title: Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients.
abstract: OBJECTIVE
  We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.
  
  
  METHODS
  The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5'-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3'-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations' results were correlated with disease control rate, progression-free survival (PFS) and overall survival.
  
  
  RESULTS
  Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.
  
  
  CONCLUSIONS
  The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland, krapa@poczta.onet.pl.
authors.forename: Paweł
authors.initials: P
authors.lastname: Krawczyk
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kucharczyk
authors.forename: Dariusz M
authors.initials: DM
authors.lastname: Kowalski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Powrózek
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.forename: Ewa
authors.initials: E
authors.lastname: Kalinka-Warzocha
authors.forename: Kinga
authors.initials: K
authors.lastname: Winiarczyk
authors.forename: Magdalena
authors.initials: M
authors.lastname: Knetki-Wróblewska
authors.forename: Kamila
authors.initials: K
authors.lastname: Wojas-Krawczyk
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kałakucka
authors.forename: Wojciech
authors.initials: W
authors.lastname: Dyszkiewicz
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzakowski
authors.forename: Janusz
authors.initials: J
authors.lastname: Milanowski
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D000068437:Pemetrexed; D010984:Platinum / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D005971:Glutamates; D000068437:Pemetrexed; D010984:Platinum; D006147:Guanine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases