Alterations affecting genes involved in the carcinogen metabolism are associated with cancer susceptibility since these can affect the detoxification capacity of the gene product. Genes regulating the carcinogen metabolism are also highly effective in the pathways involved in lung cancer development. The microsomal epoxide hydroxylase gene EPHX1 participates in the detoxification and activation of the carcinogenic compounds in the cigarette smoke. Two polymorphic changes in the EPHX1 gene result in slow and fast alleles with low and high enzyme activity. This differential effect suggests that these polymorphisms may affect individual lung cancer risk.
Myeloperoxidase (MPO) is an oxidative enzyme released in response to cigarette smoke from the lung tissue. A G>A polymorphism located in the 5' untranslated region of the MPO gene that may be responsible for reduced transcriptional activity due to the decreased binding affinity for the SP1 transcription factor. In individuals carrying the A allele metabolic procarcinogen compounds are not effectively activated. Therefore, this variant is thought to play a protective role in lung cancer.
The NAD(P)H dehydrogenase (NQO1) gene is an important mediator of lung cancer and codes for a cytoplasmic electron reductase which prevents the production of reactive radical species by detoxification of the quinones and their derivatives. Mutations in the NQO1 gene have been associated with susceptibility to various forms of cancer. A C to T substitution at codon 187 of the gene results in almost undetectable enzyme activity in the homozygote individuals carrying the variant allele. In this study we investigated the association of the EPHX1, MPO and NQO1 gene variants with lung cancer in 126 patients and 64 healthy individuals.
Gene expression analysis was performed using the LightCycler 480 Real Time PCR system and hybridization probes. To analyze the genotypes the EPHX1, MPO and NQO1 genes were amplified by polymerase chain reaction and the presence of the gene variants was investigated by restriction fragment length polymorphism after digestion with specific restriction enzymes.
No significant differences in the distribution of the genotypes and allele frequencies were observed between the patients and the control group for the MPO gene and the two different polymorphic variants of the EPHX1 gene. The NQO1 expression levels were higher in the patients when compared to the controls but the difference was not significant. On the other hand, a significant association was observed between the CC genotype and NQO1 expression.
Citation Format: Nejat Dalay, Nur Buyru, Zubeyde Yalniz. Genetic polymorphisms in the carcinogen metabolism pathway and lung cancer risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A16.