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, D. Frost, Lesley McGuffog, Steve Ellis, Bingjian Feng, Saundra S. Buys, John Hopper, Melissa Southey, Andrea Tesoriero, Paul A. James, Fiona Bruinsma, Ian Campbell, Annegien Broeks, Marjanka K. SchmidtFrans B. Hogervorst, Matthias W. Beckman, Peter A. Fasching, Olivia Fletcher, Nichola Johnson, Elinor J. Sawyer, E. Riboli, S. Banerjee, Usha Menon, Ian P M Tomlinson, Barbara Burwinkel, Ute Hamann, Frederik Marme, Anja Rudolph, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Judy E. Garber, Daniel Cramer, Kathryn L. Terry, Elizabeth M. Poole, Shelley S. Tworoger, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Andrew K. Godwin, Pascal Guenel, Therese Truong, Dominique Stoppa-Lyonnet, Francesca Damiola, Sylvie Mazoyer, Olga M. Sinilnikova, Claudine Isaacs, Christine Maugard, Stig E. Bojesen, Henrik Flyger, Anne Marie Gerdes, Thomas v O Hansen, Allen Jensen, Susanne Krüger Kjær, 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 Weitzel, Patricia A. Ganz, Robert L. Nussbaum, Salina Chan, Beth Y. Karlan, Jenny Lester, Anna 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 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, R. 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 Butzow, Natalia V. 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 Gilles 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 Cunningham, Graham Giles, Roger L. Milne, Sue Healey, Kathy Tucker, Christopher A. Haiman, Brian E. Henderson, Mark S. Goldberg, Marc Tischkowitz, Jacques Simard, Penny Soucy, Diana Eccles, Nhu Le, Anne Lise Børresen-Dale, Vessela Kristensen, Helga B. 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 Der Ouweland, Irene L. Andrulis, Julia A. Knight, Steven Narod, Peter Devilee, Robert Winqvist, Jonine D. Figueroa, Mark H. Greene, Phuong L. Mai, Jennifer T. Loud, Montse Garcia-Closas, Minouk J. Schoemaker, Kamila Czene, Hatef Darabi, Iain A. McNeish, Nadeem Siddiquil, Rosalind Glasspool, A. 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 Imyanitov, Peter J. Hulick, Olufunmilayo I. Olopade, Leigha Senter, Edith Olah, Jennifer A. Doherty, Joellen M. Schildkraut, Linetta B. Koppert, Lambartus 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 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 E. Jones, Antonis C. Antoniou, Andrew Berchuck, Anthony J. Swerdlow, Georgia Chenevix-Trench, Alison Dunning, Paul D P Pharoah, Per Hall, Douglas F. Easton, Fergus J. Couch, Amanda B. Spurdle, David Goldgar

Research output: Contribution to journalArticle

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
JournalJournal of the National Cancer Institute
Volume108
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Meeks, H. D., Song, H., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B., Buys, S. S., Hopper, J., Southey, M., Tesoriero, A., James, P. A., Bruinsma, F., Campbell, I., Broeks, A., ... Goldgar, D. (2016). BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. Journal of the National Cancer Institute, 108(2), [djv315]. https://doi.org/10.1093/jnci/djv315