title: Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
abstract: Thymidylate synthase (TYMS) has three polymorphisms that may modulate thymidylate synthase (TS) expression levels: (1) 28 base pairs (bp) variable number tandem repeat (VNTR) (rs34743033); (2) single nucleotide polymorphism (SNP) C>G at the twelfth nucleotide of the second repeat of 3R allele (rs2853542); and (3) 6 bp sequence deletion (1494del6, rs34489327). This study was conducted to evaluate the influence of TYMS polymorphisms on the survival of Portuguese patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Our results showed no statistically significant differences between VNTR genotypes; although, considering the SNP C>G, homozygotes 3RG presented a better prognostic at 36 months (p=0.004) and overall survival (p=0.003) when compared to 2R3RG patients. Patients with "median/high expression genotypes" demonstrated a better survival at 12 months (p=0.041) when compared to "low expression genotypes". Furthermore, 6 bp- carriers (p=0.006) showed a better survival at 12 months when compared to 6 bp+ homozygotes patients. When analyzing TYMS haplotypes, better survival at 12 months was observed for patients carrying haplotypes with the 6 bp- allele (2R6 bp-; p=0.026 and 3RG6 bp-; p=0.045). This is the first report that evaluates the three major TYMS polymorphisms in the therapeutic outcome of NSCLC in Portugal. According to our results, the TYMS polymorphisms may be useful tools to predict which advanced NSCLC patients could benefit more from platinum-based chemotherapy regimens.
authors.affiliation: IINFACTS/CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences (ISCS-N), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal, aurea.lima@iscsn.cespu.pt.
authors.forename: Aurea
authors.initials: A
authors.lastname: Lima
authors.forename: Vítor
authors.initials: V
authors.lastname: Seabra
authors.forename: Sandra
authors.initials: S
authors.lastname: Martins
authors.forename: Ana
authors.initials: A
authors.lastname: Coelho
authors.forename: António
authors.initials: A
authors.lastname: Araújo
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004742:Enhancer Elements, Genetic; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010984:Platinum / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D010984:Platinum; D013940:Thymidylate Synthase