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Please use this identifier to cite or link to this item: http://hdl.handle.net/2328/11105

Title: Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis
Authors: Carvalho, Marcelo
Couch, Fergus
Radice, Paolo
Monteiro, Alvaro
Karchin, Rachel
Grist, Scott Andrew
Gayol, Luis
Sali, Andrej
Goldgar, David
Marsillac, Sylvia
Baumbach, Lisa
Sutphen, Rebecca
Pickard-Brzosowicz, Jennifer
Manoukian, Siranoush
Swaby, Ramona
Silva, Rosane
Urmenyi, Turan
Rondinelli, Edson
Nathanson, Katherine
Issue Date: 2007
Citation: Carvalho, M., Marsiallac, S., Karchin, R., Manoukian, S., Grist, S.A., Swaby, R., Urmenyi, T., Rondinelli, E., Silva, R., Gayol, L., et al., 2007. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Research, 67(4), 1494-1501.
Abstract: 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 <45% of wild-type activity can be classified as deleterious whereas 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]
Description: ©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.
URI: http://hdl.handle.net/2328/11105
ISSN: 0008-5472
Appears in Collections:1112 - Oncology and Carcinogenesis
1112 - Oncology and Carcinogenesis

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