Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
2011 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 23, 4732-4747 p.Article in journal (Refereed) Published
Mutations in the BRCA1 gene substantially increase a womans 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.
Place, publisher, year, edition, pages
Oxford University Press (OUP) / Oxford University Press (OUP): Policy B , 2011. Vol. 20, no 23, 4732-4747 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-72805DOI: 10.1093/hmg/ddr388ISI: 000297049600019OAI: oai:DiVA.org:liu-72805DiVA: diva2:463458
Funding Agencies|US National Cancer Institute||Westat, Inc., Rockville, MD|NO2-CP-11019-50N02-CP-65504|Cancer Care Ontario||Fundacion Mutua Madrilena||Asociacion Espanola Contra el Cancer||Spanish Ministry of Science and Innovation|FIS PI08 1120|DKFZ||Dutch Cancer Society|NKI1998-1854NKI2004-3088NKI2007-3756|ZonMW|91109024|Cancer Research UK|C1287/A10118C1287/A11990C5047/A8385|NIHR||Royal Marsden NHS Foundation Trust||Eileen Stein Jacoby Fund||Ligue National Contre le Cancer||Association for International Cancer Research|AICR-07-0454|Association Le cancer du sein, parlons-en!||National Cancer Institute, National Institutes of Health|RFA-CA-06-503|BCFR||Cancer Care Ontario|U01 CA69467|Columbia University|U01 CA69398|Fox Chase Cancer Center|U01 CA69631|Huntsman Cancer Institute|U01 CA69446|Northern California Cancer Center|U01 CA69417|University of Melbourne|U01 CA69638|Georgetown University Informatics Support Center (RFP)|N02PC45022-46|NEYE||NCI||GOGs Cancer Prevention and Control Committee||OSU Comprehensive Cancer Center||Ministero dellUniversitae della Ricerca (MIUR)||Ministero della Salute (P.I.O. V and Progetto Tumori Femminili)||Alleanza Contro il Cancro||CRUK||German Cancer Aid|107054|Helsinki University||Academy of Finland|132473|Finnish Cancer Society||Sigrid Juselius Foundation||National Health and Medical Research Council (NHMRC)|145684288704454508|National Breast Cancer Foundation||Queensland Cancer Fund||Cancer Councils of New South Wales, Victoria, Tasmania and South Australia||Cancer Foundation of Western Australia||Breast Cancer Research Foundation (BCRF)||Komen Foundation for the Cure||Department of Defense|W81XWH-10-1-0341|US National Cancer Institute, National Institutes of Health|CA128978|Familial Cancer Registry||Tissue Culture Shared Registry at Georgetown University (NIH/NCI)|P30-CA051008|Cancer Genetics Network|HHSN261200744000C|Swing Fore the Cure||Breast Cancer Research Foundation||Susan G. Komen Foundation||Instituto de Salud Carlos III|RD06/0020/0021|European Community|223175 (HEALTH-F2-2009-223175)|INSERM/INCa||LIGUE CONTRE LE CANCER||Canadian Institutes of Health Research||Canadian Breast Cancer Research Alliance|019511||R01CA140323||U01CA69631||5U01CA113916||NIH CA74415||R01-CA083855||R01-CA102776|2011-12-092011-12-082011-12-09