RT Journal Article SR Electronic T1 Prognostic Significance of the Polymorphisms in Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene in Lung Cancer JF Anticancer Research JO Anticancer Res FD International Institute of Anticancer Research SP 4455 OP 4461 VO 25 IS 6C A1 AKIRA TAKEHARA A1 KAZUYUKI KAWAKAMI A1 NAOHIRO OHTA A1 KAEKO OYAMA A1 YASUHIKO OTA A1 MAKOTO ODA A1 GO WATANABE YR 2005 UL http://ar.iiarjournals.org/content/25/6C/4455.abstract AB Background: Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) play important roles in folate metabolism. Previous studies have suggested that TS expression is a prognostic factor in non-small cell lung cancer (NSCLC). The TS gene has a variable number of tandem repeats (VNTR) and single nucleotide polymorphism (SNP) in the 5′-untranslated region, which are associated with TS expression. This association suggests that the TS polymorphism is a novel prognostic factor in NSCLC. In the present study, multiple genetic polymorphisms, TS VNTR, TS SNP and MTHFR C677T, were analyzed in NSCLC and compared with clinicopathological features and patients' prognoses. Materials and Methods: Genomic DNA was isolated from 294 surgically resected NSCLC tissues. The genotypes were determined by PCR and PCR-RFLP. The TS VNTR and SNP were combined, followed by functional stratification of H/H (3G/3G), H/L (2R/3G, 3G/3C) and L/L (2R/2R, 2R/3C, 3C/3C). Patients' prognoses were compared with TS and/or MTHFR genotype groups. TS was divided into the H- (H/H, H/L) and L-groups (L/L) according to functional stratification and MTHFR C677T was divided into C- (C/C) and T-groups (C/T, T/T). Results: TS VNTR, the SNP and the TS functional type, along with MTHFR C677T, showed no significant association with clinicopathological factors. There were no differences in prognosis between each genotype or functional group when the TS and MTHFR groups were considered separately. However, we found a unique association between prognosis and the TS functional group in stage I NSCLC, taking both TS and MTHFR groups into consideration. The patients in the TS L-group survived longer than those in the H-group when limited to stage I and MTHFR C-group (p=0.086). This relationship between the TS genotype group and prognosis was statistically significant in the subgroup of stage IB and MTHFR C-group (p=0.030). In contrast, the patients in the TS H-group survived longer than those in the L-group when limited to stage I and MTHFR T-group (p=0.052). Conclusion: The TS and MTHFR genotypes can be prognostic factors in NSCLC, where gene-gene interactions between the genotypes may occur. Further validation and investigation of the involvement of genotypes of folate metabolizing enzymes in the prognosis of NSCLC patients are required. Copyright© 2005 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved