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High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology
Journal article   Peer reviewed

High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology

Ioannis A. Voutsadakis
Cancer treatment and research communications, Vol.36, pp.100746-100746
01/01/2023
DOI: 10.1016/j.ctarc.2023.100746
PMID: 37494750

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Abstract

•A subset of microsatellite stable (MSS) colorectal cancers display a high tumor mutation burden (TMB).•Some MSS colorectal cancers with high TMB have defects in proofreading polymerases but most cases have no mismatch repair or proofreading polymerases mutations.•Alterations of the KRAS signal transduction pathways, mutations in genes involved in DNA damage response (DDR) or epigenetic modifier mutations may contribute to the high TMB in MSS colorectal cancers.•Identification of pathogenic defects leading to high TMB in MSS cancers may provide an opportunity for advancing targeted therapies. Colorectal cancers with defects in the Mismatch Repair (MMR) system represent a minority of the disease. MMR defective cancers are characterized by high Tumor Mutation Burden (TMB) and are sensitive to immunotherapy with immune checkpoint inhibitors. In contrast, the majority of colorectal cancers are MMR proficient (Microsatellite Stable, MSS) and display a low TMB. However, a few of these MSS cancers have high TMB. Published genomic studies of colorectal cancers were examined to identify cases profiled as MSS and having a TMB above 10 mutations / Mb. Data from four studies detailed in the cBioportal for cancer genomics site and providing data on MSI status were examined. In the MSK study of metastatic colorectal cancers, 7.5% of patients with MSS tumors had a high TMB of more than 10 mutations/ Mb. The MSK study of localized rectal cancers showed that 9.5% of patients with MSS tumors had a high TMB. The DFCI cohort included 10 patients with TMB above 10 mutations/ Mb characterized as MSS and not having MMR or proofreading polymerases mutations. Mutations in genes encoding for proteins of the KRAS pathways were more frequent in MSS tumors with high TMB than in counterparts with low TMB. Moreover, genes involved in DNA damage response and in epigenetic regulations were more frequently mutated in MSS colorectal cancers with high TMB. Alterations of the KRAS signal transduction pathways, DDR gene mutations and epigenetic modifier mutations may contribute to increase mutation burden in subsets of MSS colorectal cancers.
 Biomarkers Immunotherapy Microsatellite Mismatch repair Tumor mutation burden

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