Genes that may cause lung cancer

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Individuals with particular variants of certain genes involved in metabolizing the most potent carcinogen found in cigarette smoke have an increased risk of developing lung cancer. That is the conclusion of a new study reported in the February 1, 2009 issue of CANCER, a peer-evaluated journal of the American Cancer Society. The study's results may help shed light on how lung cancer develops and could have important implications for preventing smoking-related cancers.

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. Certain enzymes act to protect the body from this type of chemical by turning it into nontoxic forms or by transporting it from cells. For example, ATP-binding cassette transporters encoded by genes known as ABCB1 and ABCC1 are involved in eliminating carcinogens from the lungs, protecting them against inhaled toxins.

Scientists suspect that individuals with alterations in these genes might have an increased susceptibility to develop lung cancer. Recently, a team of researchers led by Dr. Daru Lu and Dr. Haijian Wang of the Fudan University in Shanghai identified common variants at the beginning and end of the ABC1 and ABCC1 genes. They then analyzed these variants in 500 lung cancer patients and 517 cancer-free controls in a Chinese population.

The researchers observed that certain variants were found much more often in individuals with lung cancer than in cancer-free controls. Patients who had the variant allele of either ABCB1 rs3842 or ABCC1 rs212090 had a significantly increased risk of developing lung cancer. The former variant was especially linked to an increased risk of cancer in women and in individuals under age 60 years. It also was associated with a major type of lung cancer called adenocarcinoma.

Dr. Wang and colleagues previously identified other common genetic variants linked to lung cancer risk in NNK disposition pathways, such as CYP2A13, the most active P450 for the phase metabolic activation of NNK (Cancer Res 2003; 63: 8057) and the receptor (ADRB2) in its non-genotoxic pathway (Cancer Lett 2006; 240: 297). This study shed new insight into the toxicogenomics of NNK and further supported the hypothesis proclaiming genetic components in the metabolism and disposition machines of NNK as modifiers of risk of lung cancer.

"Because tobacco smoking is the leading preventable cause of cancer and the cancer-prone genotypes of these genetic components are relatively prevalent in the human population, our findings have important implications for the prevention of tobacco smokingrelated cancers," the authors write.


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