Results published in Cancer implicate alleles of ABCB1 rs3842 and ABCC1 rs212090.

Variants of genes involved in metabolizing a carcinogen found in cigarette smoke confer an increased risk of developing lung cancer, according to investigators from Fudan University.

Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a component of cigarette smoke that has been shown to cause lung cancer in rodents, according to the researchers. Certain enzymes like ATP-binding cassette transporters encoded by genes known as ABCB1 and ABCC1 are involved in eliminating carcinogens from the lungs.

The team identified common variants at the beginning and end of the ABC1 and ABCC1 genes were found much more often in individuals with lung cancer than in cancer-free controls. They then analyzed these variants in 500 patients with lung cancer and 517 cancer-free controls in a Chinese population.

Patients who had the variant allele of either ABCB1 rs3842 or ABCC1 rs212090 had a significantly increased risk of developing lung cancer. The ABCB1 rs3842 variant was particularly associated with an increased risk of cancer in women and in individuals under age 60 years. It also was linked to adenocarcinoma.

The scientists previously identified other common genetic variants associated with lung cancer risk in NNK disposition pathways, such as CYP2A13, the most active P450 for the phase metabolic activation of NNK and the receptor ADRB2 in its nongenotoxic pathway. This study sheds new insight into the toxicogenomics of NNK and further supports the hypothesis that genetic components in the metabolism and disposition machines of NNK are modifiers of risk of lung cancer.

The article appears online December 22 in Cancer and will appear in print on February 1, 2009.

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