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Common Genetic Variant Tied to Lung Cancer Risk

It may explain why some nonsmokers contract the disease, study says

TUESDAY, May 27 (HealthDay News) -- A common genetic variant increases the risk of lung cancer, even in nonsmokers, researchers report.

The findings -- that certain forms of the alpha1-antitrypsin gene double someones risk of developing lung cancer, regardless of whether he or she ever smoked -- could help explain why some nonsmokers develop the disease, said study author Dr. Ping Yang, of the Mayo Clinic.

The study also sheds light on why some smokers never develop lung cancer while others do, added William Phelps, scientific program director at the American Cancer Society.

"Part of the reason may be changes like this that are fairly common in the population," he said. "It is a common mutation that adds a modest amount of risk."

Alpha1-antitrypsin (AT) gene deficiencies are among the most common genetic disorders in the United States, affecting at least 10 million Americans. An estimated 11 percent to 12 percent of lung cancer patients in the study carried the defective gene variants, said the study authors, who published their findings in the May 26 issue of Archives of Internal Medicine.

According to Yang, the link between AT deficiency (ATD) and lung cancer involves another disease called chronic obstructive pulmonary disease (COPD). People with COPD are at greater risk of lung cancer, and the diseases often coexist in families, suggesting a genetic link. People with two abnormal copies of the AT gene develop early onset emphysema and ultimately COPD. But those with just one bad copy often have no symptoms at all, the study authors said.

"These carriers may be more vulnerable to carcinogen-containing tobacco smoke than non-carriers in developing lung cancer, especially when their alpha1-AT levels are compromised under physiological stress or have sub-clinical lung tissue damage," Yang explained.

For the study, Yang and her colleagues recruited 1,856 lung cancer patients and two control groups -- 902 unaffected siblings and 1,585 age-, gender-, and ethnicity-matched "community residents." Then they collected blood samples, determined the alpha1-AT status, and used statistical analyses to tease apart the effects of each variable.

The researchers saw a 70 percent increased risk of developing lung cancer among alpha1-ATD carriers, regardless of smoking history. The number increased to 100 percent for the unrelated control group -- that is, the risk of developing lung cancer doubled for those who are alpha1-ATD carriers. COPD was an independent risk factor, accounting for about a three-to-five-fold increase in risk on its own.

"Our results demonstrated that the alpha1-ATD allele can double an individual's lung cancer risk regardless of smoking history, and also confirmed that COPD is an independent risk factor for lung cancer," Yang said.

Phelps said the findings add up on a molecular level.

"It mechanistically makes sense to me in that a subtle deficiency in this gene could increase damage to the lungs. And in many types of cancer, when you see chronic damage and inflammation, that can lead to cancer," he said.

Just as the chronic liver damage that results from hepatitis viruses leads to inflammation, tissue damage, and sometimes cancer, so too might a lack of alpha1-AT lead to lung cancer, he said.

"The most interesting thing is there are a fair number of people in the population who have this mutation and don't know it, because it won't be clinically obvious. And yet it appears to double their risk of lung cancer based on this study," Phelps said.

Yang said that, although ATD appears to correlate with a high risk of lung cancer, the time is not yet right for genetic testing. Instead, she suggested that a multi-gene diagnostic test, evaluating alpha1-AT in the context of other lung cancer-related genes, might be "more sensitive and specific in predicting lung cancer risk."

"Smoking remains the overwhelming risk factor for lung cancer development," she said. "Although this study helps explain why people who have never smoked can develop lung cancer, it does not represent a pass for smokers. It doesn't mean that people who don't have the gene won't develop lung cancer."

More information

To learn more about lung cancer, visit the U.S. National Library of Medicine.

SOURCES: Ping Yang, M.D., Ph.D., professor, epidemiology, Mayo Clinic, Rochester, Minn.; William C. Phelps, Ph.D., scientific program director, Research Department, American Cancer Society, Atlanta; May 26, 2008, Archives of Internal Medicine

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