael E , Lambrechts, Diether , Brenner, Hermann , Guénel, Pascal , Hartman, Mikael , Torres, Diana , García-Closas, Montserrat , Schmidt, Marjanka K , Michailidou, Kyriaki , Bogdanova, Natalia V , Benitez, Javier , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Pylkäs, Katri , Devilee, Peter , Manoukian, Siranoush , Lubinski, Jan , Fletcher, Olivia , Bojesen, Stig E , Truong, Therese , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Kang, Daehee
Journal of Medical Genetics | April 22, 2016 | Volume: 53 | Issue: 5 | Pages: 298-309
Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.