Abstract
DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers.
Highlights
mismatch repair (MMR)-deficiency represents a well-established cause of Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility triggered by loss-of-function mutations in MMR genes (MLH1, MSH2 or MSH6) 1
EM tumors with microsatellite instability (MSI) sequenced by The Cancer Genome Atlas tumors were sequenced at low coverage depth, we identified 2,183 and 3,138 mutated genes from respectively the CRC and EM tumor datasets
We surveyed whole-genomes of MMR-deficient tumors to provide a comprehensive picture of the mutations associated with human MMR-deficiency
Summary
MMR-deficiency represents a well-established cause of Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility triggered by loss-of-function mutations in MMR genes (MLH1, MSH2 or MSH6) 1. Of endometrial (EM) or colorectal (CRC) tumors. Epigenetic silencing of MLH1 contributes to another 15-28% of these tumors 2,3. Deficiency of the MMR machinery leads to DNA replication errors in the tumor tissue, but not the normal surrounding tissue. Errors often accumulate as indel mutations in mono- and di-nucleotide repeats a phenomenon referred to as microsatellite instability (MSI) 4. MMR-deficient tumors exhibit a different prognosis and therapeutic outcome after standard chemotherapy 5. Untreated CRC patients with MMR-deficient tumors have a modestly better prognosis, but do not seem to benefit from 5-fluorouracil-based adjuvant chemotherapy, which is the first-choice chemotherapy for CRC.
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