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.