title: Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients.
abstract: BACKGROUND
  The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients.
  
  
  METHODS
  Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients.
  
  
  RESULTS
  Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients.
  
  
  CONCLUSIONS
  Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients.
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland. Electronic address: tomaszpowrozek@gmail.com.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Powrózek
authors.affiliation: Department of Lung and Chest Tumors Oncology Centre - Institute M. Sklodowska-Curie in Warsaw, Warsaw, Poland.
authors.forename: Dariusz M
authors.initials: DM
authors.lastname: Kowalski
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Krawczyk
authors.affiliation: Wielkopolskie Centrum Pulmonologii i Torakochirurgii im, Eugenii i Janusza Zeylandów, Poznań, Poland; Department of Thoracic Surgery, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland; Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kucharczyk
authors.affiliation: Regional Centre of Oncology, Łódź, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kalinka-Warzocha
authors.affiliation: Department of Lung and Chest Tumors Oncology Centre - Institute M. Sklodowska-Curie in Warsaw, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Knetki-Wróblewska
authors.affiliation: Department of Lung and Chest Tumors Oncology Centre - Institute M. Sklodowska-Curie in Warsaw, Warsaw, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Winiarczyk
authors.affiliation: Wielkopolskie Centrum Pulmonologii i Torakochirurgii im, Eugenii i Janusza Zeylandów, Poznań, Poland; Department of Thoracic Surgery, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Dyszkiewicz
authors.affiliation: Department of Lung and Chest Tumors Oncology Centre - Institute M. Sklodowska-Curie in Warsaw, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzakowski
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland; Institute of Agricultural Medicine of Lublin, Lublin, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Milanowski
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016254:Mutagenesis, Insertional / Q000235:genetics; D000068437:Pemetrexed; D010597:Pharmacogenetics; D010984:Platinum / Q000008:administration & dosage / Q000009:adverse effects; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D020080:Tandem Repeat Sequences / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; 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
keywords: Mesothelioma; Methylenetetrahydrofolate reductase; Pemetrexed; The excision repair cross-complementation group 1; Thymidylate synthase