Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks

Elife. 2014 Aug 1;3:e02725. doi: 10.7554/eLife.02725.


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.

Keywords: DNA double-strand breaks; DSB inducers; MSI; mismatch repair deficiency; mutation pattern; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Pair Mismatch
  • Biomarkers, Tumor / genetics*
  • DNA Breaks, Double-Stranded*
  • DNA Fingerprinting
  • DNA Mismatch Repair
  • Endometrial Neoplasms / diagnosis
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Female
  • Homologous Recombination
  • Humans
  • INDEL Mutation*
  • Microsatellite Instability
  • Microsatellite Repeats*
  • Neoplasm Staging
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Sensitivity and Specificity


  • Biomarkers, Tumor

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.