EBV infection and mismatch repair deficiency mediated by loss of hMLH1 expression contribute independently to the development of multiple synchronous gastric carcinomas

J Surg Oncol. 2012 Nov;106(6):777-82. doi: 10.1002/jso.23131. Epub 2012 Apr 18.

Abstract

Background: To explore the possible association between EBV, microsatellite instability (MSI), and alterations of hMLH1 protein, 282 tumors from 141 patients with multiple synchronous gastric carcinomas (MSGC) were studied.

Methods: In situ hybridization for EBV-encoded small RNA and hMLH1 immunohistochemistry were performed in tissue microarrays. In 19 MSGC cases with altered hMLH1 expression, methylation analyses by MethyLight and MSI tests were performed.

Results: Loss of hMLH1 was found in 19 of 141 MSGC patients (13.5%) and 26 of 282 MSGC tumors (9.2%). hMLH1 loss was associated with differentiated histology (P = 0.03). Out of the 38 tumors from 19 hMLH1-negative MSGCs, 12 tumors from six cases (31.6%) showed concurrent methylation of hMLH1 and MSI-high in both multiple tumors. EBV was found in 31 of 141 MSGC patients (21.9%) and 49 of 282 MSGC tumors (17.4%) and was significantly associated with undifferentiated histology and a location within the upper third of the stomach (P < 0.002). EBV was not observed in any of the tumors that had a loss of hMLH1 expression.

Conclusions: Considering that EBV-associated GCs show global CpG island methylation, our findings suggest that EBV infection allows the gastric mucosa to escape from aberrant methylation of hMLH1 and induces a malignant pathway independent of MSI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Adult
  • Aged
  • DNA Mismatch Repair*
  • Epstein-Barr Virus Infections / complications*
  • Female
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • Neoplasms, Multiple Primary / etiology*
  • Neoplasms, Multiple Primary / genetics
  • Neoplasms, Multiple Primary / virology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Stomach Neoplasms / etiology*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / virology

Substances

  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • MutL Protein Homolog 1