Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome

J Med Genet. 2019 Jul;56(7):462-470. doi: 10.1136/jmedgenet-2018-105698. Epub 2019 Mar 15.


Background: Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts.

Methods: We included patients with CRC from Ohio 2013-2016 and Iceland 2000-2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared.

Results: Of the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10-4) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10-6) and have multiple LS-associated tumours (OR=6.67, p=3.31×10-5). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts.

Conclusions: Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS.

Keywords: DNA repair system; Lynch-like syndrome; somatic mutation; tumour testing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Methylation
  • DNA Mismatch Repair*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Germ-Line Mutation
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Young Adult


  • Biomarkers, Tumor