Mutational Disparities in Survival Critical Genes in Colorectal Cancers of White Americans, Alabama African Americans, and Oklahoma American Indians

The high incidence and mortality rates of colorectal cancer (CRC) in Alabama African Americans (AAs) and Oklahoma American Indians (AIs) are recognized as cancer disparities, yet the underlying causes have been poorly demonstrated. A previous study of transcriptomic profiles of CRCs of Alabama AAs, Oklahoma AIs, and white people from both states revealed molecular disparities and differentially expressed genes (DEGs) in the racial groups. In the present study, by evaluating CRC whole exome sequencing and mutational profiles, we report sets of mutated genes whose frequencies differed significantly (p<0.05) in a race specific manner. Secondary screening with a CRC database (cBioportal database for bowel cancer) showed 42, 38, and 35 survival critical genes (SCGs) (i.e., genes whose mutations or alterations are associated with significant differences in the patients survival rates) among the differentially mutated genes, suggesting that the mutations have a functional impact on cancer. Notable SCGs with race pronounced variants were different from DEGs and their involved pathways included nucleotide catabolism (GDA, NT5M, XDH) and cell cycle checkpoints (CLIP1, PSMB2, PSMD3, TP53) for AAs, and extracellular matrix organization (COL4A4, LAMA1, LAMA2, NRXN1) for AIs (BH adjusted p<0.05). Most of the SCGs with race-pronounced variants (35 SCGs out of 42 in whites, 29 of 38 AAs, and 30 of 35 AI) are under-investigated with less than ten CRC related publications in PubMed. The inclusion of these SCGs with race-pronounced variants in the clinical CRC next generation sequencing panels and the development of targeting drugs will serve as refinements for precision medicine to overcome racial disparities in health outcomes of CRC.