Reference Detail

Ref Type Journal Article
PMID (30279230)
Authors Sato K, Kawazu M, Yamamoto Y, Ueno T, Kojima S, Nagae G, Abe H, Soda M, Oga T, Kohsaka S, Sai E, Yamashita Y, Iinuma H, Fukayama M, Aburatani H, Watanabe T, Mano H
Title Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability-High Colorectal Cancers.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2018 Oct 02
URL
Abstract Text 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 MLH1 (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 BRAF and RNF43 than LS-associated or Lynch-like MSI-H tumors. Eleven fusion kinases were exclusively detected in MM MSI-H colorectal cancers 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 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. Clin Cancer Res; 1-12. ©2018 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
EML4 - NTRK3 fusion gain of function EML4-NTRK3 results from the fusion of EML4 and NTRK3 and leads to transformation of cultured cells and activation of MAPK signaling in a reporter assay (PMID: 30279230). EML4-NTRK3 has been identified in MSI-high colorectal cancer (PMID: 30279230).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4-NTRK3 Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, Entrectinib (RXDX-101) inhibited growth of transformed cells expressing EML4-NTRK3 in culture (PMID: 30279230). 30279230