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Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors

Isabelle Sourrouille1, Florence Coulet, Jeremie H Lefevre

  • 1Department of Digestive Surgery, Hôpital Saint Antoine (AP-HP), Paris VI University, Paris, France.

Familial Cancer
|September 19, 2012
PubMed

Insights

Microsatellite instability in colorectal cancer can arise from rare MMR gene mutations. This study identified double somatic hits, mosaicism, and missed germline mutations as causes in some patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Microsatellite instability (MSI) is a hallmark of some colorectal cancers (CRCs).
  • Mismatch repair (MMR) gene alterations typically cause MSI, but some CRCs with MSI lack identifiable germline or promoter methylation defects.
  • The mechanisms underlying MMR gene inactivation in these specific cases remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms responsible for MMR gene inactivation in colorectal cancer patients presenting with MSI but without apparent germline or promoter methylation alterations.
  • To identify the specific genetic events leading to MSI in a cohort of patients with colorectal cancer and loss of MMR protein expression.

Main Methods:

  • Studied 18 patients with MSI colorectal cancer (CRC) and loss of MMR protein expression.
  • Extracted DNA from tumoral and normal colonic tissues.
  • Analyzed the three main MMR genes (MLH1, MSH2) using sequencing and large rearrangement analysis.
  • Investigated potential mosaicism for MMR gene mutations.

Main Results:

  • Seven patients showed loss of MLH1 expression; mutations were found in three (one mutation) and one (two mutations).
  • Eight patients lost MSH2 expression; mutations were found in two (one mutation) and four (two mutations).
  • In five cases with two identified mutations, MSI was attributed to double somatic hits (n=3), mosaicism (n=1), or a missed germline mutation (n=1).
  • Mosaicism was confirmed via HRM analysis and family studies, including the first described case of somatic mosaicism after a de novo MSH2 mutation.

Conclusions:

  • The study elucidated the mechanisms of MMR gene inactivation in 27.8% of patients with MSI CRC lacking typical alterations.
  • Identified double somatic hits, mosaicism, and missed germline mutations as causes of MSI in these specific colorectal cancer cases.
  • Findings can inform patient follow-up and family surveillance strategies, distinguishing sporadic from potentially heritable cases.

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