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

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title = "Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers",
abstract = "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.",
author = "Cox, {David G.} and Jacques Simard and Daniel Sinnett and Yosr Hamdi and Penny Soucy and Manon Ouimet and Laure Barjhoux and Carole Verny-Pierre and Lesley McGuffog and Sue Healey and Csilla Szabo and Greene, {Mark H.} and Mai, {Phuong L.} and Andrulis, {Irene L.} and Mads Thomassen and Anne-Marie Gerdes and Caligo, {Maria A.} and Eitan Friedman and Yael Laitman and Bella Kaufman and Paluch, {Shani S.} and {\AA}ke Borg and Per Karlsson and Askmalm, {Marie Stenmark} and Bustinza, {Gisela Barbany} and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Rebbeck, {Timothy R.} and Javier Benitez and Ute Hamann and Rookus, {Matti A.} and {van den Ouweland}, {Ans M. W.} and Ausems, {Margreet G. E. M.} and Aalfs, {Cora M.} and {van Asperen}, {Christi J.} and Peter Devilee and Gille, {Hans J. J. P.} and Susan Peock and Debra Frost and Evans, {D. Gareth} and Ros Eeles and Louise Izatt and Julian Adlard and Joan Paterson and Jacqueline Eason and Godwin, {Andrew K.} and Marie-Alice Remon and Virginie Moncoutier and Marion Gauthier-Villars and Christine Lasset and Sophie Giraud and Agnes Hardouin and Pascaline Berthet and Hagay Sobol and Francois Eisinger and {de Paillerets}, {Brigitte Bressac} and Olivier Caron and Capucine Delnatte and David Goldgar and Alex Miron and Hilmi Ozcelik and Saundra Buys and Southey, {Melissa C.} and Terry, {Mary Beth} and Singer, {Christian F.} and Anne-Catharina Dressler and Muy-Kheng Tea and Hansen, {Thomas V. O.} and Oskar Johannsson and Marion Piedmonte and Rodriguez, {Gustavo C.} and Basil, {Jack B.} and Stephanie Blank and Toland, {Amanda E.} and Marco Montagna and Claudine Isaacs and Ignacio Blanco and Gayther, {Simon A.} and Moysich, {Kirsten B.} and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Christoph Engel and Alfons Meindl and Nina Ditsch and Norbert Arnold and Dieter Niederacher and Christian Sutter and Dorothea Gadzicki and Britta Fiebig and Trinidad Caldes and Rachel Laframboise and Heli Nevanlinna and Xiaoqing Chen and Jonathan Beesley and Spurdle, {Amanda B.} and Neuhausen, {Susan L.} and Ding, {Yuan C.} and Couch, {Fergus J.} and Xianshu Wang and Paolo Peterlongo and Siranoush Manoukian and Loris Bernard and Paolo Radice and Easton, {Douglas F.} and Georgia Chenevix-Trench and Antoniou, {Antonis C.} and Dominique Stoppa-Lyonnet and Sylvie Mazoyer and Sinilnikova, {Olga M.} and H{\aa}kan Olsson",
year = "2011",
doi = "10.1093/hmg/ddr388",
language = "English",
volume = "20",
pages = "4732--4747",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",