Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 −15) and replication (adjusted OR = 2.93, P = 2.22 × 10 −3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 −22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
We examined the effects of dose, type of tobacco, cessation, inhalation, and environmental tobacco smoke (ETS) exposure on bladder cancer risk among 1,219 patients with newly diagnosed bladder cancer and 1,271 controls recruited from 18 hospitals in Spain. We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association between bladder cancer risk and various characteristics of smoking. Current (men: OR ¼ 7.9; 95% CI ¼ 5.6-11.1; women: OR ¼ 4.9; 95% CI ¼ 1.5-15.8) and former smokers (men: OR ¼ 3.8; 95% CI ¼ 2.8-5.3; women: OR ¼ 2.0; 95% CI ¼ 0.5-7.8) had significantly increased risks of bladder cancer compared to nonsmokers. A significant, positive trend in risk was observed with increasing duration and amount smoked. After adjustment for duration, risk was only 40% higher in smokers of black tobacco than that in smokers of blond tobacco (OR ¼ 1.4; 95% CI ¼ 0.98-2.0). Compared to current smokers, a significant, inverse trend in risk with increasing time since quitting smoking blond tobacco was observed (20þ years cessation: OR ¼ 0.2; 95% CI ¼ 0.1-0.9). No trend in risk with cessation of smoking black tobacco was apparent. Cumulative occupational exposure to ETS appeared to confer increased risk among female nonsmokers, but not among male nonsmokers. After eliminating the effect of cigarette smoking on bladder cancer risk in our study population, the male-to-female incidence ratio decreased from 8.2 to 1.9, suggesting that the male excess of bladder cancer observed in Spain may be explained by the higher prevalence of smoking among men compared to women.
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