The Genomics of Colorectal Cancer in Populations with African and European AncestryGenomics, Colorectal Cancer, and African and European Ancestry

Parvathi A. Myer, Jessica K. Lee, Russell W. Madison, Kith Pradhan, Justin Y. Newberg, Carmen R. Isasi, Samuel J. Klempner, Garrett M. Frampton, Jeffery S. Ross, Jeffrey M. Venstrom, Alexa B. Schrock, Sudipto Das, Leonard Augenlicht, Amit Verma, John M. Greally, Srilakshmi M. Raj, Sanjay Goel, Siraj M. Ali

Blacks have a higher incidence of colorectal cancer (CRC) and worse survival rates when compared to Whites. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer MSI-H tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations specifically KRAS G12D and KRAS G13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, RET). In patients with young onset CRC (<50 years), AFR and EUR had similar frequency of MSI-H and TMB-H tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of our diverse US population.