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

Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley and Healey, Sue, et al. (2011) In Human Molecular Genetics 20(23). p.4732-4747
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... (More)
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. (Less)
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Human Molecular Genetics
volume
20
issue
23
pages
4732 - 4747
publisher
Oxford University Press
external identifiers
  • wos:000297049600019
  • scopus:81255190718
ISSN
0964-6906
DOI
10.1093/hmg/ddr388
language
English
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yes
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506e84e6-e466-4b78-b782-8f94311bf29a (old id 2252805)
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2011-12-22 09:42:44
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2017-06-25 03:06:47
@article{506e84e6-e466-4b78-b782-8f94311bf29a,
  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 Simard, Jacques and Sinnett, Daniel and Hamdi, Yosr and Soucy, Penny and Ouimet, Manon and Barjhoux, Laure and Verny-Pierre, Carole and McGuffog, Lesley and Healey, Sue and Szabo, Csilla and Greene, Mark H. and Mai, Phuong L. and Andrulis, Irene L. and Thomassen, Mads and Gerdes, Anne-Marie and Caligo, Maria A. and Friedman, Eitan and Laitman, Yael and Kaufman, Bella and Paluch, Shani S. and Borg, Åke and Karlsson, Per and Askmalm, Marie Stenmark and Bustinza, Gisela Barbany and Nathanson, Katherine L. and Domchek, Susan M. and Rebbeck, Timothy R. and Benitez, Javier and Hamann, Ute 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 Devilee, Peter and Gille, Hans J. J. P. and Peock, Susan and Frost, Debra and Evans, D. Gareth and Eeles, Ros and Izatt, Louise and Adlard, Julian and Paterson, Joan and Eason, Jacqueline and Godwin, Andrew K. and Remon, Marie-Alice and Moncoutier, Virginie and Gauthier-Villars, Marion and Lasset, Christine and Giraud, Sophie and Hardouin, Agnes and Berthet, Pascaline and Sobol, Hagay and Eisinger, Francois and de Paillerets, Brigitte Bressac and Caron, Olivier and Delnatte, Capucine and Goldgar, David and Miron, Alex and Ozcelik, Hilmi and Buys, Saundra and Southey, Melissa C. and Terry, Mary Beth and Singer, Christian F. and Dressler, Anne-Catharina and Tea, Muy-Kheng and Hansen, Thomas V. O. and Johannsson, Oskar and Piedmonte, Marion and Rodriguez, Gustavo C. and Basil, Jack B. and Blank, Stephanie and Toland, Amanda E. and Montagna, Marco and Isaacs, Claudine and Blanco, Ignacio and Gayther, Simon A. and Moysich, Kirsten B. and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Niederacher, Dieter and Sutter, Christian and Gadzicki, Dorothea and Fiebig, Britta and Caldes, Trinidad and Laframboise, Rachel and Nevanlinna, Heli and Chen, Xiaoqing and Beesley, Jonathan and Spurdle, Amanda B. and Neuhausen, Susan L. and Ding, Yuan C. and Couch, Fergus J. and Wang, Xianshu and Peterlongo, Paolo and Manoukian, Siranoush and Bernard, Loris and Radice, Paolo and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Stoppa-Lyonnet, Dominique and Mazoyer, Sylvie and Sinilnikova, Olga M.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {23},
  pages        = {4732--4747},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers},
  url          = {http://dx.doi.org/10.1093/hmg/ddr388},
  volume       = {20},
  year         = {2011},
}