Background The increasing molecular characterization of colorectal cancers (CRC) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1-3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies. Methods Tumor and matched whole blood from 609 Chinese CRC patients were collected. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer-related genes, including: single-nucleotide variations (SNV), short and long insertions and deletions (Indel), copy number variations (CNV), and gene rearrangements. NGS-based computational algorithms also determined tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese CRC patients. For the first time, NTRK gene fusion's prevalence was observed to be around 7% in the MSI-H CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T-cell infiltration. Conclusion Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI-H CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes. IMPLICATIONS FOR PRACTICE: The increasing use of genomic profiling assays in CRC has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. Here we provide an early support for the feasibility and utility of genomic profiling in Chinese CRC patients.