Search for lung cancer genes narrows

By Scott Maier
Office of News and Publications

Researchers at UT Southwestern have helped identify a genetic region on human chromosome 6 that leads to great susceptibility to the development of lung cancer. 

The discovery, reported in the September issue of the American Journal of Human Genetics and online by a team of researchers forming the Genetic Epidemiology of Lung Cancer Consortium (GELCC), indicates there is an inherited component that contributes to the disease associated with smoking tobacco. The finding could eventually lead to early genetic screening programs for those at especially high risk.

Lung cancer is the leading cause of cancer death in the United States, more than breast, colon and prostate cancer combined. The overall five-year survival rate is only 15 percent. In the past 50 years, disease incidence has increased 249 percent and mortality 259 percent.

"This is a very important discovery in our fight against lung cancer," said Dr. John Minna, director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics and the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and a contributing author of the study. Dr. Minna holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology.

"One out of eight to one out of 12 heavy cigarette smokers will come down with lung cancer during their life, and we need to have ways to identify these people ahead of time so we can achieve a very early diagnosis or, even better, prevent the development of lung cancer," Dr. Minna said. "If we can identify the specific gene or genes in this chromosomal region, we can begin a massive screening effort similar to what has been done for inherited susceptibility to breast cancer."

Researchers believe specific genes increase the risk of developing lung cancer through smoking and/or other environmental exposures. As a result, UT Southwestern and 11 other institutions collaborated to create a registry of high-risk families for genetic linkage studies of the disease. By analyzing each family's data, they hoped to identify any genetic susceptibility regions.

For the study - headed by the University of Cincinnati - researchers with the GELCC recruited families with two or more close blood relatives (parents, brothers, sisters or grandparents), living or deceased, who had been diagnosed with lung, throat or laryngeal cancer. More than 26,000 cancer cases were screened, and 771 high-risk families were found with at least three first-degree relatives with the disease. 

The most informative 52 families (241 individuals) then were studied for linkage analysis. Drs. Minna and Adi Gazdar, a professor in the Hamon Center for Therapeutic Oncology Research and of pathology, reviewed clinical data and pathology on all patients and prepared tissue material of the final 52 families for genetic analysis.

The resulting examination found strong evidence that people with a genetic mutation in a specific region on chromosome 6 were more likely to develop lung cancer, and these individuals could contract the disease even by smoking a small amount. Humans have 23 pairs of chromosomes, 46 in all.

"Because we have found that if you carry the mutant form in this genetic region that even very light cigarette smoking predisposes to lung cancer, we urge all people to stop smoking," Dr. Minna said. "There are new ways to help with smoking cessation being employed here at UT Southwestern, and we want to get smokers into this program."

The next step is to more closely examine the newly identified region on chromosome 6, said Dr. Minna. This area contains at least 50 genes, including several suspected tumor suppressor genes and cell growth genes.

"Dr. Gazdar and I are currently involved in a team hunting for the gene or genes in the localized region," Dr. Minna said. The researchers also plan to screen more families that could have familial lung cancer while searching for additional susceptibility regions. Once the genes for susceptibility are fully determined, methods can be developed to identify people predisposed to lung cancer and to prevent, control and manage it.

The study was supported by grants from the National Cancer Institute to the GELCC and to the Specialized Programs of Research Excellence (SPORE), National Institute of Environmental Health Sciences, U.S. Department of Energy and the National Center for Research Resources.