Spectrum of DNA mismatch repair failures viewed through the lens of cancer genomics and implications for therapy

Abstract

Abstract Genome sequencing can be used to detect DNA repair failures in tumors and learn about underlying mechanisms. Here, we synthesize findings from genomic studies that examined deficiencies of the DNA mismatch repair (MMR) pathway. The impairment of MMR results in genome-wide hypermutation and in the ‘microsatellite instability’ (MSI) phenotype—occurrence of indel mutations at short tandem repeat (microsatellite) loci. The MSI status of tumors was traditionally assessed by molecular testing of a selected set of MS loci or by measuring MMR protein expression levels. Today, genomic data can provide a more complete picture of the consequences on genomic instability. Multiple computational studies examined somatic mutation distributions that result from failed DNA repair pathways in tumors. These include analyzing the commonly studied trinucleotide mutational spectra of single-nucleotide variants (SNVs), as well as of other features such as indels, structural variants, mutation clusters and regional mutation rate redistribution. The identified mutation patterns can be used to rigorously measure prevalence of MMR failures across cancer types, and potentially to subcategorize the MMR deficiencies. Diverse data sources, genomic and pre-genomic, from human and from experimental models, suggest there are different ways in which MMR can fail, and/or that the cell-type or genetic background may result in different types of MMR mutational patterns. The spectrum of MMR failures may direct cancer evolution, generating particular sets of driver mutations. Moreover, MMR affects outcomes of therapy by DNA damaging drugs, antimetabolites, nonsense-mediated mRNA decay (NMD) inhibitors, and immunotherapy by promoting either resistance or sensitivity, depending on the type of therapy.