Journal Article

Common variants of the <i>BRCA1</i> wild-type allele modify the risk of breast cancer in <i>BRCA1</i> mutation carriers

David G. Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabo, Mark H. Greene, Phuong L. Mai, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Maria A. Caligo, Eitan Friedman, Yael Laitman, Bella Kaufman, Shani S. Paluch, Åke Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Javier Benítez, Ute Hamann, Matti A. Rookus, Ans M.W. van den Ouweland, Margreet G.E.M. Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Hans J.J.P. Gille, Susan Peock, Debra Frost, D. Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K. Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, François Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C. Southey, Mary Beth Terry, Christian F. Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas V.O. Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C. Rodriguez, Jack B. Basil, Stephanie Blank, Amanda E. Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A. Gayther, Kirsten B. Moysich, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldes, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer and Olga M. Sinilnikova

in Human Molecular Genetics

Volume 20, issue 23, pages 4732-4747
Published in print December 2011 | ISSN: 0964-6906
Published online September 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr388
Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

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Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Journal Article.  9388 words.  Illustrated.

Subjects: Genetics and Genomics

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