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

Clin Cancer Res 2019 01 2;25(1):378-389. Epub 2018 Oct 2.

Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Purpose: Colorectal cancers 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 colorectal cancers with promoter methylation of (called MM) had a clinicopathological profile that was distinct from that of colorectal cancers of patients with germline mutations (Lynch syndrome, LS-associated) or somatic, Lynch-like mutations in mismatch repair genes. MM tumors had more insertions and deletions and more recurrent mutations in and than LS-associated or Lynch-like MSI-H tumors. Eleven fusion kinases were exclusively detected in MM MSI-H colorectal cancers lacking oncogenic / 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 colorectal cancers, identifying 16 MM tumors and 2 fusion kinases.

Conclusions: We discovered that fusion kinases are frequently observed among sporadic MM MSI-H colorectal cancers. The new method to identify MM tumors enables us to straightforwardly group MSI-H patients into candidates of LS or fusion kinase carriers.

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Source
http://clincancerres.aacrjournals.org/lookup/doi/10.1158/107
Publisher Site
http://dx.doi.org/10.1158/1078-0432.CCR-18-1574DOI Listing
January 2019
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