Though difficult to imagine today, the knowledge of lung cancer risk from exposure to tobacco didn’t evolve until after World War II—a period when U.S. military rations included cigarettes. Soon after, scientists began to pick up the trail of killer tobacco with epidemiologic studies, comparing groups of smokers and non-smokers. They noted that individual susceptibility appeared to be a factor in cancer and addiction and, in the 1980s, produced the first evidence linking genetic factors to human lung cancer risk.
|On hand at the Trent Lecture were (from l) NHGRI director Dr. Eric Green; lecture namesake and former NHGRI scientific director Dr. Jeffrey Trent; speaker Dr. Christopher Amos and NHGRI scientific director Dr. Daniel Kastner.
Dr. Christopher Amos, professor of epidemiology and biomathematics at the University of Texas MD Anderson Cancer Center, recently described the evolution of our current understanding of the complex genetic and environmental relationship between smoking tobacco and lung cancer risk. His talk was the 9th annual Jeffery M. Trent Lecture, organized by NHGRI. Amos leads the coordinating center for a collaborative group called the Genetic Epidemiology of Lung Cancer Consortium.
Researchers such as Amos classify a smoker as a person who lights up 100 or more times. Citing the work of Laura Beirut at Washington University in St. Louis, Amos said that, among people who have smoked more than 100 cigarettes, 80 percent develop a tobacco dependency while 20 percent do not.
Amos described genetic susceptibility to lung cancer.
Photos: Bill Branson
Research in this area has advanced over recent decades. Initial studies in the early 1960s identified an increased risk for lung cancer among relatives of lung cancer patients, but these were not confirmed until the 1980s, when researchers presented evidence linking genetic factors to lung cancer risk. The first genetic epidemiologic study on lung cancer considered individual risk rather than classifying the population as a vast group. Then, in 1986, NHGRI senior investigator Dr. Joan Bailey-Wilson and collaborators showed that lung cancer was more prevalent in some families even after adjusting for cigarette smoking.
In 1990, Bailey-Wilson’s group found statistical evidence that a specific genetic factor increases a person’s risk of lung cancer. In 2004, her team, including Amos and other members of the Genetic Epidemiology Consortium, identified the first region in the human genome that increases lung cancer risk. In 2008, Amos led a group that identified common risk alleles for lung cancer on chromosome 15q, which has led to many other studies of both lung cancer risk and nicotine dependence genes in this chromosomal region. Alleles are the alternate gene forms an individual inherits from each parent that, in this case, put them at higher risk for lung cancer.
Researchers in Amos’s field of genetic epidemiology continue to gain understanding of lung cancer and the ongoing public health concern it presents. Using linkage analysis—tracking a trait in families and linking genetic factors to the trait—they can find high-risk alleles. By performing large genome-wide association studies that scan many different individuals’ genomes for a genetic marker that can predict disease, they can find common, low-risk alleles. A person with multiple risk alleles in different disease genes has a higher probability of developing cancer.
The outcomes of these analyses are shedding light on the relationship between smoking and lung cancer. For example, we now understand that relatives of lung cancer patients—who are also smokers—have a 2.5 percent higher risk of lung cancer. And, people with rare mutations in the p53 gene have been shown to have a higher risk of lung cancer along with higher risks for breast cancer, sarcomas, leukemias and other cancers.
Amos described an increasing sophistication in the questions that researchers are asking and showed that these questions are leading to answers—and more questions. For instance, they have found that African-American males who smoke the same amount as Caucasian males have a 30 percent higher risk for lung cancer. Hispanic groups have a lower risk than Caucasians. Amos explained that complex genetic and environmental factors may contribute to these differences.
The future of lung cancer research lies in trans-disciplinary groups that can approach questions of the genetics of lung cancer risk and smoking from different directions, Amos said. Among his goals is screening high-risk populations for their risk for lung cancer to help them make important life choices, especially to avoid smoking.