Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia

N. Horowitz, K. Pinto, D. G. Mutch, T. J. Herzog, J. S. Rader, R. Gibb, T. Bocker-Edmonston, P. J. Goodfellow

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Objective. MLH1 methylation is associated with the microsatel-lite instability (MSI) phenotype in endometrial cancer and atypical endometrial hyperplasia, a premalignant precursor to carcinoma. The observation that methylation is also seen in atypical endometrial hyperplasia without MSI suggests that methylation is an early event in endometrial tumorigenesis. Our objective was to determine if methylation is always present in MSI-positive atypical hyperplasia concomitant with MSI-positive, methylation-positive carcinoma. Methods. We used laser capture microdissection to study MLH1 methylation and MSI in a large series of endometrial cancer cases that had previously been shown to have methylation and the MSI-high (MSI-H) phenotype. We resampled areas of carcinoma from 27 patients along with 51 foci of concomitant atypical endometrial hyperplasia. Results. Consistent with previous reports, we saw MLH1 methylation in areas of atypical endometrial hyperplasia that did not show MSI. In addition, we noted that 18% of the MSI-H atypical endometrial hyperplasia DNAs lacked methylation of critical cytosines in the MLH1 promoter. Immunohistochemistry studies showed that these MSI-H unmethylated foci of atypical endometrial hyperplasia failed to express MLH1, as did regions of simple hyperplasia. Conclusion. Methylation of the MLH1 promoter is an early event in endometrial tumorigenesis. Given that not all MSI-positive tissues had methylation at cytosines 3229 and 3231, it appears that methylation may not be required for MLH1 silencing and loss of mismatch repair.

Original languageEnglish
Pages (from-to)62-68
Number of pages7
JournalGynecologic oncology
Volume86
Issue number1
DOIs
StatePublished - Jan 1 2002

Keywords

  • Atypical endometrial hyperplasia
  • Endometrial carcinoma
  • MLH1 methylation
  • Microsatellite instability

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