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).
Summary
- 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.