Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer

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Sarah Louise Dombernowsky, Maren Weischer, Jacob Johannes Freiberg, Stig Egil Bojesen, Anne Tybjaerg-Hansen, Børge Grønne Nordestgaard

PURPOSE: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear. EXPERIMENTAL DESIGN: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Tyr1915Met). We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls. RESULTS: We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study. CONCLUSIONS: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms.
Original languageEnglish
JournalCancer Epidemiology, Biomarkers & Prevention
Volume18
Issue number8
Pages (from-to)2339-42
Number of pages4
ISSN1055-9965
DOIs
Publication statusPublished - 2009

Bibliographical note

Keywords: Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Incidence; Ovarian Neoplasms; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors

ID: 20569782