AbstractUnderstanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is vital to addressing the regions rising burden of disease. Tissue from unselected Nigerian patients was analyzed with a multigene, next-generation sequencing assay. The rate of microsatellite instability is significantly higher among Nigerian CRC patients (28.1%) than patients from The Cancer Genome Atlas (TCGA, 14.2%) and Memorial Sloan Kettering Cancer Center (MSKCC, 8.5%,P < 0.001). In microsatellite-stable cases, tumors from Nigerian patients are less likely to haveAPCmutations (39.1% vs. 76.0% MSKCCP < 0.001) and WNT pathway alterations (47.8% vs. 81.9% MSKCC,P < 0.001); whereas RAS pathway alteration is more prevalent (76.1% vs. 59.6%,P = 0.03). Nigerian CRC patients are also younger and more likely to present with rectal disease (50.8% vs. 33.7% MSKCC,P < 0.001). The findings suggest a unique biology of CRC in Nigeria, which emphasizes the need for regional data to guide diagnostic and treatment approaches for patients in West Africa.