Molecular and Pathologic classification of BRCA unclassified variants
The two major breast cancer susceptibility genes, BRCA1 and BRCA2, account for the majority of familial breast and ovarian cancer and a modest proportion of breast cancer families without ovarian or male breast cancer. Germ-line mutations in these two genes are highly penetrant and associated with a high risk of both breast and ovarian cancer. Genetic heterogeneity and existence of variants in the population has long been an issue to proper classification of mutations. Using tumor cell lines and tissue culture based model systems we wish to establish the pathogenic potential of commonly occurring and disease related unclassified mutations.
Functional analysis of Cancer susceptibility genes
BRCA1 and BRCA2 proteins participate in common cellular repair processes. Functional loss in either of these two gene products leads to genomic instability, suggesting that transformation and tumor development are governed by mechanisms other than DNA repair deficiency. We wish to elucidate novel functions for these proteins using detailed genomic and proteomic analysis. Characterization of the components in the BRCA signaling pathways will further likely uncover novel breast cancer genes.
Role of ATM in breast cancer susceptibility
The significance of BRCA1 and BRCA2 in breast cancer families without epithelial ovarian cancer or male breast cancer is modest. It is conceivable that genetic predisposition to breast cancer includes other factors and mechanisms. The ataxia-telangiectasia gene (ATM) predisposes heterozygotes to cancer, particularly of the breast. The reported increased breast cancer risk for AT family members has been most evident among younger women. We wish to elucidate the co-operativity of ATM mutations with BRCA alterations to dissect cancer susceptibility in tumors bearing multiple losses. Our aim is to understand the cellular functions of ATM and further clarify if mutations in ATM increase risk to cancer predisposition in carriers of BRCA mutations.
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