title: The thymidylate synthase tandem repeat promoter polymorphism: A predictor for tumor-related survival in neoadjuvant treated locally advanced gastric cancer.
abstract: We evaluated DNA polymorphisms in the thymidylate synthase (TS) and 5,10-methylene-tetrahydrofolate reductase (MTHFR) genes for an association with response and survival in locally advanced gastric cancer treated with 5-FU based preoperative chemotherapy (CTx). DNA of 238 patients (CTx-group: total n = 135, completely resected (R0) n = 102; without CTx: R0 n = 103) was isolated from blood or from nontumorous tissues. In the CTx-group, genotyping of the tandem repeat and the G/C polymorphism in the triple repeat in the promoter region of the TS gene and of the C677T polymorphism of the MTHFR gene was performed. None of the TS or MTHFR genotypes were associated with histopathological response and only the TS tandem repeat polymorphism was significantly related to survival (all patients n = 135, p = 0.002; R0 resected patients n = 102, p = 0.007; log-rank test). Multivariate analysis revealed ypN (p < 0.001) and the TS tandem repeat polymorphism as independent prognostic factors in the CTx-R0-group (p = 0.003). Analyzing the prognostic significance of the TS polymorphisms in the R0-group without CTx, TS genotypes were not significantly associated with survival. Comparing survival between R0 patients with and without CTx in the respective TS genotype groups of the tandem repeat polymorphism, a significant survival benefit for the patients with CTx was found for the 2rpt/2rpt (n = 49; p = 0.002) and 2rpt/3rpt genotypes (n = 99; p = 0.004), but not for the 3rpt/3rpt genotype (n = 57; p = 0.93). Patients' survival after CTx was associated with the TS tandem repeat polymorphism. CTx did not improve survival of patients with the 3rpt/3rpt genotype. Thus, a different therapy might be more appropriate for these patients.
authors.affiliation: Department of Surgery, Technical University, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Ott
authors.forename: Holger
authors.initials: H
authors.lastname: Vogelsang
authors.forename: Noemi
authors.initials: N
authors.lastname: Marton
authors.forename: Karen
authors.initials: K
authors.lastname: Becker
authors.forename: Florian
authors.initials: F
authors.lastname: Lordick
authors.forename: Michael
authors.initials: M
authors.lastname: Kobl
authors.forename: Christoph
authors.initials: C
authors.lastname: Schuhmacher
authors.forename: Alexander
authors.initials: A
authors.lastname: Novotny
authors.forename: James
authors.initials: J
authors.lastname: Mueller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Fink
authors.forename: Kurt
authors.initials: K
authors.lastname: Ulm
authors.forename: Jörg Rüdiger
authors.initials: JR
authors.lastname: Siewert
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016019:Survival Analysis; D020080:Tandem Repeat Sequences / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase