Faculty Collaboration Database

Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia. Gynecol Oncol 2002 Jul;86(1):62-8

Date

06/25/2002

Pubmed ID

12079302

DOI

10.1006/gyno.2002.6724

Scopus ID

2-s2.0-0036311084 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

OBJECTIVE: MLH1 methylation is associated with the microsatellite 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 -229 and -231, it appears that methylation may not be required for MLH1 silencing and loss of mismatch repair.

Author List

Horowitz N, Pinto K, Mutch DG, Herzog TJ, Rader JS, Gibb R, Bocker-Edmonston T, Goodfellow PJ

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Base Pair Mismatch
Carrier Proteins
DNA Methylation
DNA Repair
Endometrial Hyperplasia
Endometrial Neoplasms
Female
Humans
Immunohistochemistry
Microsatellite Repeats
MutL Protein Homolog 1
Neoplasm Proteins
Nuclear Proteins
Precancerous Conditions
Promoter Regions, Genetic