Genetic variation in the DNA repair genes is predictive of outcome in lung cancer

Hum Mol Genet. 2007 Oct 1;16(19):2333-40. doi: 10.1093/hmg/ddm190.

Abstract

To assess whether DNA repair gene variants influence the clinical behaviour of lung cancer we examined the impact of a comprehensive panel of 109 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 50 DNA repair genes on overall survival (OS) in 700 lung cancer patients. Fifteen nsSNPs were associated with OS, significantly greater than that expected (P = 0.04). SNPs associated with prognosis mapped primarily to two repair pathways--nucleotide excision repair (NER): ERCC5 D1104H (P = 0.004); ERCC6 G399D (P = 0.023), ERCC6 Q1413R (P = 0.025), POLE (P = 0.014) and base excision repair: APEX1 D148E (P = 0.028); EXO1 E670G (P = 0.007); POLB P242R (P = 0.018). An increasing number of variant alleles in EXO1 was associated with a poorer prognosis [hazard ratio (HR) = 1.24; P = 0.0009]. A role for variation in NER and BRCA2/FA pathway genes as determinants of OS was provided by an analysis restricted to the 456 patients treated with platinum-based agents. Our data indicate that the pathway-based approach has the potential to generate prognostic markers of clinical outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • DNA Helicases / genetics
  • DNA Polymerase II / genetics
  • DNA Polymerase theta
  • DNA Repair / genetics*
  • DNA Repair Enzymes / genetics
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Directed DNA Polymerase / genetics
  • Endonucleases / genetics
  • Exodeoxyribonucleases / genetics
  • Genetic Variation*
  • Genotype
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • RecQ Helicases
  • Transcription Factors / genetics

Substances

  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Transcription Factors
  • DNA Polymerase II
  • DNA-Directed DNA Polymerase
  • POLE protein, human
  • EXO1 protein, human
  • Endonucleases
  • Exodeoxyribonucleases
  • Adenosine Triphosphatases
  • Bloom syndrome protein
  • DNA Helicases
  • ERCC6 protein, human
  • RecQ Helicases
  • APEX1 protein, human
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • DNA Repair Enzymes