Human Molecular Genetics, Vol 8, 661-666, Copyright © 1999 by Oxford University Press
SB Simpkins, T Bocker, EM Swisher, DG Mutch, DJ Gersell, AJ Kovatich, JP Palazzo, R Fishel and PJ Goodfellow
Defective DNA mismatch repair in human tumors leads to genome-wide
instability of microsatellite repeats and a molecular phenotype referred to
as microsatellite instability (MSI). MSI has been reported in a variety of
cancers and is a consistent feature of tumors from patients with hereditary
non-polyposis colorectal cancer. Approximately 20% of cancers of the
uterine endometrium, the fifth most common cancer of women world-wide,
exhibit MSI. Although the frequency of MSI is higher in endometrial cancers
than in any other common malignancy, the genetic basis of MSI in these
tumors has remained elusive. We investigated the role that methylation of
the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large
series of sporadic endometrial cancers. The MLH1 promoter was methylated in
41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors on
the other hand, there was evidence for limited methylation in only one of
11 tumors studied. Immunohistochemical investigation of a subset of the
tumors revealed that methylation of the MLH1 promoter in MSI-positive
tumors was associated with loss of MLH1 expression. Immunohistochemistry
proved that two MSI-positive tumors lacking MLH1 methylation failed to
express the MSH2 mismatch repair gene. Both of these cancers came from
women who had family and medical histories suggestive of inherited cancer
susceptibility. These observations suggest that epigenetic changes in the
MLH1 locus account for MSI in most cases of sporadic endometrial cancers
and provide additional evidence that the MSH2 gene may contribute
substantially to inherited forms of endometrial cancer.
ARTICLES
MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers
Department of Surgery, Washington University School of Medicine, 660 South Euclid Street, St Louis, MO 63110, USA.
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