Carcinogenesis Advance Access originally published online on February 16, 2007
Carcinogenesis 2007 28(9):1902-1905; doi:10.1093/carcin/bgm039
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Evidence of gene–gene interactions in lung carcinogenesis in a large pooled analysis
1 Epidemiology Department, Univerisitá degli Studi di Torino, 10126 Torino, Italy
2 Department of Epidemiology and Public health, Imperial College London, Norfolk Place W2 1PG, London, UK
3 Orion Pharma, Research Centre, Orionintie 1, FI-02200 Espoo P.O. Box 65, FI-02101 Espoo, Finland
4 INSERM, U794, Evry, France
5 Department of Experimenta; Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy
6 Department of Preventive Medicine, Graduate School of Medical sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
7 Cancer Institute, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, PA 15232, USA
8 Department of Epidemiology and Biostatics, National Cancer Research Institute, 16100 Genoa, Italy
9 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, and Division of Cellular and Genetic Toxicology, Stockholm University, SE-171 77 Stockholm, Sweden
10 Keele Multiple Sclerosis Research, Human Genomics Research Group, Institute of Science and Technology in Medicine, Keele University Medical School, Hartshill Campus, University Hospital of North Staffordshire, Stoke on Trent, Staffordshire ST4 7LN, UK
* To whom correspondence should be addressed. Tel: +412 623 2217; Fax: +412 623 1382; Email: taiolien{at}upmc.edu
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.
Abbreviations: CI, confidence interval; GSEC, Genetic Susceptibility to Environmental Carcinogens; OR, odds ratio
Received November 18, 2006; revised February 10, 2007; accepted February 11, 2007.
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