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%; 14-3-3sigma, 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.
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 cancerpatients. 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%; 14-3-3sigma, 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.
Authors: C Matuschek; Edwin Bölke; M Peiper; W T Knoefel; W Budach; A Erhardt; A Scherer; P A Gerber; B A Buhren; N Gattermann; S E Baldus; E Rusnak; V Shukla; K Orth Journal: Eur J Med Res Date: 2011-06-21 Impact factor: 2.175