Pathogenic somatic mutation (SM) of mismatch repair (MMR) genes and associations with microsatellite instability (MSI), tumor mutational burden (TMB) and SM in other DNA repair pathways in 24,223 tumor genomic profiles


J. Nicholas Bodor, Elizabeth A. Handorf, Rebecca Feldman, Michael J. Hall

Study Objectives

  • Determine the frequency of mSM and bSM in the MMR genes (MLH1, MSH2, MSH6, PMS2) in a large sample of histologically diverse tumors undergoing commercial tumor genomic testing.
  • Associate these with the MSI-H phenotype, TMB, and SM in other DNA repair pathways.
  • Associate these with tumor histology and CRC sidedness (L vs R).


  • MMR mSM are found in a diverse range of tumor histologies.
  • MMR bSM occur more often in younger patients and primarily in Lynch syndrome spectrum tumors, suggesting:
    • Germline MMR mutations precede many bSM and/or
    • Some organs are more vulnerable to develop bSM in the setting of mSM
  • MMR mSM and bSM are associated with high TMB, MSI-H, and mutations in non-MMR DNA repair pathways (i.e. HR and NER DNA repair pathways).
  • Findings suggest both interactive and cascade effects of DNA repair pathways, which may elucidate tumor biology and new treatment targets.

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