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

Huong D. Meeks, Honglin Song, Kyriaki Michailidou, Manjeet K. Bolla, Joe Dennis, Qin Wang, Daniel Barrowdale, Debra Frost, Lesley McGuffog, Steve Ellis, Bingjian Feng, Saundra S. Buys, John L. Hopper, Melissa C. Southey, Andrea A Tesoriero, Paul A. James, Fiona Bruinsma, Ian G. Campbell, Annegien Broeks, Marjanka K. SchmidtFrans B.L. Hogervorst, Matthias W Beckman, Peter A. Fasching, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Elio B Riboli, Susana N. Banerjee, Usha N Menon, Ian P Tomlinson, Barbara Burwinkel, Ute Hamann, Frederik Marme, Anja Rudolph, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Judy Garber, Daniel Cramer, Kathryn L Terry, Elizabeth M Poole, Shelley S Tworoger, Cecilia M. Dorfling, Elizabeth J. Van Rensburg, Andrew K. Godwin, Pascal Guénel, Thérèse Truong, Dominique Stoppa-Lyonnet, Francesca Damiola, Sylvie Mazoyer, Olga M. Sinilnikova, Claudine Janet Diana Isaacs, Christine Maugard, Stig E Bojesen, Henrik Flyger, Anne-Marie Gerdes, Thomas V.O. Hansen, Allen Jensen, Susanne Krüger Kjaer, Claus Hogdall, Estrid Hogdall, Inge Sokilde Pedersen, Mads Thomassen, Javier Benitez, Anna González-Neira, Ana Osorio, Miguel De La Hoya, Pedro Perez Segura, Orland Diez, Conxi Lazaro, Joan Brunet, Hoda Anton-Culver, Lee Eunjung, Esther M. John, Susan L Neuhausen, Yuan Chun Ding, Danielle Castillo, Jeffrey N. Weitzel, Patricia A. Ganz, Robert L. Nussbaum, Salina B. Chan, Beth Y. Karlan, Jenny Lester, Anna H Wu, Simon A Gayther, Susan J Ramus, Weiva Sieh, Alice S. Whittermore, Alvaro N.A. Monteiro, Catherine M Phelan, Mary Beth Terry, Marion Piedmonte, Kenneth Offit, Mark E Robson, Douglas 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, Celeste Leigh Pearce, Marc T Goodman, Pamela J Thompson, Hermann Brenner, Katja Butterbach, Alfons Meindl, Eric T Hahnen, Barbara Wappenschmidt, Hiltrud Brauch, Thomas Brüning, Carl Blomqvist, Sofia Khan, Heli Nevanlinna, Liisa M Pelttari, Kristiina Aittomäki, Ralf Butzow, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Johanna Rantala, Veli-Matti Kosma, Arto Mannermaa, Diether Lambrechts, Patrick Neven, Kathleen B.M. 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 Le, Anne-Lise Borresen-Dale, Vessela Kristensen, Helga Birgitte Salvesen, Line Bjorge, Elisa V. Bandera, Harvey A Risch, Wei Zheng, Alicia Beeghly-Fadiel, Hui Cai, Katri Pylkäs, Robert A.E.M. Tollenaar, Ans M W van den Ouweland, Irene L Andrulis, Julia A Knight, 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 M Glasspool, Ava Kwong, Sue K. Park, Soo-Hwang Teo, Sook Yee Yoon, Keitaro Matsuo, Satoyo Hosono, Yin Ling Woo, Yu-Tang Gao, Lenka Foretova, Christian F. Singer, Christine Rappaport-Feurhauser, Eitan Friedman, Yael Laitman, Gad Rennert, Evgeny N. Imyanitov, Peter J. Hulick, Olufunmilayo I. Olopade, Leigha Senter, Edith Olah, Jennifer Anne Doherty, Joellen M Schildkraut, Linetta B. Koppert, Lambertus A. Kiemeney, Leon F A G Massuger, Linda S. Cook, Tanja Pejovic, Jingmei Li, Ake Borg, Anna Öfverholm, Mary Anne Rossing, Nicolas Wentzensen, Karin Henriksson, Angela Cox, Simon S Cross, Barbara J. Pasini, Mitul Shah, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bjarni A. Agnarsson, Jolanta Kupryjanczyk, Joanna Moes-Sosnowska, Florentia Fostira, Irene Konstantopoulou, Susan Slager, Michael Jones, Antonis C Antoniou, Andrew Berchuck, Anthony J Swerdlow, Georgia Chenevix-Trench, Alison M Dunning, Paul D P Pharoah, Per Hall, Douglas F Easton, emBRAce, kConFab Investigators, Australia Ovarian Cancer Study Group, HeBon, GEMO Study Collaborators, OCGN, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome (PRACTICAL)

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Abstract

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 hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 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 = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). 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 = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1×10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

Original languageEnglish
Article numberdjv315
Number of pages10
JournalJournal of the National Cancer Institute
Volume108
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016
Externally publishedYes

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