Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis

©2007 American Association for Cancer Research. Published version of the paper reproduced here in accordance with the copyright policy of the publisher. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the publisher.Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with 50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability. [Cancer Res 2007;67(4):1494–501

Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. The current study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n=283), BRCA2 mutations (n=204) or negative for both BRCA1 and BRCA2 mutations (n=894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2