Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability-High Colorectal Cancers

Purpose: Colorectal cancers (CRCs) with microsatellite instability-high (MSI-H) status, due to mismatch repair deficiency, are associated with poor patient outcomes after relapse. We aimed to identify novel therapeutic targets for them. Experimental Design: We performed MSI analyses of over 2,800 surgically resected colorectal tumors obtained from consecutive patients treated in Japan from 1998 through June 2016. Whole-exome sequencing, transcriptome sequencing, and methylation analyses were performed on 149 of 162 tumors showing MSI in BAT25 and BAT26 loci. We analyzed patient survival times using Bonferroni-adjusted log-rank tests. Results: Sporadic MSI-H CRCs with promoter methylation of MLH1 (called MM) had a clinicopathological profile that was distinct from that of CRCs of patients with germline mutations (Lynch syndrome-associated) or somatic, Lynch-like mutations in mismatch repair genes. MM tumors had more insertions and deletions and more recurrent mutations in BRAF and RNF43 than Lynch syndrome-associated or Lynch-like MSI-H tumors. Eleven fusion kinases were exclusively detected in MM MSI-H CRCs lacking oncogenic KRAS/BRAF missense mutations and were associated with worse post-relapse prognosis. We developed a simple method to identify MM tumors and applied it to a validation cohort of 28 MSI-H CRCs, identifying 16 MM tumors and 2 fusion kinases. Conclusions: We discovered that fusion kinases are frequently observed among sporadic MM MSI-H CRCs. The new method to identify MM tumors enables us to straightforwardly group MSI-H patients into candidates of Lynch syndrome or fusion kinase carriers.