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

Abstract

Purpose: Colorectal cancers with microsatellite instabilityhigh (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.

Streamlining Detection of Fusion Genes in Colorectal Cancer: Having “Faith” in Precision Oncology in the (Tissue) “Agnostic” Era

“…In line with the data reported by Cocco and colleagues (5), Sato and colleagues analyzed nearly 3,000 colorectal cancer cases from Japan and described remarkably similar results, with tumors harboring fusions in kinase genes being enriched in sporadic MSI-H, MLH1p, and RAS/BRAF wild-type colorectal cancer cases (6). Fifty-five percent of patients with sporadic colorectal cancer with MMR deficiency, MLH1p, and lack of mutations in the RAS/BRAF pathway harbored fusion genes.…”

Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin‐fixed paraffin‐embedded specimens

“…Because the MSI status of cancer cells is used as a response predictor for immune checkpoint inhibitors, we designed DNA capture probes for 10 microsatellite regions including those designated in the Bethesda panel . Moreover, additional probes were included in the TOP DNA panel V2 to interrogate 500 microsatellite loci that were commonly altered in our WES analysis of high‐MSI colorectal cancer . To detect MMR‐deficient tumors, MSIsensor scores were calculated using the TOP DNA sequence data.…”

“…Marker, 1-kb DNA ladder; NC, negative control the Bethesda panel 40. Moreover, additional probes were included in the TOP DNA panel V2 to interrogate 500 microsatellite loci that were commonly altered in our WES analysis of high-MSI colorectal cancer 41. To detect MMR-deficient tumors, MSIsensor scores 42 were calculated using the TOP DNA sequence data.…”

Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer

“…The data used in this study were obtained and described in the previous report . Patients with CRC gave written informed consent prior to their participation in the study.…”

“…CIMP is found in various types of cancers, and was reported to be a clinically distinct subset in CRC . Using the recently enriched transcriptome database and our recently published data from genome‐wide methylation analysis of MSI‐H CRC, here we analyzed the methylation status of div‐CGI and found that div‐CGI were less methylated compared with CGI within unidirectional promoters (uni‐CGI) in normal colon cells as well as in CRC cells. These results provide important insights to understand the aberrant promoter CGI methylation in cancer cells.…”