BRCA Genes.ppt

BRCA Genes Dallas Henson BReast CAncer Women have about a 1 in 7 chance of getting breast cancer in their lifetime. Most cancer is sporadic, about 5-10% of cases are genetically linked Women inheriting mutation of BRCA gene have increased chance of disease Also can lead to ovarian cancer The Numbers BRCA Genes BRCA 1 and BRCA 2 Roles they play What are they? BRCA 1 and BRCA 2 Known as breast and ovarian cancer susceptibility genes Tumor suppressor genes regulate the cycle of cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way inhibit the growth of cells that line the milk ducts in the breast Involved in many other functions including control of DNA replication and damage repair BRCA 1 Cloned in 1994 (Miki et al) Mapped to chromosome 17q21 5,592kb long 24 exons BRCA1 protein Consists of 1863 amino acids Expressed in most proliferation cells Part of large protein complex 3 MDa BRCT (C-terminal of BRCA) domain Consists of 2 conserved BRCT repeats~90-100 amino acids long N-terminal – ring-finger domain BRCA 2 Cloned in 1995 (Wooster et al.) Mapped to chromosome 13q12-13 10,254 kb (3,418 aa) 27 exons BRCA 2 protein 3,418 amino acids 385 kDa Very large exon 11 Encodes peptide motifs for interaction with the RAD51 protein BRCA1 Mutations Germline mutations within BRCA1 predispose carriers (heterozygotes) to early onset breast Heterozygous carriers of BRCA1 mutations have an 80% risk of breast cancer increase risk of ovarian cancer BRCA2 Mutations Similar statistics for BRCA2 carriers, but later age of onset and lead to other tumors: gastric, colon, pancreatic, prostate, and melanoma BRCA2 mutations confer higher risk of male breast cancer More Numbers How does this happen? Tumor Suppressor paradox Once thought to that loss of BRCA genes resulted from Knudson’s 2-hit model of carcinogenesis How does this happen? Tumor suppressor paradox cont’d Unlike other tumor suppressors, there have been no disease-dominant