BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

作者：Huong Meeks, Honglin Song, Kyriaki Michailidou, Manjeet K. Bolla, Joe Dennis, Qin Wang, Daniel Barrowdale, Debra Frost, EMBRACE, Lesley McGuffog, Steve Ellis, Bing Feng, Saundra S. Buys, John L. Hopper, Melissa C. Southey, Andrea Tesoriero, kConFab Investigators, Paul A. James, Fiona Bruinsma, Ian Campbell, Australia Ovarian Cancer Study Group, Annegien Broeks, Marjanka K. Schmidt, Frans B.L. Hogervorst, HEBON, Matthias W. Beckman, Peter A. Fasching, Olivia Fletcher, Nichola Johnson, Elinor J. Sawyer, Elio Ríboli, Susana Banerjee, Usha Menon, Ian Tomlinson, Barbara Burwinkel, Ute Hamann, Frederik Marmé, Anja Rudolph, Ramūnas Janavičius, Laima Tihomirova, Nadine Tung, Judy E. Garber, Daniel W. Cramer, Kathryn L. Terry, Elizabeth M. Poole, Shelley S. Tworoger, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Andrew K. Godwin, Pascal Guénel, Thérèse Truong, GEMO Study Collaborators, Dominique Stoppa‐Lyonnet, Francesca Damiola, Sylvie Mazoyer, Olga M. Sinilnikova, Claudine Isaacs, Christine Maugard, Stig E. Bojesen, Henrik Flyger, Anne‐Marie Gerdes, Thomas van Overeem Hansen, Allen Jensen, Susanne K. Kjær, Claus Høgdall, Estrid Høgdall, Inge Søkilde Pedersen, Mads Thomassen, Javier Benı́tez, Anna González‐Neira, Ana Osório, Miguel de la Hoya, Pedro Pérez Segura, Orland Dı́ez, Conxi Lázaro, Joan Brunet, Hoda Anton‐Culver, Eunjung Lee, Esther M. John, Susan L. Neuhausen, Yuan Chun Ding, Danielle Castillo, Jeffrey N. Weitzel, Patricia A. Ganz, Robert L. Nussbaum, Salina Chan, Beth Y. Karlan, Jenny Lester, Anna H. Wu, Simon A. Gayther, Susan J. Ramus, Weiva Sieh, Alice S. Whittermore, Álvaro N.A. Monteiro, Catherine M. Phelan, Mary Beth Terry, Marion Piedmonte, Kenneth Offit, Mark E. Robson, Douglas A. Levine, Kirsten B. Moysich, Rikki Cannioto, Sara H. Olson, Mary B. Daly, Katherine L. Nathanson, Susan M. Domchek, Karen H. Lu, Dong Liang, Michelle A. T. Hildebrant, Roberta B. Ness, Francesmary Modugno, Leigh Pearce, Marc T. Goodman, Pamela J. Thompson, Hermann Brenner, Katja Butterbach, Alfons Meindl, Eric Hahnen, Barbara Wappenschmidt, Hiltrud Brauch, Thomas Brüning, Carl Blomqvist, Sofia Khan, Heli Nevanlinna, Liisa M. Pelttari, Kristiina Aittomäki, Ralf Bützow, Natalia Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Johanna Rantala, Veli-Matti Kosma, Arto Mannermaa, Diether Lambrechts, Patrick Neven, Kathleen Claes, Tom Van Maerken, Jenny Chang-Claude, Dieter Flesch‐Janys, Florian Heitz, Raymonda Varon-Mateeva, Paolo Peterlongo, Paolo Radice, Alessandra Viel, Monica Barile, Bernard Peissel, Siranoush Manoukian, Marco Montagna, Cristina Oliani, Ana Peixoto, Manuel R. Teixeira, Anita Collavoli, Emily Hallberg, Janet E. Olson, Ellen L. Goode, Steven N. Hart, Hermela Shimelis, Julie M. Cunningham, Graham G. Giles, Roger L. Milne, Sue Healey, Kathy Tucker, Christopher A. Haiman, Brian E. Henderson, Mark S. Goldberg, Marc Tischkowitz, Jacques Simard, Penny Soucy, Diana M. Eccles, Nhu D. Le, Anne‐Lise Børresen‐Dale, Vessela N. Kristensen, Helga B. Salvesen, Line Bjørge, Elisa V. Bandera, Harvey A. Risch, Wei Zheng, Alicia Beeghly‐Fadiel, Hui Cai, Katri Pylkäs, Robert A.E.M. Tollenaar, Ans M. W. van der Ouweland, Irene L. Andrulis, Julia A. Knight, OCGN, Steven A. Narod, Peter Devilee, Robert Winqvist, Jonine D. Figueroa, Mark H. Greene, Phuong L. Mai, Jennifer T. Loud, Montserrat García‐Closas, Minouk J. Schoemaker, Kamila Czene, Hatef Darabi, Iain A. McNeish, Nadeem Siddiquil, Rosalind Glasspool, Ava Kwong, Sue K. Park, Soo‐Hwang Teo, Sook-Yee Yoon, Keitaro Matsuo, Satoyo Hosono, Yin Ling Woo, Yu-Tang Gao, Lenka Foretová, Christian F. Singer, Christine Rappaport-Feurhauser, Eitan Friedman, Yael Laitman, Gad Rennert, Evgeny N. Imyanitov, Peter J. Hulick, Olufunmilayo I. Olopade, Leigha Senter, Edith Oláh, Jennifer A. Doherty, Joellen M. Schildkraut, Linetta B. Koppert, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Linda S. Cook, Tanja Pejović, Jingmei Li, Åke Borg, Anna Öfverholm, Mary Anne Rossing, Nicolas Wentzensen, Karin Henriksson, Angela Cox, Simon S. Cross, Barbara Pasini, Mitul Shah, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Bjarni A. Agnarsson, Jolanta Kupryjańczyk, Joanna Moes-Sosnowska, Florentia Fostira, Irene Konstantopoulou, Susan Slager, Michael E. Jones, Antonis C. Antoniou, Andrew Berchuck, Anthony J. Swerdlow, Georgia Chenevix‐Trench, Alison M. Dunning, Paul D.P. Pharoah, Per Hall, Douglas F. Easton, Fergus J. Couch, Amanda B. Spurdle, David E. Goldgar · 发表于：JNCI Journal of the National Cancer Institute · 年份：2015 · DOI：10.1093/jnci/djv315 · 被引用次数：92 · 研究领域：BRCA gene mutations in cancer、PARP inhibition in cancer therapy、DNA Repair Mechanisms

BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of o...