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


METHODS
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 Thr1915Met). [corrected] 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.
Dombernowsky
Sarah Louise
SL
Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark.
Weischer
Maren
M
Freiberg
Jacob Johannes
JJ
Bojesen
Stig Egil
SE
Tybjaerg-Hansen
Anne
A
Nordestgaard
Børge Grønne
BG
D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors