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Microsatellite Instability and Epigenetic Inactivation of MLH1 and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type

Israel Zighelboim, Paul J. Goodfellow, Feng Gao, Randall K. Gibb, Matthew A. Powell, Janet S. Rader, David G. Mutch

From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; Division of Endocrine and Oncologic Surgery, Department of Surgery; and the Division of Biostatistics, Washington University School of Medicine and Siteman Cancer Center, St Louis, MO

Address reprint requests to Israel Zighelboim, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes Jewish Plaza, Box 8064, St Louis, MO 63110; e-mail: zighelboimi{at}wustl.edu

Purpose Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type.

Patients and Methods Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated.

Results MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI– as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72).

Conclusion MSI is not associated with survival in patients with endometrioid endometrial cancer.

Supported by RO1 CA71754 (P.J.G.) and Barnes-Jewish Foundation 00161-0205. The Siteman Cancer Center is supported by National Cancer Institute Cancer Center Support Grant No. P30 CA91842.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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