Lung Cancer and DNA Repair Genes: Multilevel Association Analysis from the International Lung Cancer Consortium

Lung cancer is the leading cause of cancer-related death worldwide and tobacco smoking is the major associated risk factor. DNA repair is an important process, maintaining genome integrity, and polymorphisms in DNA repair genes may contribute to susceptibility to lung cancer. To explore the role of DNA repair genes in lung cancer, we conducted a multilevel association study with 1,655 Single Nucleotide Polymorphisms (SNPs) in 211 DNA repair genes using 6,911 individuals pooled from four genome-wide case-control studies. Single SNP association corroborates previous reports of association with rs3131379, located on the gene MSH5 (P = 3.57 × 10-5), and returns a similar risk estimate. The effect of this SNP is modulated by histological subtype. On the log-additive scale, the odds ratio per allele is 1.04 [0.84 – 1.30] for adenocarcinomas, 1.52 [1.28 – 1.80] for squamous cell carcinomas and 1.31 [1.09 – 1.57] for other histologies (Heterogeneity test: P = 9.1 × 10-3). Gene-based association analysis identifies 3 repair genes associated with lung cancer (P < 0.01): UBE2N, SMC1L2, and POLB. Two additional genes (RAD52 and POLN) are borderline significant. Pathway-based association analysis identifies 5 repair pathways associated with lung cancer (P < 0.01): chromatin structure, DNA polymerases, homologous recombination, genes involved in human diseases with sensitivity to DNA-damaging agents, and Rad6 pathway and ubiquitination. This first international pooled analysis of a large dataset unravels the role of specific DNA repair pathways in lung cancer and highlights the importance of accounting for gene and pathway effects when studying lung cancer.

http://carcin.oxfordjournals.org/content/early/2012/03/01/carcin.bgs116.abstract

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