Citations 14
Clarifying risk-factor associations with quantitative breast tumor features: a pooled analysis of 24 studies
Adams, Daniel , Hurson, Amber N. , Ahearn, Thomas U, Andrulis, Irene L, Antoniou, Antonis C, Auvinen, Päivi, Bane, Anita, González, Amy Berrington de , Bodelon, Clara, Bolla, Manjeet K. , Borrero, Maria , Brenner, Hermann, Brock, Ian W., Camp, Nicola J. , Cessna, Melissa H., Chanock, Stephen J, Chenevix-Trench, G, Copson, ER, Fh, Couch, Devilee, P, Easton, Douglas F, Eccles, Diana, Figueroa, Jonine D, Glendon, Gord, Hamann, U, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette A M, Hodge, James M, Holleczek, Bernd, Hollestelle, A M, Mj, Hooning, Investigators, kConFab, Amor, David, Andrews, Lesley , Antill, Y , Rl, Balleine, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Bodek, Simon, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Caldon, Liz, Campbell, Ian, Chakrabarti, Anannya , Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Cohen, Paul, Colley, Alison, Cui, James, Courtney, Eliza, Cummings, Margaret, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Duijf, Pascal, Edwards, Stacey, Farshid, Gelareh , Fellows, AM, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet , Friedlander, Michael, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Harraka, Philip, Hayward, Nick, Hoskins, Cass , Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Koehler, Jessica, Kollias, J, Lakhani, Sunil, Lawrence, Mitchell, Lee, Jason , Li, Shuai, Lindeman, Geoff, Lippey, Jocelyn, Lipton, Lara, Loi, Sherene, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Reed, Amy McCart, Milne, Roger, Nightingale, Sophie , O’Connell, Shona, O’Sullivan, Sarah, Reilly, Robert O', Ortega, David Gallego, Pachter, Nick, Pang, Jia-Min, Pathak, Gargi, Patterson, Briony, Phillips, Kelly, Pieper, Ellen, Ramus, Susan, Rickard, Edwina, Ragunathan, Abi, Robinson, Bridget, Skandarajah, Anita, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Rodney, Scott, Clare, Sexton, Adrienne, Shaw, Joanne, Shelling, Andrew, Srinivasa, Shweta , Simpson, Peter, Mc, Southey, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, A H, Tucker, Kathy , Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, I, Young, Mary Ann, Zaheed, Milita , Investigators, S On Behalf Of The Chlovis Study, Tan, Veronique Kiak Mien , Lim, Geok Hoon, Tan, Ern Yu , Tan, Su-Ming, Iau, Philip Tsau Choong , Jakubowska, A, Jones, Michael E. , Jones, Louise , Jones, Brandt, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske , Lawrence, Scott, Li, J M, Lubiński, J, Mannermaa, Arto, Manoochehri, Mehdi, Martens, John W M, Mesker, Wilma E, Muhammad, Noor , Obi, Nadia, Olson, Janet E, Patel, Alpa V, Prajzendanc, Karolina , Ruddy, Kathryn J, Safizadeh, Fatemeh , Schöttker, Ben, Tengström, Maria , Le, Teras, Timmermans, M, Tollenaar, RA, Vachon, Celine M, Wang, Q, Yang, Xiaohong R, Zamora, M Pilar, Chang-Claude, Jenny, Schmidt, M K, Pharoah, Paul D P, Abubakar, Mustapha, Eccles, Diana , Ahearn, Thomas U. , Eccles, Diana , Jones, Michael E , Jones, J. Louise , Berrington de Gonzalez, Amy , Antoniou, Antonis C. , Bane, Anita, Behrens, Sabine , Białkowska, Katarzyna , Bodelón, Clara , Brenner, Hermann , Broeks, Annegien , Chanock, Stephen Jacob , Chenevix‐Trench, Georgia , Copson, Ellen , Couch, Fergus J, Cox, Angela , Cross, Simon S. , Devilee, Peter , Dunning, Alison M. , Easton, Douglas F. , Figueroa, Jonine D. , Glendon, Gord, González‐Neira, Anna , Hartikainen, Jaana M. , Hartman, Mikael , Heemskerk‐Gerritsen, Bernadette A. M. , Ho, Peh Joo , Hodge, James M. , Holleczek, Bernd , Hollestelle, Antoinette , Hooning, Maartje J. , Investigators, kConFab, Balleine, Rosemary L. , Bennett, Ian, Bogwitz, Michael R. , Bodek, Simon , Botes, Leon P., Buckley, Michael , Cohen, Paul A. , Crook, Ashley , Courtney, Eliza , Dawson, Sarah‐Jane , DeFazio, Anna , Delatycki, Martin B. , Duijf, Pascal H. G. , Fellows, Andrew, Fenton, Georgina L. , Flanagan, James M. , Forrest, Laura Elenor , Friedländer, Michael , Harraka, Philip A. , Kidd, Alexa, Kollias, James, Lakhani, Sunil R. , Lawrence, Mitchell, Lindeman, Geoffrey J. , Lippey, Jocelyn , Loi, Sherene , Reed, Amy E. McCart , Milne, Roger L , Gallego‐Ortega, David , Pathak, Gargi, Pearn, Amy , Robinson, Bridget A. , Skandarajah, Anita Rohini , Salisbury, Elizabeth, Saunders, Christobel , Saunus, Jodi M. , Savas, Peter Stephen , Sexton, Adrienne , Shelling, Andrew Neil , Simpson, Peter, Spurdle, Amanda B. , Visvader, Jane E. , Williams, Rachael, Tan, Bien‐Keem , Lim, Geok Hoon , Kaaks, Rudolf , Lawrence, Scott M. , Lissowska, Jolanta , Mannermaa, Arto , Manoochehri, Mehdi, Mesker, Wilma E. , Mulligan, Anna Marie , Obi, Nadia , Olson, Janet E. , Osório, Ana , Ottewell, Penelope Dawn , Patel, Alpa V , Pita, Guillermo , Rashid, Muhammad Usman , Ruddy, Kathryn J. , Schöttker, Ben , Seibold, Petra , Tapper, William , Teras, Lauren R , Timmermans, Mieke, Vachon, Celine M. , Wesseling, Jelle , Yadav, Siddhartha , Chang‐Claude, Jenny , Schmidt, Marjanka K. , Abubakar, Mustapha , García‐Closas, Montserrat
JNCI: Journal of the National Cancer Institute | July 18, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.
Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women
Ho, Peh Joo , Loo, Christine Kim Yan , Lim, Ryan Jak Yang, Goh, Mui Heng, Abubakar, Mustapha , Ahearn, Thomas U. , Andrulis, Irene L. , Antonenkova, Natalia, Aronson, Kristan J. , Augustinsson, Annelie , Behrens, Sabine , Bodelón, Clara , Bogdanova, Natalia , Bolla, Manjeet K. , Brantley, Kristen D. , Brenner, Hermann , Byers, Helen L., Camp, Nicola J. , Cessna, Melissa H., Chang-Claude, Jenny, Choi, Ji-Yeob , Czene, Kamila , Dörk, Thilo , Eliassen, A. Heather , Engel, Christoph , Eriksson, Mikael , Evans, D. Gareth , Fritschi, Lin , Genkinger, Jeanine M. , Geurts-Giele, Willemina R.R. , Glendon, Gord, Hall, Per , Hamann, U. , Ho, Cecilia Y.S., Hooning, Maartje J. , Hoppe, Reiner , Humphreys, Keith , Ito, Hidemi , Jakubowska, Anna , Jernström, Helena , John, Esther M. , Johnson, Nichola , Kang, Daehee , Kim, Sung‐Won , Kitahara, Cari M. , Ko, Yon-Dschun, Kraft, Peter, Kwong, Ava , Lambrechts, Diether, Larsson, Susanna C. , Li, Shuai , Lindblom, Annika , Linet, Martha, Lissowska, Jolanta , Lophatananon, Artitaya , MacInnis, Robert J. , Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro , Michailidou, Kyriaki , Taib, Nur Aishah Mohd , Murphy, Rachel A. , Newman, William G. , Obi, Nadia , Olopade, Olufunmilayo I., Panayiotidis, Mihalis I. , Park, Sue K. , Park‐Simon, Tjoung‐Won , Patel, Alpa V , Peterlongo, Paolo , Plaseska‐Karanfilska, Dijana , Pylkäs, Katri , Rashid, Muhammad Usman , Rodríguez, Juan , Sandler, Dale P. , Sawyer, Elinor J. , Scott, Christopher G. , Shahi, Shamim , Shu, Xiao‐Ou , Shulman, Katerina, Simard, Jacques , Southey, Melissa C., Stone, Jennifer , Taylor, Jack A. , Teo, Soo‐Hwang , Teras, Lauren R. , Vachon, Celine M., Houdt, Maxime Van , Verhoeven, Jelle , Weinberg, Clarice R. , Wolk, Alicja , Yamaji, Taiki , Yip, Cheng Har , Zheng, Wei , Hartman, Mikael , Li, Jingmei , Investigators, on behalf of the ABCTB, Investigators, kConFab, Investigators, MyBrCa, Investigators, SGBCC, Olopade, Olufunmilayo I. , Lambrechts, Diether , Lambrechts, Diether , Hamann, Ute , Hooning, Maartje J. , Bogdanova, Natalia V , Czene, Kamila , Dörk, Thilo , Eliassen, A Heather , Engel, Christoph , Eriksson, Mikael , Evans, D Gareth , Fletcher, Olivia , Fritschi, Lin , Genkinger, Jeanine , Hall, Per N , Ho, Cecilia Y S , Humphreys, Keith , Ito, Hidemi , Jakubowska, Anna , Jernström, Helena , Johnson, Nichola , Kim, Sung-Won , Kitahara, Cari M , Kwong, Ava , Larsson, Susanna C , Li, Shuai , Lindblom, Annika , Lissowska, Jolanta , Lophatananon, Artitaya , Maclnnis, Robert , Matsuo, Keitaro , Michailidou, Kyriaki , Mohd Taib, Nur Aishah , Murphy, Rachel A , Newman, William G , Obi, Nadia , Panayiotidis, Mihalis I , Park, Sue K , Park-Simon, Tjoung-Won , Peterlongo, Paolo , Plaseska-Karanfilska, Dijana , Pylkäs, Katri , Rashid, Muhammad U , Rennert, Gad , Rodriguez, Juan , Sandler, Dale P , Sawyer, Elinor J , Scott, Christopher , Shu, Xiao-Ou , Simard, Jacques , Stone, Jennifer , Taylor, Jack A , Teo, Soo H , Teras, Lauren R , Houdt, Maxime Van , Verhoeven, Jelle , Weinberg, Clarice R , Wolk, Alicja , Zheng, Wei , Hartman, Mikael , Li, Jingmei , Lambrechts, Diether , Behrens, Sabine , John, Esther M , Olopade, Olufunmilayo I , Lambrechts, Diether , Augustinsson, Annelie , Brenner, Hermann , Camp, Nicola J , Brantley, Kristen D , Lim, Ryan Jak Yang, Byers, Helen, Castelao, Jose E. , Chang‐Claude, Jenny , Chanock, Stephen Jacob , Chenevix‐Trench, Georgia , Colonna, Sarah V. , Daly, Mary Beryl , Derouane, Françoise , Fletcher, Olivia , Gago-Domínguez, Manuela , Ho, Weang-Kee , Howell, Anthony , Iwasaki, Motoki , Ko, Yon‐Dschun, Mannermaa, Arto , Manoukian, Siranoush , Margolin, Sara , Milne, Roger L. , Muir, Kenneth , O’Brien, Katie M. , Rennert, Gad , Saloustros, Emmanouil , Southey, Melissa C. , Terry, Mary Beth , Torres, Diana , Investigators, on behalf of the ABCTB, Investigators, kConFab, Investigators, MyBrCa, Investigators, SGBCC
Cancers | November 3, 2025 | Volume: 17 | Issue: 21 | Pages: 3561
Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.
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.
TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer
Fagerholm, Rainer, Khan, Sofia , Schmidt, Marjanka K. , García‐Closas, Montserrat , Saarela, Jani , Beesley, Jonathan, Jamshidi, Maral, Aittomäki, Kristiina, Liu, Jianjun , Ali, H. Raza , Andrulis, Irene L. , Beckmann, Matthias W. , Blows, Fiona M., Brenner, Hermann , Chang‐Claude, Jenny, Couch, Fergus J. , Fasching, Peter A. , Figueroa, Jonine D. , Floris, Giuseppe , Glendon, Gord, Guo, Qi , Hallberg, Emily, Hamann, Ute , Holleczek, Bernd , Hooning, Maartje J. , Hopper, John L. , Jager, Agnes , Kabisch, Maria, Investigators, kConFab AOCS, Keeman, Renske , Kosma, Veli‐Matti, Lambrechts, Diether , Lindblom, Annika , Mannermaa, Arto, Margolin, Sara , Provenzano, Elena , Shah, Mitul , Southey, Melissa C. , Michailidou, Kyriaki , Wang, Qin, Bolla, Manjeet K. , Dunning, Alison M. , Easton, Douglas F. , Chenevix‐Trench, Georgia , Blomqvist, Carl , Thorne, Heather , Bowtell, David D.L. , Lambrechts, Diether , Heikkilä, Päivi , Behrens, Sabine , Couch, Fergus J. , Czene, Kamila , Hall, Per N , Hooning, Maartje J. , Mannermaa, Arto, Dennis, Joe , Lush, Michael J. , Wang, Qin, Pharoah, Paul D.P. , Nevanlinna, Heli , Lambrechts, Diether , Southey, Melissa C , Dunning, Alison M , Lambrechts, Diether , Brenner, Hermann , García-Closas, Montserrat , Schmidt, Marjanka K , Michailidou, Kyriaki , Chenevix-Trench, Georgia , Figueroa, Jonine D , Bowtell, David D , Lindblom, Annika , Liu, Jing
Oncotarget | February 7, 2017 | Volume: 8 | Issue: 11 | Pages: 18381-18398
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.
Investigation of gene‐environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors
Truong, Thérèse , Knight, Julia A. , Flesch‐Janys, Dieter, Eilber, Ursula, Bolla, Manjeet K. , Wang, Qin , Dunning, Alison M. , Shah, Mitul , Munday, Hannah, Darabi, Hatef, Eriksson, Mikael , Brand, Judith S. , Vachon, Celine M. , Hallberg, Emily, Castelao, Jose E. , Carracedo, Ãngel , Torres, María , Li, Jingmei , Humphreys, Keith , Cordina‐Duverger, Emilie, Ménégaux, F. , Flyger, Henrik, Nordestgaard, Børge G. , Nielsen, Sune F. , Yesilyurt, Betül T., Floris, Giuseppe , Leunen, Karin, Engelhardt, Ellen G. , Rutgers, Emiel J. , Glendon, Gord, Mulligan, Anna Marie , Reed, Malcolm , González‐Neira, Anna , Pérez, José Ignacio Arias , Provenzano, Elena , Apicella, Carmel, Southey, Melissa C. , Investigators, kConFab, Group, AOCS, Häberle, Lothar , Beckmann, Matthias W. , Ekici, Arif B. , Dieffenbach, Aida Karina, Stegmaier, Christa, McLean, Catriona , Baglietto, Laura , Lissowska, Jolanta , Sherman, Mark E., Brüning, Thomas , Hamann, Ute, Ko, Yon‐Dschun, Orr, Nick , Schoemaker, Minouk J. , Ashworth, Alan , Kosma, Veli‐Matti , Kataja, Vesa , Hartikainen, Jaana M. , Mannermaa, Arto, Swerdlow, Anthony J. , GENICA‐Network, Giles, Graham G. , Brenner, Hermann , Fasching, Peter A. , Chenevix‐Trench, Georgia , Hopper, John L. , Benı́tez, Javier , Cox, Angela , Andrulis, Irene L. , Lambrechts, Diether , Gago-Domínguez, Manuela , Couch, Fergus J., Czene, Kamila , Bojesen, Stig E. , Easton, Doug , Schmidt, Marjanka K. , Guénel, Pascal , García‐Closas, Montserrat , Chang‐Claude, Jenny , Thorne, Heather , Lambrechts, Diether , Rudolph, Anja , Milne, Roger L. , Seibold, Petra , Behrens, Sabine , Dennis, Joe , Eriksson, Mikael , Olson, Janet E. , Vachon, Celine M. , Broeks, Annegien , Cross, Simon S. , Spurdle, Amanda B. , Investigators, kConFab, Group, AOCS, Arndt, Volker , Chanock, Stephen Jacob , Mannermaa, Arto, GENICA‐Network, Couch, Fergus J. , Hall, Per N , Pharoah, Paul D.P. , Lambrechts, Diether , Giles, Graham G , Swerdlow, Anthony J , Lissowska, Jolanta , Southey, Melissa C , Dunning, Alison M , Lambrechts, Diether , Brenner, Hermann , Cox, Angela , Gago-Dominguez, Manuela , Guénel, Pascal , Li, Jingmei , García-Closas, Montserrat , Schmidt, Marjanka K , Ekici, Arif B , Hartikainen, Jaana M , Benitez, Javier , Chenevix-Trench, Georgia , Czene, Kamila , Baglietto, Laura , Bojesen, Stig E , Schoemaker, Minouk J , Truong, Therese , Mclean, Catriona , Orr, Nick
International Journal of Cancer | September 16, 2014 | Volume: 136 | Issue: 6 | Pages: No page available
A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes‐type shrinkage estimator. Six SNPs showed interactions with associated p ‐values ( p int ) <1.1 × 10 −3 . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER‐negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER‐negative BC risk in women <160 cm (OR = 0.83, p = 0.039, p int = 1.9 × 10 −4 ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10 −4 ), and absent in women who had had just one (OR = 0.96, p = 0.19, p int = 6.1 × 10 −4 ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10 −5 ), but no association was observed in current smokers (OR = 1.07, p = 0.14, p int = 3.4 × 10 −4 ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk
Lin, Wei‐Yu , Camp, Nicola J. , Ghoussaini, Maya , Beesley, Jonathan, Michailidou, Kyriaki , Hopper, John L. , Apicella, Carmel, Southey, Melissa C. , Stone, Jennifer , Schmidt, Marjanka K. , Veer, Laura J. van’t , Muir, Kenneth , Lophatananon, Artitaya, Stewart‐Brown, Sarah , Siriwanarangsan, Pornthep, Fasching, Peter A. , Haeberle, Lothar, Ekici, Arif B. , Beckmann, Matthias W. , Peto, Julian, dos‐Santos‐Silva, Isabel , Fletcher, Olivia , Johnson, Nichola , Bolla, Manjeet K. , Wang, Qin, Sawyer, Elinor J. , Cheng, Timothy, Tomlinson, Ian , Kerin, Michael J. , Miller, Nicola, Surowy, Harald , Burwinkel, Barbara , Guénel, Pascal , Truong, Thérèse , Ménégaux, F. , Mulot, Claire , Bojesen, Stig E. , Nordestgaard, Børge G. , Nielsen, Sune F. , Flyger, Henrik, Benı́tez, Javier , Zamora, M. Pilar , Pérez, José Ignacio Arias , Menéndez, Primitiva, González‐Neira, Anna , Pita, Guillermo , Alonso, M. Rosario, Álvarez, Núria, Herrero, Daniel, Brenner, Hermann , Dieffenbach, Aida Karina, Stegmaier, Christa, Meindl, Alfons , Lichtner, Peter , Schmutzler, Rita K., Müller‐Myhsok, Bertram , Brauch, Hiltrud , Brüning, Thomas , Ko, Yon‐Dschun, Network, The GENICA, Tessier, Daniel C., Vincent, Daniel , Bacot, François, Nevanlinna, Heli , Aittomäki, Kristiina, Blomqvist, Carl , Khan, Sofia , Matsuo, Keitaro , Iwata, Hiroji, Horio, Akiyo, Bogdanova, Natalia , Antonenkova, Natalia, Dörk, Thilo , Lindblom, Annika , Margolin, Sara , Mannermaa, Arto, Kataja, Vesa , Kosma, Veli‐Matti, Hartikainen, Jaana M. , Investigators, kConFab, Group, Australian Ovarian Cancer Study, Wu, Anna H. , Tseng, Chiu-Chen , Neven, Patrick , Wauters, Els , Wildiers, Hans , Lambrechts, Diether , Chang‐Claude, Jenny , Flesch‐Janys, Dieter, Radice, Paolo , Peterlongo, Paolo , Manoukian, Siranoush , Couch, Fergus