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–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 murine model systems we wish to establish the pathogenic potential of commonly occurring and disease related unclassified mutations.
BRCA1 and BRCA2 participate in common cellular processes and lack
of either gene’s function 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. Gene expression profiling offers a
powerful instrument to elucidate differences in tumor phenotypes, and could
potentially be used to define novel subgroups of non-BRCA1/2 hereditary breast
cancer. Characterization of the components in the BRCA signaling pathways will
further likely uncover novel breast cancer genes.