TY - JOUR
T1 - Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer
AU - Dombernowsky, Sarah Louise
AU - Weischer, Maren
AU - Freiberg, Jacob Johannes
AU - Bojesen, Stig Egil
AU - Tybjaerg-Hansen, Anne
AU - Nordestgaard, Børge Grønne
N1 - Keywords: Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Incidence; Ovarian Neoplasms; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1158/1055-9965.EPI-09-0447
DO - 10.1158/1055-9965.EPI-09-0447
M3 - Journal article
C2 - 19661094
SN - 1055-9965
VL - 18
SP - 2339
EP - 2342
JO - Cancer Epidemiology, Biomarkers & Prevention
JF - Cancer Epidemiology, Biomarkers & Prevention
IS - 8
ER -
