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Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients.

AbstractINTRODUCTION:
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.
PATIENTS AND 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.
CONCLUSION:
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.
AuthorsTomasz Powrózek, Dariusz M Kowalski, Paweł Krawczyk, Rodryg Ramlau, Tomasz Kucharczyk, Ewa Kalinka-Warzocha, Magdalena Knetki-Wróblewska, Kinga Winiarczyk, Wojciech Dyszkiewicz, Maciej Krzakowski, Janusz Milanowski
JournalClinical lung cancer (Clin Lung Cancer) Vol. 15 Issue 6 Pg. 455-65 (Nov 2014) ISSN: 1938-0690 [Electronic] United States
PMID25246386 (Publication Type: Journal Article, Multicenter Study)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Glutamates
  • Pemetrexed
  • Platinum
  • Guanine
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Thymidylate Synthase
  • ERCC1 protein, human
  • Endonucleases
Topics
  • Antineoplastic Agents (administration & dosage, adverse effects)
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
  • DNA-Binding Proteins (genetics)
  • Drug Resistance, Neoplasm (genetics)
  • Endonucleases (genetics)
  • Female
  • Glutamates (administration & dosage, adverse effects)
  • Guanine (administration & dosage, adverse effects, analogs & derivatives)
  • Humans
  • Male
  • Mesothelioma (drug therapy, genetics, mortality)
  • Methylenetetrahydrofolate Reductase (NADPH2) (genetics)
  • Middle Aged
  • Mutagenesis, Insertional (genetics)
  • Pemetrexed
  • Pharmacogenetics
  • Platinum (administration & dosage, adverse effects)
  • Pleural Neoplasms (drug therapy, genetics, mortality)
  • Polymorphism, Genetic
  • Prognosis
  • Retrospective Studies
  • Survival Analysis
  • Tandem Repeat Sequences (genetics)
  • Thymidylate Synthase (genetics)
  • Treatment Outcome

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