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AACR: Reduced Transcription Activity of Key Genes May Unmask Lung Cancer


ATLANTA -- The solution to a key mystery in smokers' lung cancer risk may lie in reduced transcription activity of certain antioxidant and DNA repair genes, investigators reported here.

ATLANTA, Sept. 21 -- The solution to a key mystery in smokers' lung cancer risk may lie in reduced transcription activity of certain antioxidant and DNA repair genes, investigators reported here.

A biomarker comprising the transcript abundance levels of 15 genes distinguished lung cancer patients from non-lung cancer patients with 96% sensitivity, James C. Willey, M.D., of the University of Toledo in Ohio, reported at a molecular diagnostics conference sponsored by the American Association for Cancer Research.

The test yielded false-positive results in seven people who did not have cancer, but Dr. Willey and colleagues believe the positive test results might actually represent a group of people who eventually will develop lung cancer.

"Smoking causes about 90% of all lung cancer cases, yet only about 10% to 15% of heavy smokers will develop lung cancer," said Dr. Willey. "We are looking for new techniques that will allow us to pick out the individuals at highest risk from the enormous pool of current and former smokers."

The researchers had previously reported that low transcript abundance levels of certain antioxidant enzyme genes in bronchial cells increased the likelihood of bronchogenic carcinoma compared with people who had higher, presumably protective, levels (BMC Cancer 2005;5:141).

In the current study, the investigators evaluated transcript abundance levels of 15 genes involved in DNA repair and inhibition of oxidation. The study population consisted of 25 lung cancer patients and 24 individuals who did not have lung cancer.

Using previously established threshold levels for the genes, they assigned a value of 0 or 1 for each gene's transcript abundance level in bronchial cells. A total score of 7 or higher was defined as a biomarker for individuals with lung cancer.

Cumulative results in all 49 individuals revealed a single false-negative result, in addition to the seven false-positives, translating into a sensitivity of 96% and a specificity of 71%.

"These results justify a larger, prospective study to determine whether this biomarker will be useful in predicting risk for lung cancer in current and former smokers," said Dr. Willey.

The researchers have validated two of the 15 genes in more than 120 individuals, and the validation of the other genes in a larger number of patients is a major focus of the group's current activities.

The research has already identified one gene (known as CEBPG) as the transcription factor responsible for regulating transcription of antioxidant and DNA repair genes in normal bronchial cells. The gene likely has a key role in the evolution of lung cancer, as well.

"We think that suboptimal regulation of these key antioxidant and DNA repair genes by CEBPG is a key characteristic of people at increased risk for lung cancer," said Dr. Willey.

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