Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters

PLoS One. 2015 Mar 27;10(3):e0121980. doi: 10.1371/journal.pone.0121980. eCollection 2015.

Abstract

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients' age, but not with patients' gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients' age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aberrant Crypt Foci / genetics*
  • Aberrant Crypt Foci / pathology
  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Age Factors
  • Aged
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology*
  • DNA-Binding Proteins / genetics
  • Humans
  • Intestinal Mucosa / pathology*
  • Microsatellite Instability*
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics
  • Nuclear Proteins / genetics
  • Proteins / genetics
  • Young Adult
  • bcl-2-Associated X Protein / genetics

Substances

  • AIM2 protein, human
  • ASTE1 protein, human
  • Adaptor Proteins, Signal Transducing
  • BAX protein, human
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Nuclear Proteins
  • Proteins
  • bcl-2-Associated X Protein
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein

Grant support

This work was funded partly by grants of the Deutsche Krebshilfe (grant number 70-2369, MvKD) and the Deutsche Forschungsgemeinschaft (grant numbers BL-554/3, HB; and DFG-KFO 227, MK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.