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.

Automated summary

We report a prevalence of approximately 0.7% for NTRK-positive colorectal cancer (CRC) by genetically profiling 2519 colonic and rectal tumors. NTRK gene fusions frequently co-occur with APC and TP53 aberrations, while they are almost always mutually exclusive with RAS/BRAF oncogenic alterations. NTRK-driven CRC patients show increased TMB, high microsatellite instability, and an enrichment for POLE/POLD1 mutations when compared to the molecularly unstratified CRC population.