title: Genetic variation in the DNA repair genes is predictive of outcome in lung cancer.
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.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.
authors.forename: Athena
authors.initials: A
authors.lastname: Matakidou
authors.forename: Rachid
authors.initials: R
authors.lastname: el Galta
authors.forename: Emily L
authors.initials: EL
authors.lastname: Webb
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Rudd
authors.forename: Helen
authors.initials: H
authors.lastname: Bridle
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004257:DNA Polymerase II / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D053484:RecQ Helicases; D014157:Transcription Factors / Q000235:genetics; D000097462:DNA Polymerase theta; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D004257:DNA Polymerase II; D045643:DNA Repair Enzymes; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D004720:Endonucleases; D005090:Exodeoxyribonucleases; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D053484:RecQ Helicases; D014157:Transcription Factors; D000097462:DNA Polymerase theta; D000099250:DNA Excision Repair Protein ERCC-5; C119525:POLE protein, human; C114331:EXO1 protein, human; C097151:Bloom syndrome protein; C078673:ERCC6 protein, human; C085108:APEX1 protein, human