Study: JGAS00000000113




TitleComprehensive genomic analysis of colorectal cancer with microsatellite instability
AbstractMicrosatellite instability-high (MSI-H) colorectal cancers (CRCs) account for 10–15% of all CRCs. MSI-H CRC is characterized by a large number of somatic insertions/deletions (indels) resulting from either mutations within or the silencing of genes involved in the DNA mismatch repair (MMR) system. A subset of MSI-H CRCs is associated with Lynch syndrome (LS), which is caused by germline MMR gene mutations, leading to hereditary cancer predisposition. Other than frequent somatic mutations in BRAF, the transformation mechanisms underlying MSI-H CRC are largely unknown. Here, genomic DNA from 149 MSI-H CRC specimens was analyzed using whole-exome sequencing, and 93 of these samples were subjected to genome-wide DNA methylation analysis. Furthermore, transcriptome sequencing was conducted on 111 samples. Genomic/epigenomic analyses identified three subgroups within our cohort: (1) MSI-H CRCs with silenced MLH1 that share frequent indels, a specific mutation/copy number alteration profile and promoter DNA methylation; (2) LS-associated MSI-H CRCs with MMR genes containing germline mutations; and (3) the remaining MSI-H CRCs with frequent somatic disruptive mutations of MLH1 or MSH2. Unexpectedly, only the first group was found to frequently carry fusion-type protein kinases (15% of this group and 9.9% of all MSI-H CRCs) that are promising therapeutic targets. Thus, MSI-H CRCs can be classified into three subgroups with distinctive genomic as well as epigenomic statuses, probably reflecting the oncogenic processes of these cancers. Fusion-type kinases are enriched in MSI-H CRCs, shedding new light on potential treatment strategies.
Study Type 1
Study TypeExome Sequencing
Study Type 2
Study TypeTranscriptome Sequencing


PubMed ID30279230
Publication Statuspublished

Study Attribute

NBDC Numberhum0094
Registration date2017-06-15
Submitting organizationDepartment of Celluar Signaling, Graduate School of Medicine, The University of Tokyo
Principal InvestigatorHiroyuki Mano
Molecular Data TypeWhole Exome Sequencing
Molecular Data TypeRNA Sequencing
Molecular Data TypeDNA Microarray
PlatformiScan system
Primary PhenotypeColon cancer
PhenotypeHereditary nonpolyposis colorectal carcinoma
PhenotypeNeoplasm of the rectum
Accession Title Dataset type Data objects Policy
JGAD00000000122 Bam, fastq and array files of CRC 407 JGAP00000000001