Searching for Commonalities between Two Deadly Lung Diseases

by Sharon Reynolds
National Cancer Institute

[March 9, 2010] Despite enormous strides in tobacco education during the last few decades, more than 20 percent of adult Americans still smoke, and tobacco use causes more than 400,000 deaths each year in the United States alone. The majority of these tobacco-related deaths are caused by two diseases: lung cancer and chronic obstructive pulmonary disease (COPD). These diseases often occur together in patients

“With a background of tobacco exposure, you have several disease pathways that are studied separately even if they co-exist,” explained Dr. Eva Szabo, chief of NCI’s Lung and Upper Aerodigestive Cancer Research Group in the Division of Cancer Prevention.

“Having COPD is a risk factor for lung cancer,” said Dr. Antonello Punturieri, program director in the Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI). “Many patients have moderate and often severe COPD in addition to lung cancer. But we don’t understand how tobacco exposure may lead to only COPD, or only lung cancer but not COPD, or COPD and lung cancer.”

Until recently, scientists have tended to study either lung cancer or COPD. But that is beginning to change. More laboratories are now looking at the complicated interplay between the two diseases and their risk factors, including smoking.

Roles for Both Exposure and Genetics

Among smokers, only 15 to 20 percent get either lung cancer or COPD, leading researchers to propose a genetic component of risk. Dr. Laura Bierut, professor of psychiatry at Washington University School of Medicine, and her colleagues recently identified a single-nucleotide polymorphism (SNP)—a variation in a single unit of DNA—on chromosome 15 that is associated with smoking behavior. This same variant increases the risk of lung cancer and COPD.

As more of these genetic risk factors are discovered, “the million-dollar question will be, Is the link between these genetic variants to lung cancer and COPD driven only through their influence on smoking behavior—such as increasing the number of cigarettes smoked per day—thus increasing the risk of disease? Or is there a direct pathogenic effect of these genetic variants on lung cancer and COPD?” said Dr. Bierut.

The SNP on chromosome 15 does appear to have an independent effect on disease risk. “If you incorporate the pack-years someone has smoked or how many cigarettes someone smokes per day into the statistical analyses, the genetic variant continues to contribute to lung cancer risk, above and beyond the behavior.”

She added that translational animal studies will likely be needed to tease apart the relationships between behavior, exposure, and disease, which are incredibly complex to study in humans.

A Cancer-friendly Microenvironment

Dr. James Crapo, professor of medicine at National Jewish Health, is interested in the role that chronic inflammation plays in both COPD and lung cancer.

“Clearly there are some shared factors that create risk for people who develop COPD and lung cancer. My hypothesis is that some individuals develop chronic inflammation that’s progressive even if they stop smoking,” he said.

“As we move into studying lung cancer and COPD associations, it’s very important that we start thinking of COPD as a syndrome with different subtypes,” he continued. “People tend to think of COPD as destruction of the lung tissue, but that only describes a subset of COPD. In fact, a large proportion of our COPD patients predominantly have airway inflammation and not tissue destruction, and inflammation is an environment in which cancer can develop.”

Dr. Crapo believes that there is a subtype of COPD that has a much stronger cancer association than others COPD subtypes. “And I’d bet that it’s the COPD patients who predominantly have airway disease who are at greater risk of cancer,” he said.

As part of the 12,000-person COPDGene cohort study, Dr. Crapo and his colleagues are performing genome-wide association studies to look for genetic links to airway inflammation and other possible risk factors for COPD. Although the cohort is designed to primarily examine COPD, the researchers hope to also collect data on lung cancer incidence.

“Once we find out what’s driving both of these diseases to occur in the same subjects, if it’s something like inflammation that we can treat at an early stage, we could potentially prevent the lung cancer and COPD from developing. That’s the long-term hope for us,” he explained.

Encouraging an Emerging Field of Research

On March 2, NCI and NHLBI released a joint request for applications (RFA) to encourage cross-disciplinary, translational research into common disease-causing mechanisms of lung cancer and COPD. The RFA will fund 8 to 12 new research projects and will favor applications with two principal investigators—one from the pulmonary community and one from the cancer community—to foster collaborative activities.

The two main objectives of the research effort will be to identify the genotypic and phenotypic characteristics that determine individual susceptibility to lung cancer and COPD, and to better understand the shared biochemical, molecular, and immunological pathways involved in the origin and progression of the two diseases.

“These patients are complex. Though they may die from one disease, they often have other tobacco-related diseases at the same time,” said Dr. Szabo. “A better understanding of one disease may lead to clues for the other; not only clues about pathogenesis, but clues to possible therapeutic targets.”