Genetic variation in the DNA repair genes is predictive of outcome in lung cancer.
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.
Matakidou
Athena
A
Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.
el Galta
Rachid
R
Webb
Emily L
EL
Rudd
Matthew F
MF
Bridle
Helen
H
Eisen
Tim
T
Houlston
Richard S
RS
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
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