The University of Southampton
University of Southampton Institutional Repository

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

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
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.
4732-4747
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Cox, D.G., Simard, J. and Sinnett, D. et al. (2011) Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. Human Molecular Genetics, 20 (23), 4732-4747. (doi:10.1093/hmg/ddr388). (PMID:21890493)

Record type: Article

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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e-pub ahead of print date: 2 September 2011
Published date: 1 December 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 384854
URI: http://eprints.soton.ac.uk/id/eprint/384854
PURE UUID: 6f4c4e90-f30c-4220-ad1a-6157b4e3e0ed
ORCID for D. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 07 Dec 2015 14:46
Last modified: 15 Mar 2024 02:40

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Contributors

Author: D.G. Cox
Author: J. Simard
Author: D. Sinnett
Author: Y. Hamdi
Author: P. Soucy
Author: M. Ouimet
Author: L. Barjhoux
Author: C. Verny-Pierre
Author: L. McGuffog
Author: S. Healey
Author: C. Szabo
Author: M. H. Greene
Author: P. L. Mai
Author: I. L. Andrulis
Author: M. Thomassen
Author: A.-M. Gerdes
Author: M. A. Caligo
Author: E. Friedman
Author: Y. Laitman
Author: B. Kaufman
Author: S. S. Paluch
Author: A. Borg
Author: P. Karlsson
Author: M. Stenmark Askmalm
Author: G. Barbany Bustinza
Author: K. L. Nathanson
Author: S. M. Domchek
Author: T. R. Rebbeck
Author: J. Benitez
Author: U. Hamann
Author: M. A. Rookus
Author: A. M. W. van den Ouweland
Author: M. G. E. M. Ausems
Author: C. M. Aalfs
Author: C. J. van Asperen
Author: P. Devilee
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