Promoter polymorphisms of TOP2A and ERCC1 genes as predictive factors for chemotherapy in non-small cell lung cancer patients

Cancer Med. 2020 Jan;9(2):605-614. doi: 10.1002/cam4.2743. Epub 2019 Dec 3.

Abstract

Background: Topoisomerase 2-alpha (TOP2A) is an enzyme that controls topologic changes in DNA during transcription and replication. ERCC1 is an enzyme that takes part in DNA repair processes. The purpose of this study was to assess the predictive role of particular single nucleotide polymorphisms (SNPs) in the promoter regions of TOP2A and ERCC1 genes in non-small cell lung cancer patients (NSCLC) treated with chemotherapy.

Materials and methods: We enrolled 113 NSCLC patients treated in the first line with platinum-based chemotherapy. Effectiveness was available for 71 patients. DNA was isolated from whole blood using the Qiamp DNA Blood Mini kit (Qiagen). We examined five SNPs: rs11615 (ERCC1), rs3212986 (ERCC1), rs13695 (TOP2A), rs34300454 (TOP2A), rs11540720 (TOP2A). Quantitative PCR using the TaqMan probe (ThermoFisher) was performed on a Eco Illumina Real-Time PCR system device (Illumina Inc).

Results: Patients with the A/A genotype in rs11615 of the ERCC1 gene had significantly longer median progression free survival (PFS) (8.5 months; P = .0088). Patients with the C/C genotype in rs3212986 of the ERCC1 gene had longer median PFS (7 months; P = .05). Patients with the C/C genotype in rs34300454 of TOP2A gene had significantly higher median PFS (7.5 months; P = .0029). Carriers of the C/C genotype in rs34300454 of the TOP2A gene had significantly longer median OS (15.5 months; P = .0017). Patients with the A/A genotype in rs11615 of the ERCC1 gene had significantly higher risk of neutropenia (P = .0133).

Conclusions: Polymorphisms of the TOP2A and ERCC1 genes may be a predictive factor of toxicities and survival for chemotherapy in NSCLC patients.

Keywords: ERCC1; TOP2A; non-small cell lung cancer; single-nucleotide polymorphisms.

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • DNA Topoisomerases, Type II / genetics*
  • DNA-Binding Proteins / genetics*
  • Endonucleases / genetics*
  • Female
  • Follow-Up Studies
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Promoter Regions, Genetic*
  • Survival Rate

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • ERCC1 protein, human
  • Endonucleases
  • DNA Topoisomerases, Type II
  • TOP2A protein, human