Environmental and genetic factors in lung cancer : epidemiologocal and biomolecular studies focusing on nonsmokers

Abstract

Tobacco smoking is the major cause of lung cancer. Other risk factors include exposure to environmental tobacco smoke (ETS), dietary habits and genetic factors. When studying such risk factors, confounding from smoking presents a pervasive methodological problem. The aim of this thesis was to study some risk factors for lung cancer other than smoking, by focusing on never-smokers, and to clarify some methodological aspects of studies of passive smoking and lung cancer.

A case-control study involving 359 never-smokers (124 lung cancer cases and 235 population controls) was conducted in Stockholm in 1989-1995. The never-smoking status of participants was validated by interview with next-of-kin. Detailed information on ETS exposure was collected at personal interviews and information on dietary habits as well as residential and occupational histories were obtained. From 1992, blood was also drawn from participants, and 193 smokers (99 cases and 94 controls) were additionally recruited, for studies of genetic factors in lung cancer. Smoking misclassification was initially studied using reports of smoking several years apart in two large survey cohorts (18,419 and 9,558 individuals). Approximately 5% of ever-smokers were misclassified as never-smokers on the second occasion. They were, however, mainly light smokers or long-term former smokers and in a follow-up 1961-1992 had only moderately elevated relative risk of lung cancer (1.9, 95% confidence interval 0.4-9.1).

Misclassification of such smokers was shown to be unlikely to produce spurious risks large enough to explain the observed association between lung cancer and passive smoking. In the validation of never-smokers within the case- control study, only 1.2% were reported by next-of-kin to be former regular smokers and 2.6% to ever have smoked >400 cigarettes, but most had stopped long ago (median 21 years) and all had smoked less than 400 packs. These results suggest misclassification is even more limited with careful screening of smoking habits.

For passive smoking, increased relative risks were suggested forever cohabiting with a smoking spouse (1.2, 95% confidence interval 0.7-1.9) and forever exposure at work (1.6, 0.9-2.9). Risks tended to be more elevated in high exposure groups and with recent exposures. Both sources of ETS appeared important and considerable misclassification of total exposure occurred for each variable used separately, in particular forever/never variables and for the less common spousal exposure used alone. When combined, the relative risk for those currently exposed to ETS from the spouse and/or at work was 2.6 (1.0-6.5) in comparison with those unexposed to either source.

Among never-smokers, a protective effect was associated with consumption of vegetables, mediated primarily by carrots. Non-citrus fruits were likewise protective, whereas citrus fruits and juice instead were associated with a suggested increase in the risk of lung cancer. A protective effect with dose-response was also seen for beta-carotene and total carotenoids. Increased risks were suggested for cultured milk products in both genders and for milk among high consumers in men only, which may be consistent with dietary fat as a risk factor for lung cancer.

The overall relative risk for lung cancer associated with the glutathione S transferase null genotype was only slightly below unity, with lower relative risk suggested among never-smokers. For N-acetyl transferase 2, there was a suggested increased risk for slow acetylators among never-smokers, whereas among smokers a steeper increase in risk with increasing pack-years of smoking exposure was suggested for rapid acetylators. Aromatic DNA adducts and mutations in the hypoxanthine-guanine phosphoribosyl transferase (hprt) gene in white blood cells were investigated as markers of exposure and early genotoxic effect. Adduct levels were higher in current than in former or never smokers, whereas both former and current smokers had elevated hprt mutant frequencies. Age affected both markers significantly, and they were also associated with smoking dose, particularly among cases.