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Methylation of Tumor-Related Genes in Neoadjuvant-Treated Gastric Cancer: Relation to Therapy Response and Clinicopathologic and Molecular Features

Authors' Affiliations: Departments of ¹ Pathology, ² Surgery, ³ Medical Statistics and Epidemiology, and ⁴ Third Department of Internal Medicine, Technische Universität München, Munich, Germany; and ⁵ Institute of Pathology, National Research Center for Environment and Health, GSF-Forschungszentrum, Oberschleissheim, Germany

Requests for reprints: Gisela Keller, Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Trogerstrasse 18, D-81675 Munich, Germany. Phone: 49-89-4140-4592; Fax: 11-49-89-4140-4915; E-mail: gisela.keller{at}lrz.tum.de.

Purpose: The objective of this study was to analyze the hypermethylation of tumor-related gene promoters for an association with therapy response and clinicopathologic features of neoadjuvant-treated gastric cancer patients. Furthermore, we analyzed the relationship of promoter hypermethylation with microsatellite instability and loss of heterozygosity (LOH) of the tumors.

Experimental Design: Pretherapeutic biopsies of 61 patients, subsequently treated with cisplatin and 5-fluorouracil, were studied. Methylation analysis of six gene promoters was done using MethyLight technology. Microsatellite analysis was mainly done in previous studies.

Results: The methylation frequencies for the analyzed genes were MGMT, 44%; LOX, 53%; p16, 46%, E-cadherin, 30%; 14-3-3, 69%; and HPP1, 82%. Concordant methylation of more than three genes was found in 46% of the tumors and was inversely correlated with the LOH rate (P = 9 x 10^–5) and associated with female gender (P = 0.049), nonintestinal type tumors (P = 0.04), and a nonproximal tumor location (P = 0.003). No statistically significant association between the methylation of a single gene or the concordant methylation of multiple genes was found with response or survival. However, patients with none or only one methylated gene showed a trend for an increase in survival (5-year survival rate, 83% versus 35%; P = 0.067).

Conclusion: The highly significant inverse correlation of promoter methylation and LOH rate reflects major alternative molecular pathways in gastric carcinogenesis. Methylation was not statistically significantly associated with the response to cisplatin/5-fluorouracil–based therapy. However, a concordant methylation of more than three genes defines subgroups of gastric cancer with distinct biological and genetic characteristics.