title: Evidence of gene gene interactions in lung carcinogenesis in a large pooled analysis.
abstract: To test the hypothesis of interaction among genetic variants in increasing the individual risk of cancer, we have studied the cumulative effect on lung cancer risk of variants in three metabolic genes, CYP1A1, GSTM1 and GSTT1, which are involved in the metabolism of the tobacco smoke constituents and environmental contaminants, polycyclic aromatic hydrocarbons and of other lung carcinogens. We have selected from the Genetic Susceptibility to Environmental Carcinogens pooled analysis all the studies on lung cancer conducted after 1991 in which all variants were available. The data set includes 611 cases and 870 controls. We found a cumulative effect of the combination of the a priori 'at-risk' alleles for these genes (P for trend 0.004). The risk of lung cancer was increased with the combination of CYP1A1*2B or CYP1A1*4 alleles and the double deletion of both GSTM1 and GSTT1 up to an odds ratio (OR) of 8.25 (95% confidence interval 2.29-29.77) for the combination including CYP1A1*4; among never smokers, the latter combination was associated with an OR of 16.19 (1.90-137). Estimates did not change after adjustment by the number of cigarettes smoked and duration of smoking were consistent across ethnicities and were approximately the same for adenocarcinomas and squamous cell carcinomas. These observations from a large pooled analysis strongly suggest the existence of gene-gene interactions in lung carcinogenesis. People with rare combinations of common gene variants have a high risk of cancer and can be assimilated to subjects with highly penetrant mutations.
authors.affiliation: Epidemiology Department, Univerisitá degli Studi di Torino, 10126 Torino, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Sisko
authors.initials: S
authors.lastname: Anttila
authors.forename: Simone
authors.initials: S
authors.lastname: Benhamou
authors.forename: Monica
authors.initials: M
authors.lastname: Spinola
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
authors.forename: Chikako
authors.initials: C
authors.lastname: Kiyohara
authors.forename: Seymour J
authors.initials: SJ
authors.lastname: Garte
authors.forename: Riccardo
authors.initials: R
authors.lastname: Puntoni
authors.forename: Agneta
authors.initials: A
authors.lastname: Rannug
authors.forename: Richard C
authors.initials: RC
authors.lastname: Strange
authors.forename: Emanuela
authors.initials: E
authors.lastname: Taioli
mesh_terms: D016001:Confidence Intervals; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D012016:Reference Values; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects
chemical_list: D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1