AbstractBackgorundColorectal cancer (CRC) is among the leading causes of cancer‐related deaths among Hispanics living in the United States (USH). Understanding the most common carcinogenic molecular pathways that affect Hispanics with CRC is crucial to guide research efforts in developing new therapeutic modalities incorporating genomically diverse populations. Tumor profiling techniques help identify actionable alternatives to recommend treatment and improve survival in cancer patients.MethodsWe conducted a secondary data analysis to evaluate the mutational profile of 218 CRC tumors in Hispanics living in Puerto Rico (PRH) who underwent next‐generation sequencing (NGS) testing from 2015 to 2020. We compared the prevalence of CRC tumor somatic mutations in PRHs with the mutational profiles reported for CRC from The Cancer Genome Atlas (TCGA) Pan‐Cancer Clinical Data, the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE)‐Non‐Hispanic, and GENIE‐Hispanic datasets.ResultsAmong the top mutated genes in CRC tumors in PRHs wereAPC,TP53, andKRAS, which had significantly higher mutational frequencies in PRH compared to the examined datasets, including GENIE‐Hispanics. The most frequent gene amplifications for PRH wereCDX2, CDKN1B, andHNRNPA2B1. Targetable biomarkers for CRC, such as microsatellite instability‐high (MSI), wild‐typeKRAS, wild‐typeNRAS, V600EBRAF, andERBB2gene amplifications were found in 2.0%, 43.8%, 97.8%, 3.9%, and 2.3%, respectively, of PRH patients.ConclusionThis is the first study to report the mutational profile of CRC tumors in PRHs and make comparisons to other non‐Hispanic and USH populations.