Carcinogenesis Advance Access originally published online on January 27, 2007
Carcinogenesis 2007 28(6):1287-1293; doi:10.1093/carcin/bgm021
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Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes
1 Genetics, Department of Biology, University of Pisa, 56100 Pisa, Italy
2 International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon, France
3 Department of Epidemiology, Institute of Occupational Medicine, 92-348 Lodz, Lodz, Poland
4 Institute of Carcinogenesis, Cancer Research Centre, 115478 Moscow, Moscow, Russia
5 Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, 02-784 Warsaw, Warsaw, Poland
6 National Institute of Environmental Health, Fodor József National Center for Public Health, 1097 Budapest, Budapest, Hungary
7 Specialized Institute of Hygiene and Epidemiology, 97556 Banska-Brystica, Banska Bystrica, Slovakia
8 Department of Hygiene, Institute of Public Health, 76256 Bucharest, Romania
9 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653 Brno, Brno, Czech Republic
10 Department of Preventive Medicine, Faculty of Medicine, Palacky University, 77180 Olomouc, Olomouc, Czech Republic
11 Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University of Prague, 11636 Prague 1, Prague, Czech Republic
12 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
13 Inserm U612 Institut Curie, 91405 Orsay, Paris, France and
14 Division of Epidemiology, Department School of Public Health, University of California, Berkeley, CA 94720 USA
* To whom correspondence should be addressed. Tel +33 472738391; Fax: +33 472738342; Email: brennan{at}iarc.fr
The role of genes coding for xenobiotic metabolizing enzymes (XMEs) and the risk of lung cancer is unclear. Under the assumption that these genes may be more important among people having a diagnosis of lung cancer at younger ages, we have investigated the role of single-nucleotide polymorphisms (SNPs) within phase I and phase II XME genes, and also genes involved in the metabolism of nucleic acids in a series of young onset patients and matched controls. We genotyped 299 lung cancer cases diagnosed before the age of 50 and 317 controls, from six countries of Central and Eastern Europe, by use of an oligonucleotide microarray and arrayed primer extension technique for 45 SNPs in 15 phase I XME genes, 46 SNPs in 17 phase II genes and 9 SNPs in 4 genes related to metabolism of nucleic acids. Heterozygote carriers of SNPs in CYP1A2 1545T>C, –164C>A and –740T>G; CYP2A6 –47A>C; MDR1 3435T>C; NAT1 1088T>A and 1095A>C; GSTA2 S112T; GSTM3 V224I and MTHFR A222V had altered risk of developing lung cancer. Phenotypes reconstructed after haplotype analyses showed that the carriers of the combined NAT1 fast+ NAT2 fast phenotypes were at lower risk when compared with those with the combined NAT1 slow + NAT2 slow acetylator phenotypes. Finally, extensive EPHX1 metabolizers showed an increased risk as compared with the poor metabolizers.
Abbreviations: CI, confidence interval; FPRP, false positive report probability; HWE, Hardy–Weinberg equilibrium; OR, odds ratio; SNP, single-nucleotide polymorphisms; UDP, uridine diphosphate; XME, xenobiotic-metabolizing enzyme
These authors contributed equally to this work. Received October 3, 2006; revised January 12, 2007; accepted January 18, 2007.
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