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

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  • Additional Information
    • Corporate Authors:
      Ontario Cancer Genetics Network; SWE-BRCA Collaborators; HEBON; EMBRACE; GEMO Study Collaborators; Breast Cancer Family Registry; Consortium of Investigators of Modifiers of BRCA1/2
    • Source:
      Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
    • Subject Terms:
      Alleles* ; Genetic Predisposition to Disease* ; Heterozygote*; BRCA1 Protein/*genetics ; Breast Neoplasms/*genetics ; Mutation/*genetics ; Polymorphism, Single Nucleotide/*genetics; Electrophoretic Mobility Shift Assay ; Female ; Genes, Reporter/genetics ; Genetic Association Studies ; Haplotypes/genetics ; HeLa Cells ; Humans ; Linkage Disequilibrium/genetics ; Luciferases/metabolism ; Risk Factors
    • 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.
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    • Grant Information:
      U01 CA069417 United States CA NCI NIH HHS; U01 CA069638 United States CA NCI NIH HHS; R01-CA102776 United States CA NCI NIH HHS; U01 CA69417 United States CA NCI NIH HHS; U01 CA069398 United States CA NCI NIH HHS; CA74415 United States CA NCI NIH HHS; R01 CA128978 United States CA NCI NIH HHS; R01 CA083855 United States CA NCI NIH HHS; P30 CA051008 United States CA NCI NIH HHS; R01 CA102776 United States CA NCI NIH HHS; U01 CA069446 United States CA NCI NIH HHS; U01 CA69467 United States CA NCI NIH HHS; N02CP11019 United States CP NCI NIH HHS; R01 CA140323 United States CA NCI NIH HHS; R01CA140323 United States CA NCI NIH HHS; CA128978 United States CA NCI NIH HHS; 11174 United Kingdom CRUK_ Cancer Research UK; P30-CA051008 United States CA NCI NIH HHS; U01 CA069467 United States CA NCI NIH HHS; RFA-CA-06-503 United States CA NCI NIH HHS; 11022 United Kingdom CRUK_ Cancer Research UK; N02-CP-11019-50 United States CP NCI NIH HHS; Canada CAPMC CIHR; G0801875 United Kingdom MRC_ Medical Research Council; U01 CA113916 United States CA NCI NIH HHS; U01 CA069631 United States CA NCI NIH HHS; U01 CA69398 United States CA NCI NIH HHS; R01-CA083855 United States CA NCI NIH HHS; N02CP65504 United States CP NCI NIH HHS; United States ImNIH Intramural NIH HHS; 5U01CA113916 United States CA NCI NIH HHS; U01 CA69638 United States CA NCI NIH HHS; U01 CA69446 United States CA NCI NIH HHS; U01 CA69631 United States CA NCI NIH HHS; U01CA69631 United States CA NCI NIH HHS; R01 CA074415 United States CA NCI NIH HHS; 10118 United Kingdom CRUK_ Cancer Research UK
    • Contributed Indexing:
      Investigator: G Glendon; T Selander; N Weerasooriya; P Karlsson; M Nordling; A Bergman; Z Einbeigi; M Stenmark-Askmalm; S Liedgren; Å Borg; N Loman; H Olsson; U Kristoffersson; M Soller; H Jernström; K Harbst; K Henriksson; A Lindblom; B Arver; A von Wachenfeldt; A Liljegren; G Barbany-Bustinza; J Rantala; B Melin; H Grönberg; EL Stattin; M Emanuelsson; H Ehrencrona; RR Brandell; N Dahl; FB Hogervorst; S Verhoef; M Verheus; LJ van't Veer; FE van Leeuwen; MA Rookus; M Collée; AM van den Ouweland; A Jager; MJ Hooning; MM Tilanus-Linthorst; C Seynaeve; CJ van Asperen; JT Wijnen; MP Vreeswijk; RA Tollenaar; P Devilee; MJ Ligtenberg; N Hoogerbrugge; MG Ausems; RB van der Luijt; CM Aalfs; TA van Os; JJ Gille; Q Waisfisz; HE Meijers-Heijboer; EB Gomez-Garcia; CE van Roozendaal; MJ Blok; B Caanen; JC Oosterwijk; AH van der Hout; MJ Mourits; HF Vasen; DF Easton; S Peock; M Cook; D Frost; R Platte; Z Miedzybrodzka; H Gregory; P Morrison; L Jeffers; T Cole; KR Ong; J Hoffman; A Donaldson; M James; J Paterson; S Downing; A Taylor; A Murray; MT Rogers; E McCann; MJ Kennedy; D Barton; M Porteous; S Drummond; C Brewer; E Kivuva; A Searle; S Goodman; K Hill; R Davidson; V Murday; N Bradshaw; L Snadden; M Longmuir; C Watt; S Gibson; E Haque; E Tobias; A Duncan; L Izatt; C Jacobs; C Langman; A Whaite; H Dorkins; J Barwell; J Adlard; C Chu; J Miller; I Ellis; C Houghton; DG Evans; F Lalloo; J Taylor; L Side; A Male; C Berlin; J Eason; R Collier; F Douglas; O Claber; I Jobson; L Walker; D McLeod; D Halliday; S Durell; B Stayner; R Eeles; S Shanley; N Rahman; R Houlston; E Bancroft; L D'Mello; E Page; A Ardern-Jones; K Kohut; J Wiggins; E Castro; A Mitra; L Robertson; J Cook; O Quarrell; C Bardsley; S Hodgson; S Goff; G Brice; L Winchester; C Eddy; V Tripathi; V Attard; D Eccles; A Lucassen; G Crawford; D McBride; S Smalley; O Sinilnikova; L Barjhoux; C Verny-Pierre; S Giraud; M Léone; S Mazoyer; D Stoppa-Lyonnet; M Gauthier-Villars; B Buecher; C Houdayer; V Moncoutier; M Belotti; C Tirapo; A de Pauw; B Bressac-de-Paillerets; A Remenieras; V Byrde; O Caron; G Lenoir; YJ Bignon; N Uhrhammer; C Lasset; V Bonadona; A Hardouin; P Berthet; H Sobol; V Bourdon; T Noguchi; F Eisinger; F Coulet; C Colas; F Soubrier; I Coupier; P Pujol; JP Peyrat; J Fournier; F Révillion; P Vennin; C Adenis; E Rouleau; R Lidereau; L Demange; C Nogues; D Muller; JP Fricker; M Longy; N Sevenet; C Toulas; R Guimbaud; L Gladieff; V Feillel; D Leroux; H Dreyfus; C Rebischung; F Coron; L Faivre; F Prieur; M Lebrun; SF Ferrer; M Frénay; L Vénat-Bouvet; C Delnatte; I Mortemousque; HT Lynch; CL Snyder
    • Accession Number:
      0 (BRCA1 Protein)
      0 (BRCA1 protein, human)
      EC 1.13.12.- (Luciferases)
    • Publication Date:
      Date Created: 20110906 Date Completed: 20120222 Latest Revision: 20240318
    • Publication Date:
      20240318
    • Accession Number:
      PMC3733139
    • Accession Number:
      10.1093/hmg/ddr388
    • Accession Number:
      21890493