Alpha1-Antitrypsin Deficiency Significantly Increases Risk for Lung Cancer

Roxanne Nelson

May 27, 2008

May 27, 2008 — Alpha1-antitrypsin deficiency (AATD) can greatly increase the risk for lung cancer, researchers report. AATD carriers might have a risk of developing lung cancer that is 70% higher than that for noncarriers, according to new data published in the May 26 issue of Archives of Internal Medicine.

Previous studies have shown that chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer. "COPD in general is associated with an increased risk of lung cancer, but alpha-1 antitrypsin deficiency carriers are more prone to early-onset emphysema," lead author Ping Yang, MD, PhD, professor of epidemiology at the Mayo Clinic, in Rochester, Minnesota, told Medscape Oncology.

AATD is one of the most common genetic conditions affecting people in the United States, particularly those of European descent. Among homozygous people, it can lead to early-onset of emphysema; heterozygous people might be unaware of their status as carriers and generally do not experience AATD-related diseases. However, carriers of AATD might be more vulnerable to the carcinogenic effects of tobacco smoke than the general population, especially when their levels of alpha1-antirypsin are compromised by physiologic stress or if they already have some degree of lung-tissue damage.

The authors note that the development of lung cancer is a complex and multistage process that involves numerous factors that are intrinsic and extrinsic to the host. Noxious substances in tobacco smoke can damage the DNA of cells and also stimulate an inflammatory response in the lung. Conversely, host mechanisms can inactivate harmful substances in tobacco smoke, remove or repair damaged DNA, and adapt the stimulants by structural changes in the lung tissue. The underlying mechanism of lung cancer encompasses an intricate interplay of these factors.

In this study, Dr. Yang and colleagues evaluated the interplay of AATD, COPD, and cigarette smoking in lung cancer development and estimated the relative contributions of such factors to lung cancer risk in the general population. They tested AAT allele types in 1443 patients with lung cancer treated at the Mayo Clinic from 1997 to 2003, 797 unrelated and healthy controls, and 902 full siblings of the lung cancer patients.

Their analysis showed that the risk for lung cancer in people with COPD was more than 6 times the risk in people without COPD and, depending on the intensity of tobacco use, the risk for smokers was 2 to 9 times higher than the risk for nonsmokers. Environmental tobacco smoke (ETS) did not significantly increase the risk for lung cancer, but a trend test of 5-level cigarette-smoking-exposure intensity was significant; it included never smokers with no ETS, never smokers with ETS, and light, moderate, and heavy smokers.

Comparison With Unrelated Controls

The overall carrier rate of AATD among the lung cancer patients was 13.4%; for the unrelated control group it was 7.8%. The risk for lung cancer was 70% higher in carriers than in noncarriers. A history of COPD increased lung cancer risk 2.5- to 5.9-fold among smokers and nonsmokers, with the greatest influence in never smokers

Among carriers, the risk of developing lung cancer was similar regardless of smoking history. The risk for lung cancer in carriers was 2.2 times the risk in noncarriers, after adjustment for confounders that included a history of unspecified COPD. Carriers who were light smokers had a risk for lung cancer that was more than 2 times greater than the risk for noncarriers; carriers who were moderate to heavy smokers had a risk 2.3 times greater than noncarriers.

Comparison With Siblings

When lung cancer patients were compared with their cancer-free siblings, the results were similar to those seen in the comparison between patients and unrelated controls: the AATD carriers had twice the risk of developing lung cancer as the sibling controls. The researchers estimated that AATD carrier status might account for 11% to 12% of the lung cancer in patients who participated in this study.

The authors note that according to estimates from the World Health Organization, there are at least 10 million Americans and 120 million people worldwide who are AATD carriers. These results indicate a potentially significant impact of AATD on the risk for lung cancer, and highlight the potential benefit of identifying people who might have an increased vulnerability to carcinogens.

Dr. Yang believes that people who appear to be at a higher risk for AATD, such as those with a family history of lung cancer or early-onset emphysema, should be screened. "However, the current test is protein based and meant for clinical diagnosis," she said. "It is not feasible to use it for screening purposes. A DNA-based test, which still needs to be developed, is more suitable for the purpose of screening."

Eventually, this information could lead to more targeted therapy for lung cancer patients who are AATD carriers, and that is under investigation, she added.

The study was supported by grants from the National Institutes of Health. The researchers have disclosed no relevant financial relationships.

Arch Intern Med. 2008;168:1097-1103