Methylation of tumor-related genes in neoadjuvant-treated gastric cancer: relation to therapy response and clinicopathologic and molecular features.
OBJECTIVE
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.


METHODS
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).


CONCLUSIONS
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.
Napieralski
Rudolf
R
Department of Pathology, Technische Universität München, Munich, Germany.
Ott
Katja
K
Kremer
Markus
M
Becker
Karen
K
Boulesteix
Anne-Laure
AL
Lordick
Florian
F
Siewert
Jörg Rüdiger
JR
Höfler
Heinz
H
Keller
Gisela
G
D000328:Adult; D000368:Aged; D002945:Cisplatin / Q000008:administration & dosage; D019175:DNA Methylation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology