Genetic variation in the DNA repair genes is predictive of outcome in lung cancer
1 Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK, 2 Department of Oncology, University of Cambridge, Cambridge CB2 2RE, UK and 3 GELCAPS Consortium
* To whom correspondence should be addressed at:, Section of Cancer Genetics, Brookes Lawley Building, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. Tel: +44 2087224175; Fax: +44 2087224359; Email: richard.houlston{at}icr.ac.uk
Received February 15, 2007; Accepted July 14, 2007
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.
List of GELCAPS Consortium collaborators available on request.
The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint First Authors.