Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 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 KaufmanShani 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, Ontario Cancer Genetics Network, Zofia Miedzybrodzka

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4732-4747
Number of pages16
JournalHuman Molecular Genetics
Issue number23
Publication statusPublished - 1 Dec 2011


  • alleles
  • BRCA1 protein
  • breast neoplasms
  • electrophoretic mobility shift assay
  • female
  • genes, reporter
  • genetic association studies
  • genetic predisposition to disease
  • haplotypes
  • HeLa cells
  • heterozygote
  • humans
  • linkage disequilibrium
  • luciferases
  • mutation
  • polymorphism, single nucleotide
  • risk factors


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