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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):ERCC5D1104H (P= 0.004);ERCC6G399D (P= 0.023),ERCC6Q1413R (P= 0.025),POLE(P= 0.014) and base excision repair:APEX1D148E (P= 0.028);EXO1E670G (P= 0.007);POLBP242R (P= 0.018). An increasing number of variant alleles inEXO1was 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.

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