J. , Vachon, Celine M. , Purrington, Kristen S. , Giles, Graham G. , McLean, Catriona , Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick R. , Simard, Jacques , Goldberg, Mark S. , Dumont, Martine , Teo, Soo‐Hwang , Yip, Cheng Har , Vithana, Eranga N. , Kristensen, Vessela N. , Deming-Halverson, Sandra, Shrubsole, Martha J. , Long, Jirong , Winqvist, Robert , Pylkäs, Katri , Jukkola‐Vuorinen, Arja , Kauppila, Saila , Andrulis, Irene L. , Knight, Julia A. , Glendon, Gord, Tchatchou, Sandrine, Devilee, Peter , Tollenaar, Robert A.E.M., Seynaeve, Caroline, García‐Closas, Montserrat , Figueroa, Jonine D. , Lissowska, Jolanta , Brinton, Louise A. , Czene, Kamila , Darabi, Hatef, Eriksson, Mikael , Brand, Judith S. , Hooning, Maartje J. , Hollestelle, Antoinette , Ouweland, Ans M.W. van den, Jager, Agnes , Li, Jingmei , Liu, Jianjun , Humphreys, Keith , Shu, Xiao‐Ou , Lu, Wei , Gao, Yu‐Tang , Cai, Hui , Cross, Simon S. , Reed, Malcolm , Blot, William J. , Signorello, Lisa B., Cai, Qiuyin, Perkins, Barbara, Shah, Mitul, Blows, Fiona M., Kang, Daehee , Yoo, Keun-Young, Noh, Dong‐Young , Hartman, Mikael , Miao, Hui , Chia, Kee Seng , Putti, Thomas Choudary , Hamann, Ute , Luccarini, Craig , Baynes, Caroline, Maranian, Mel, Healey, Catherine S., Jakubowska, Anna , Lubiński, Jan , Jaworska–Bieniek, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn , Gaborieau, Valérie , Brennan, Paul , McKay, James , Slager, Susan, Yannoukakos, Drakoulis , Hsiung, Chia‐Ni , Wu, Pei‐Ei , Ding, Shian-ling, Ashworth, Alan , Jones, Michael E. , Orr, Nick , Swerdlow, Anthony J. , Makalic, Enes , Bui, Minh , Hunter, David J. , Hein, Rebecca, Dahmen, Norbert, Beckmann, Lars , Aaltonen, Kirsimari, Muranen, Taru , Heikkinen, Tuomas , Irwanto, Astrid , Rahman, Nazneen , Turnbull, Clare , Study, The Breast and Ovarian Cancer Susceptibility (BOCS), Waisfisz, Quinten , Meijers‐Heijboer, Hanne , Adank, Muriel A. , Luijt, Rob B. van der , Chenevix‐Trench, Georgia , Dunning, Alison M. , Easton, Douglas F. , Cox, Angela , Durocher, Francine , Zheng, Wei , Thorne, Heather , Lambrechts, Diether , Vachon, Celine, Broeks, Annegien , Rutgers, Emiel J. , Wang, Qin, Dennis, Joe , Marmé, Frederik , Anton‐Culver, Hoda , Arndt, Volker , Meindl, Alfons , Network, The GENICA, Ito, Hidemi , Iwata, Hiroji , Mannermaa, Arto , Investigators, kConFab, Group, Australian Ovarian Cancer Study, Berg, David Van Den , Stram, Daniel O. , Rudolph, Anja , Seibold, Petra , Bonanni, Bernardo , Couch, Fergus J. , Wang, Xianshu , Vachon, Celine M. , Milne, Roger L. , Marchand, Loı̈c Le , Labrèche, France , Rudolph, Anja , Zheng, Wei , Asperen, Christi J. van , Eriksson, Mikael , Hooning, Maartje J. , Pharoah, Paul D.P. , Ahmed, Shahana , Toland, Amanda Ewart , Shen, Chen‐Yang , Tsimiklis, Helen , Schmidt, Daniel Frederick , Bui, Minh , Chanock, Stephen Jacob , Study, The Breast and Ovarian Cancer Susceptibility (BOCS), Hall, Per N , Nevanlinna, H , Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , Peterlongo, Paolo , Teo, Soo H , Shrubsole, Martha J , Swerdlow, Anthony J , Radice, Paolo , Lissowska, Jolanta , Southey, Melissa C , van der Luijt, Rob B , Muir, Kenneth , Shu, Xiao-Ou , Matsuo, Keitaro , Dunning, Alison M , Jakubowska, Anna , Jones, Michael E , Lambrechts, Diether , Brenner, Hermann , Cox, Angela , Guénel, Pascal , Hartman, Mikael , Li, Jingmei , Muranen, Taru A , García-Closas, Montserrat , Schmidt, Marjanka K , Makalic, Enes , Ekici, Arif B , Michailidou, Kyriaki , Hartikainen, Jaana M , Bogdanova, Natalia V , Benitez, Javier , Simard, Jacques , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Czene, Kamila , Stone, Jennifer , Pylkäs, Katri , Yannoukakos, Drakoulis , Devilee, Peter , Manoukian, Siranoush , Lubinski, Jan , Fletcher, Olivia , Bojesen, Stig E , Purrington, Kristen S , Truong, Therese , Wildiers, Hans , Mclean, Catriona , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Orr, Nick , Liu, Jing , Kang, Daehee
Human Molecular Genetics | August 29, 2014 | Volume: 24 | Issue: 1 | Pages: 285-298
Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene‐Environment Interactions
Schoeps, Anja , Dunning, Alison M. , Bojesen, Stig E. , Swerdlow, Anthony J. , Andrulis, Irene L. , Brenner, Hermann , Orr, Nicholas, Jones, Michael E. , Ashworth, Alan , Li, Jingmei , Cramp, Helen, Connley, Dan, Czene, Kamila , Darabi, Hatef, Lissowska, Jolanta , Figueroa, Jonine D. , Knight, Julia A. , Glendon, Gord, Mulligan, Anna Marie , Dumont, Martine , Severi, Gianluca , Baglietto, Laura , Vachon, Celine M., Purrington, Kristen S. , Moisse, Matthieu , Neven, Patrick , Wildiers, Hans , Spurdle, Amanda B. , Kosma, Veli‐Matti , Kataja, Vesa , Hartikainen, Jaana M. , Hamann, Ute, Ko, Yon‐Dschun, Dieffenbach, Aida Karina, Stegmaier, Christa, Malats, Núria , Flyger, Henrik, Nordestgaard, Børge G. , Truong, Thérèse , Cordina‐Duverger, Emilie, Ménégaux, F. , Fletcher, Olivia , Johnson, Nichola , Häberle, Lothar , Beckmann, Matthias W. , Ekici, Arif B. , Braaf, Linde M., Atsma, Femke , Broek, Alexandra J. van den, Makalic, Enes , Southey, Melissa C. , Cox, Angela , Simard, Jacques , Giles, Graham G. , Lambrechts, Diether , Mannermaa, Arto, Brauch, Hiltrud , Guénel, Pascal , Peto, Julian , Fasching, Peter A. , Hopper, John L. , Flesch‐Janys, Dieter, Couch, Fergus, Chenevix‐Trench, Georgia , García‐Closas, Montserrat , Schmidt, Marjanka K. , Easton, Douglas F. , Chang‐Claude, Jenny, Durocher, Francine , Orr, Nick , Thorne, Heather , Lambrechts, Diether , Rudolph, Anja , Seibold, Petra , Milne, Roger L. , Behrens, Sabine , Orr, Nicholas, Chanock, Stephen Jacob , Olson, Janet E. , Arndt, Volker , Pérez, José Ignacio Arias , Benı́tez, Javier , dos‐Santos‐Silva, Isabel , Schmidt, Daniel F. , Mannermaa, Arto, Pharoah, Paul D.P. , Hall, Per N , Lambrechts, Diether , Giles, Graham G , Spurdle, Amanda B , Swerdlow, Anthony J , Lissowska, Jolanta , Southey, Melissa C , Malats, Nuria , Dunning, Alison M , Jones, Michael E , Lambrechts, Diether , Brenner, Hermann , Cox, Angela , Guénel, Pascal , Li, Jingmei , García-Closas, Montserrat , Schmidt, Marjanka K , Severi, Gianluca , Makalic, Enes , Ekici, Arif B , Moisse, Matthieu , Hartikainen, Jaana M , Simard, Jacques , Chenevix-Trench, Georgia , Figueroa, Jonine D , Czene, Kamila , Baglietto, Laura , Fletcher, Olivia , Bojesen, Stig E , Purrington, Kristen S , Truong, Therese , Wildiers, Hans , Brauch, Hiltrud , Orr, Nick
Genetic Epidemiology | November 19, 2013 | Volume: 38 | Issue: 1 | Pages: 84-93
ABSTRACTGenes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene‐environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P‐values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.