MSI in endometrial cancer: Prevalence and clinical applications

Abstract

Background: Loss of DNA mismatch repair is a frequent event in endometrial cancers, leading to an easily recognizable molecular phenotype referred to as microsatellite instability (MSI). In colorectal cancers MSI appears to be of prognostic significance. The relationship between MSI and outcome and other clinicopathologic variables in endometrial cancer has not been firmly established. Objectives: Assess the relationship between tumor MSI and clinicopathologic variables in our large cohort of endometrial cancer cases, and compare our findings with previous reports on MSI in endometrial cancers. Methods: 600 hundred prospectively acquired uterine cancers were assessed for MSI using 5 microsatellite repeat markers and MSI status classified using standard conventions. All MSI-positive tumors were evaluated for methylation of the MLH1 DNA mismatch repair gene promoter. Information on patient age at diagnosis, tumor histology and stage were obtained at time of surgery. For 411 patients treated in the period 1991–2001, medical records were reviewed for evidence of other malignancies. Follow-up for 178 patients with endometrioid adenocarcinomas treated in the period 1992–1999 was completed mid-2004 by contacting patients and/or their physicians. Detailed family histories of cancer were developed for 164 probands in the series. Results: MSI was seen in 28% of the endometrial tumors in our series. There was a significant association between MSI and endometrioid histology but not with any of the other clinicopathologic variables investigated. However, when MSI was further classified according to MLH1 promoter methylation status, clear associations between high-level MSI in the absence of MLH1 methylation and clinical variables became evident. Women with MSI-positive tumors lacking MLH1 methylation were younger than women with tumors that showed MLH1 methylation. Furthermore, women with MSI-positive tumors lacking MLH1 methylation had significantly increased risk for second tumors that are associated with the hereditary nonpolyposis colorectal cancer syndrome. Women with MSI-positive tumors that lack methylation frequently harbor inherited mutations in DNA mismatch repair. There was no association between tumor MSI and survival for patients with endometrioid endometrial cancers. Conclusions: MSI is a common defect in endometrial cancers. MSI in the absence of MHL1 methylation may point to women who are at increased risk for second cancers associated with the hereditary nonpolyposis colorectal cancer syndrome. Typing tumors for MSI and MLH1 methylation coupled with immunohistochemistry to assess mismatch repair gene expression may prove useful in identifying women with inherited forms of endometrial cancer.