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Prognostic Significance of CpG Island Methylator Phenotype and Microsatellite Instability in Gastric Carcinoma

Departments of ¹ Pathology, ² Gastrointestinal Medical Oncology, and ³ Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Tsung-Teh Wu, Department of Pathology, Unit 85, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4096. Phone: 713-745-4977; Fax: 713-792-4049; E-mail: twu{at}mdanderson.org.

Purpose: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer.

Experimental Design: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation–specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival.

Results: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001).

Conclusions: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not an independent predictor of prognosis in resected gastric cancer.

Key Words: methylation • epigenetic alterations • survival

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