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Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Anne Ml Jansen1,2, Tom van Wezel1, Brendy Ewm van den Akker1

  • 1Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.

European Journal of Human Genetics : EJHG
|December 10, 2015
PubMed

Insights

This study investigated unexplained suspected Lynch Syndrome (sLS) cases. Faulty DNA proofreading by POLE/POLD1 variants can lead to mismatch repair deficiency and microsatellite instability, explaining some sLS cases.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Suspected Lynch Syndrome (sLS) patients often lack identifiable germline variants in mismatch repair (MMR) genes or MLH1/MSH2 hypermethylation.
  • Current explanations for unexplained sLS include somatic MMR gene variants or rare germline POLE variants.

Purpose of the Study:

  • To investigate the genetic basis of sLS in patients with unexplained cases.
  • To identify novel genetic factors contributing to microsatellite instability in sLS.

Main Methods:

  • Analysis of leukocyte and tumor DNA from 62 sLS patients.
  • Gene panel sequencing targeting POLE, POLD1, and MMR genes.

Main Results:

  • Forty tumors exhibited one or more somatic MMR variants affecting function.
  • Nine sLS tumors with an ultramutated phenotype carried germline or somatic variants in the POLE/POLD1 exonuclease domain (EDM).
  • Six of these POLE/POLD1-EDM mutated tumors also had somatic MMR variants.

Conclusions:

  • Faulty DNA proofreading by POLE/POLD1 exonuclease domain variants can lead to loss of MMR.
  • This mechanism contributes to microsatellite instability and may explain a subset of unexplained suspected Lynch Syndrome cases.

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