NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability

TRK fusions are rare but targetable mutations which occur across a wide variety of cancer types. We report the prevalence of approximately 0.7% for NTRK‐positive colorectal cancer (CRC) by genetically profiling 2519 colonic and rectal tumors. The aberrations of APC and TP53 frequently co‐occurred with NTRK gene fusions, whereas RAS/BRAF oncogenic alterations and NTRK fusions were almost always mutually exclusive. NTRK‐driven colorectal cancer patients demonstrated increased TMB (median = 53 mut/MB, 95% CI: 36.8–68.0 mut/MB), high microsatellite instability, and an enrichment for POLE/POLD1 mutations when compared to molecularly unstratified colorectal cancer population. These data shed light on possible future approach of multimodality treatment regimen including TRK‐targeted therapy and immune checkpoint inhibitor therapy in NTRK‐positive CRCs.