Project Description: African Americans are diagnosed with breast and colon cancer at young ages more frequently than are European Americans, however, the reasons are not clear. Germline sequence variations in p53 pathway genes that are unequally distributed between people of African and European ancestry may influence the rate at which cancer-causing somatic mutations develop. We seek to functionally characterize single nucleotide polymorphisms in the TP53 and MDM2 genes, to determine how they may contribute to early-onset breast and colon cancer in African Americans. To characterize the unique somatic mutation landscapes of colon and breast cancers that develop from these different genetic backgrounds, our group uses next-gen sequencing approaches to identify novel germline variants that correlate with ethnic ancestry and age of diagnosis. To better understand the interplay between germline variants (SNPS) and cancer phenotype caused by somatic mutations, we use somatic cell knockout technology to create isogenic pairs of cell lines differing only in the polymorphic loci of interest and then biochemically and phenotypically characterize the resulting derivatives. The approach has lead to important discoveries about how a common germline variant in p53 (Pro72Arg) causes profound differences in cancer risk and longevity in humans, and points to novel therapeutic intervention strategies. Our project on African American cancer health disparities will further evaluate the germline and somatic mutation landscapes of breast and colon cancers, to uncover additional genetic differences that are associated with age of diagnosis, and functionally characterize variant alleles to establish their mechanisms of action.