Funded by the Stuart Scott Memorial
Cancer Research Fund
Colorectal cancer is the second leading cause of cancer deaths in the United State, with African Americans having a significantly higher risk of developing colorectal cancer and of dying from colorectal cancer than do Caucasians. This study is based on the recent milestone publication from our team finding that 41% of colorectal cancers from African Americans are molecularly distinct from colorectal cancers from Caucasians, with African American colorectal cancers bearing mutations in certain genes that are never or rarely mutated in Caucasian colorectal cancers (dubbed: African American Colorectal Cancer, or AACC, genes). This proposal will examine whether AACC genes are similarly targeted for mutation in cancers from African Americans that live in different regions of the country; whether AACC gene mutations are associated with more aggressive colon cancer behavior; whether cancers with AACC gene mutations appear different under the microscope; whether AACC gene mutations show molecular footprints of exposures to environmental carcinogens; and whether mutations of AACC genes preferentially target genes that are inherited from African versus from Caucasian forebearers. We further will develop functional models for two AACC genes (EPHA6 and FLCN) that are mutated exclusively in African Americans and will test effects of these mutations on the ability of cancer cells to grow and to metastasize. We moreover will determine if the presence of these mutations turns on any signaling pathways whose activation would render these cancers sensitive to treatment with new types of anti-cancer drugs that are designed to target and shut down specific cancer-associated signaling pathways.