Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer

DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant, and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P<0.05. The strongest associations were observed for rs2074508 in GTF2H4 (P_additive=0.003), rs10500298 in LIG1 (P_recessive=2.7×10^-4), rs747658 and rs3219073 in PARP1 (rs747658: P_additive=5.8×10^-5; rs3219073: P_additive=4.6×10^-5), and rs1799782 and rs3213255 in XRCC1 (rs1799782: P_dominant=0.006; rs3213255: P_recessive=0.004). Compared to individuals with first quartile (lowest) risk summary scores, individuals with third and fourth quartile summary score results were at increased risk for lung cancer (OR: 2.21, 95% CI: 1.66-2.95 and OR: 3.44, 95% CI: 2.58-4.59, respectively; P_trend<0.0001). Our data suggests that variation in DNA repair and cell cycle control pathway genes is associated with smoking-related lung cancer risk. Additionally, combining genotype information for SNPs in these pathways may assist in classifying current and ex-cigarette smokers according to lung cancer risk.