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Clinical Laboratories Strategies: July 10, 2008

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Using Genetics to Gauge Lung Cancer Risk 
Increased Incidence Linked to Deficiency in Alpha-1 Antitrypsin

By John R. Bell


The primary risk factors for lung cancer are exposure to tobacco smoke and history of chronic obstructive pulmonary disease (COPD). However, a deficiency in alpha-1 antitrypsin, known as α1ATD, has long been linked with increased risk for other types of cancer, COPD, and particularly early-age emphysema. In this issue of Strategies, researchers report that carriers of this deficiency gene—even in the absence of smoking and COPD—have a markedly increased risk of developing lung cancer, compared to persons without the α1ATD mutation. This raises the question: Who should be tested?

Although tobacco exposure is the most common risk factor for emphysema and lung cancer, researchers have speculated on why some smokers develop lung cancer and others do not. Previous research, including a 2004 review by Ping Yang, MD, PhD, professor of epidemiology, and her colleague Zhifu Sun, MD, both of the Mayo Clinic in Rochester, Minn., identified a deficiency mutation in the glycoprotein alpha-1 antitrypsin gene as a risk factor (Lancet Oncol. 2004 Mar;5[3]:182-90). In that review, the investigators concluded that this deficiency, called α1ATD, might make lung tissue more susceptible to damage. However, it was unclear to what degree carriers of this alteration are at increased risk for lung cancer.

Although tobacco exposure is the most common risk factor for emphysema and lung cancer, researchers have speculated on why some smokers develop lung cancer and others do not. Previous research, including a 2004 review by Ping Yang, MD, PhD, professor of epidemiology, and her colleague Zhifu Sun, MD, both of the Mayo Clinic in Rochester, Minn., identified a deficiency mutation in the glycoprotein alpha-1 antitrypsin gene as a risk factor (Lancet Oncol. 2004 Mar;5[3]:182-90). In that review, the investigators concluded that this deficiency, called α1ATD, might make lung tissue more susceptible to damage. However, it was unclear to what degree carriers of this alteration are at increased risk for lung cancer.

Risk Doubled in Non-Smokers

According to new findings published by Yang and her Mayo colleagues in the May 26 Archives of Internal Medicine, persons with α1ATD showed more than twice the incidence of lung cancer as those without, after confounding factors were controlled for. But for almost all types of lung cancer, the increase in risk conferred by being an α1ATD carrier was dwarfed by the risk associated with smoking and by a history of COPD (Arch Intern Med. 2008;168[10]:1097-1103).

The investigators enrolled 1,856 patients diagnosed with lung cancer, identified in the Mayo reporting system over a 6-year period, and two control groups, matched to patients by age, sex, and race: 1,585 unrelated controls, enrolled from the community, and 902 full siblings of the patients. They then tested all participants for the deficiency, using isoelectric focusing electrophoresis to phenotype proteins, followed by quantitation of the protein’s level.
Logistic regression analysis showed that carriers of the α1ATD, including smokers and nonsmokers, were 70% more likely to have been diagnosed with lung cancer than nonrelated controls (odds ratio 1.7) and twice as likely to have lung cancer as their cancer-free siblings (OR 2.0). But perhaps the most striking association was seen among people who had never smoked and who carried the α1ATD deficiency: they were more than twice as likely (OR 2.2) as non-smoking non-carriers to have lung cancer.

Significantly more of the lung cancer patients were positive for α1ATD (13.4%) than were unrelated controls (7.8%) or full-sibling controls (9.9%). At the same time, the increased risk for lung cancer was even greater for COPD of all types (OR 3.9) and highest for all combined levels of smoking exposure (OR 4.0).

Smoking, COPD Still Pose Greatest Risk Increase

The increase in risk for lung cancer seen with α1ATD was greater for some types of cancers—but for most, smoking and COPD each conferred more risk. The greatest risk increase associated with α1ATD was seen for squamous cell lung cancer (SQCLC), with an adjusted OR of 2.5. However, this increase in risk was eclipsed by the twelve-fold increase (OR 12.1) for SQCLC conferred by smoking. COPD risk was nearly four-fold (OR 3.9) for SQCLC.

Although Yang and colleagues first examined the link between α1ATD and lung cancer in 1999, the doubling of lung cancer risk for unrelated controls and the nearly double risk for community controls was “a small, pleasant surprise,” she said. Yang cautioned, however, that “due to the complexity of genomic variations across ethnicity groups, even within a race—say, Caucasians—substructure revolutionary heterogeneity could bias the risk estimation in many of similar studies like ours that produce inconsistent results between using different control groups.” The literature reports that approximately 7% of Caucasians are α1ATD carriers—a rate much higher than for other ethnic groups.

To Screen or Not to Screen?

Yang suggested that a DNA-based test be developed, but “only if mass screening is justified” and only if it could be offered at low cost. Many alleles of α1ATD exist, though the currently available test is for the most common z and s mutations, she noted. In addition, she pointed to the possibility that smokers who test negative for α1ATD mutation may interpret this as a license to smoke. “Not having this gene mutation is definitely not a pass for a smoker. Compared to the risk that smoking imposes on risk of lung cancer, any gene-mutation effect pales to a tiny fraction,” she said.

Another researcher who has studied α1ATD sees more potential good than harm in screening. “Since this is a genetic disorder, if you’re a person who’s unfortunately got advanced lung cancer … someone else in the family may be an α1ATD carrier. And from a family-history perspective, that’s clearly important,” said D. Kyle Hogarth, MD, assistant professor of medicine at the University of Chicago Medical Center. He added: “This study doesn’t give you data to say that the relatives need to be tested, but the counter-argument is that there are 20 to 25 million carriers out there, and they clearly don’t know their carrier status.”

“Screening is a strong word,” said Joshua Bornhorst, PhD, assistant professor and director of chemistry in the Department of Pathology at the University of Arkansas for Medical Sciences, who also studies α1ATD. “Although screening may be feasible from a technology standpoint, I think it remains to be seen whether it’s practical and advisable.” Cost is an impediment to screening by genetic or phenotype testing, he said. “Frankly, it’s somewhat expensive, ranging anywhere from approximately 10 to 50 dollars.”

Bornhorst noted it is not difficult to test for the most common variants of α1ATD but that the more rare alleles present a greater challenge. “Doing genetic testing for all possible variants is fairly difficult. But it’s really not that difficult to test for at least the major alleles—the s and z alleles.” He noted that protein phenotype testing for variants such as the P variant can also be performed. “However, there are underlying genetic variations [of the phenotypes] that need to be investigated further.”

Mechanism of Action

Yang said her group at the Mayo Clinic is particularly interested in studying sub-clinical conditions of lung damage, as well as variations of other genes related to α1ATD —“those directly or indirectly interactive mechanistic pathways—such as inflammation and tissue remodeling.”

Bornhorst shared this vision for future research.  “I think this paper will stimulate a lot of research into elucidating the mechanism by which alpha-1 deficiency causes this increase in lung cancer. It also may stimulate research into other disorders that may be linked” to the α1ATD, he said.

Hogarth agreed with Yang and Bornhorst that inflammation is a likely culprit. “There’s an inflammatory component going on here. And if you look at the COPD perspective for lung cancer, the α1ATD changes play just as big a role as COPD. When you have an α1 patient, the typical story with them is that no one in the family has had lung disease, because the patient is the product of two carriers. You actually don’t know unless you test,” he said.

Disclosures

Dr. Hogarth receives funding and/or speaker fees from three companies with interest in α1ATD: CSL Behring, Talecris Biotherapeutics, and Baxter International.


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