A molecular portrait of microsatellite instability across multiple cancers

Isidro Cortes-Ciriano,Peter J Park,Tae-Min Kim,Woong-Yang Park,Sejoon Lee

doi:10.1038/ncomms15180

Abstract

Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.

Highlights

Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair
Our joint analysis of MSI-H tumours from multiple cancer types has revealed that several DNA repair pathways other than mismatch repair (MMR), including ATR, BER, homologous recombination (HR) and non-homologous end joining (NHEJ), are altered by singlenucleotide and MS mutations
We have uncovered new genes affected by frameshift MSI events in MSI-prone tumours as well as in tumour types not frequently affected by MSI

Summary

Introduction

Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. This represents a major expansion of our previous MSI analysis in 277 colorectal and uterine endometrial exomes[15] and complements a recent large-scale analysis by Hause et al.[16] We systematically profile the patterns of MSI mutations in both nuclear and mitochondrial DNA, characterize the affected pathways, and find associations with epigenomic features These analyses uncover new genes harbouring frameshift MSI events with varying degrees of cancer-type specificity and generate the most comprehensive catalogue to date of MS loci selectively subject to DNA slippage events in MSI-H tumours. We describe highly accurate predictive models of MSI-H status based on exome data

Methods

Results

Conclusion