The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes

Abstract

Summary Microsatellites - simple tandem repeats present at millions of sites in the human genome - can shorten or lengthen due to a defect in DNA mismatch repair. We present here the first comprehensive genome-wide analysis of the prevalence, mutational spectrum and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type-specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wildtype alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type-specificity, impact on gene expression, and the role of chromatin organization.

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

“…13 Somatic POLE mutations have been reported in both microsatellite stable and MSI tumours. 10,12 The Lynch syndrome phenotype reported here is not because of the germline variants in the MMR genes but more likely the result of somatic inactivation (PT1 and PT2). The hypermutator phenotype associated with inherited POLE mutations suggests a causative role for the somatic mutations although the second hit could not be identified.…”

“…Eight of the eleven POLE-mutated tumours showed additional MSH6 somatic mutations, and of these, five cases also showed MSH2 mutations. 12 Moreover, MSI tumours with two somatic MSH2 mutations, lacking MSH2 and MSH6 protein expression, 22 or with loss of MLH1 protein staining in the tumour, [23][24][25] have also been reported for patients with bi-allelic variants in the base excision repair gene MUTYH. Similarly to POLE germline variants, MUTYH missense variants can also induce somatic mutations in MMR genes, although the mechanism behind the co-occurrence of mutations in the different DNA repair defects remains elusive.…”

“…8,9 In addition, somatic mutations in the proofreading domains of POLD1 and POLE have been identified in microsatellite instable (MSI) and hypermutated subgroups of colorectal cancers (CRCs). [10][11][12] Recently, Palles et al reported that heterozygous germline variants in the proofreading domain of the DNA polymerases POLE and POLD1 predispose, with a high penetrance, to multiple colorectal adenomas, early onset CRC (OMIM #114500) and endometrial cancer (OMIM #608089). These variants were found by whole-genome sequencing and linkage analysis in three large families with a dominant pattern of CRC and multiple adenomas.…”

Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers

“…16 The same phenomenon was observed on fluorescent PCR amplification of two mono-and three dinucleotide markers and capillary electrophoresis. 17,18 With MSI testing available at our institution and IHC testing recently implemented, we sought to optimize our screening algorithm, which relied on determining whether these previously reported findings were applicable to the five mononucleotide markerebased MSI commercial kit in use by our laboratory and in most clinical laboratories for CRC and EMC testing.…”

Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review

“…We hypothesized that a lesion-promoting functional significance of a certain microsatellite mutation would be reflected by an accelerated outgrowth of the affected cell, which should result in a higher likelihood of the mutation to be detectable in the resulting lesion. Accordingly, we hypothesized that an increased frequency of a certain microsatellite mutation may suggest functional relevance during plaque development, according to models that have convincingly demonstrated associations in cancers with MMR deficiency (10)(11)(12)(13)(14).…”