Mechanisms of Tumorigenesis in African American Colorectal Cancer

Abstract

While colorectal cancer (CRC) incidence has decreased over the past 20 years, the reduction in incidence has not been uniform across all stages of disease. The reduction in late stage (distant) CRC was significantly less than that of than earlier stage CRC, a trend enriched for early-onset CRCs. African Americans have the highest incidence and mortality rates of CRC of any ethnic group in the United States and are more likely to present before recommended guidelines for screening (i.e., age of 50 years). Despite this ongoing health disparity, relatively few studies have sought to address risk factors and etiological signatures unique to African American CRC. We hypothesized that molecular characteristics in the gut microenvironment and tumor mutation profiles of African American CRCs are unique. The studies presented here sought to address this hypothesis through molecular studies in a low-income cohort from urban Chicago, the Chicago Colorectal Cancer Consortium, as well as a publicly available cohort, The Cancer Genome Atlas. We found that African Americans have higher abundances of the sulfidogenic bacterium Bilophila wadsworthia, a trend that remained after adjusting for covariates including diet. African American cases had significantly higher abundances than African American controls, a trend that did not exist in non-Hispanic Whites. We found that African American CRCs had molecular features that were distinct from non-Hispanic Whites. CCCC African American CRCs had significantly fewer mutations than expected in APC, a gene typically mutated in 80% of CRCs, and that the lack of APC mutation was associated with younger age, chromosome stability, and a non-CIMP DNA methylation profile. Together, the findings presented here suggest that unknown risk factors and unique tumorigenic processes drive CRC in African Americans.