Increased Risk for Hereditary Nonpolyposis Colorectal Cancer-Associated Synchronous and Metachronous Malignancies in Patients with Microsatellite Instability-Positive Endometrial Carcinoma Lacking MLH1 Promoter Methylation

• Published in: Clinical cancer research 2004-01, Vol.10 (2), p.481-490
• Main Authors: BUTTIN, Barbara M, POWELL, Matthew A, MUTCH, David G, RADER, Janet S, HERZOG, Thomas J, GIBB, Randall K, HUETTNER, Phyllis, EDMONSTON, Tina Bocker, GOODFELLOW, Paul J
• Format: Article
• Language: English
• Subjects: Age of Onset; Aged; Antineoplastic agents; Biological and medical sciences; Cohort Studies; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA - metabolism; DNA Methylation; Endometrial Neoplasms - complications; Endometrial Neoplasms - genetics; Female; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Medical sciences; Microsatellite Repeats; Middle Aged; Models, Biological; Neoplasms, Second Primary - genetics; Pharmacology. Drug treatments; Promoter Regions, Genetic; Risk; Tamoxifen - therapeutic use; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-1110-03

Purpose: The aim of this study was to evaluate number and types of synchronous and metachronous malignancies in patients with endometrial carcinoma with and without microsatellite instability (MSI). Experimental Design: From a series of 413 endometrial cancer patients, we identified 94 patients with MSI-positive (MSI+) cancers and grouped them by tumor MLH1 promoter methylation status. These 94 patients were matched by year of surgery to 94 patients with MSI-negative (MSI−) endometrial cancers from the same series. Medical records were reviewed for clinicopathologic information including rates and types of synchronous and metachronous malignancies. Hereditary nonpolyposis colorectal cancer (HNPCC)-associated second and third cancers were analyzed for MSI and MSH2 , MSH6 , and MLH1 expression for comparison with the corresponding endometrial cancers. Results: The MSI+ and MSI− cohorts were similar with regard to age, race, grade, and histology. Twenty-eight MSI+ endometrial cancers (29.8%) were MLH1 unmethylated. Rates of synchronous and metachronous cancers were also similar in the MSI+ and MSI− groups at 20 and 23%, respectively. However, patients with MSI+ MLH1 unmethylated endometrial cancers had an excess of HNPCC-associated second and third cancers compared with those with MSI+ MLH1 methylated and MSI− endometrial cancers (18% versus 4.5%, P = 0.034, and 2.1%, P = 0.002). Six of seven second tumors from 5 patients with MSI+ MLH1 unmethylated endometrial cancers showed concordant MSI and mismatch repair protein expression status. Conclusions: Our observation that patients with MSI-positive MLH1 unmethylated endometrial carcinoma are at increased risk for HNPCC-associated synchronous and metachronous malignancies suggests inherited cancer susceptibility. These patients and their families may warrant more intense cancer surveillance.