Two genes may interact to increase risk of lung cancer in smokers

July 14, 2003

WASHINGTON, July 13- Researchers have long sought to explain why some smokers get lung cancer and others do not. In one of the first studies to suggest that the interaction of two genes may play a role, researchers at the University of Pittsburgh Cancer Institute (UPCI) have found that inheriting alterations in both a DNA repair gene and a cyclin D1 gene may increase the risk of lung cancer in those exposed to tobacco carcinogens. The preliminary findings are being presented at a poster session at the rescheduled annual meeting of the American Association for Cancer Research (AACR) on Sunday, July 13, in Washington, D.C.

"In our study, we found a strong correlation between genetic polymorphisms in two genes and lung cancer risk," said Marjorie Romkes, Ph.D., study co-investigator and associate professor, Center for Clinical Pharmacology, department of medicine and director, General Clinical Research Center Pharmacogenetics Care Laboratory, University of Pittsburgh. "Our findings, while preliminary, suggest that the co-inheritance of mutations in a DNA repair gene called XPD and the cyclin D1 gene may be linked to increased risk of lung cancer in those exposed to tobacco smoke. While we have known that these genes are linked to lung cancer on their own, this is the first time we have observed that they may interact to increase lung cancer risk."

The study compared 173 patients with lung cancer to a control group of 184 healthy individuals and found that mutations in both XPD and cyclin D1 (CCND1) occurred more often in the lung cancer patients. In addition, a strong increase in lung cancer risk was observed among individuals with a smoking history and a combination of mutations in both the XPD and CCND1 genes. Those with a smoking history had an odds ratio of 17.0 compared to non-smokers who had an odds ratio of 6.3.

"These findings are important because they have the potential to help us identify those smokers who have a greater likelihood of developing lung cancer," said Dr. Romkes. "If we can identify individuals at high risk and screen them early, we could have a real impact on morbidity and mortality from lung cancer." Dr. Romkes added that for the first time these results suggest an interaction between damage to the DNA repair pathway and the cell cycle control pathway, exposure to carcinogens present in cigarette smoke and resultant lung cancer risk.

Cancer is caused when damage in cells results in unregulated cellular growth. When DNA repair genes (whose job is to ensure that genetic information is accurately copied when cells divide) are damaged or mutated, they increase the frequency of other genetic mutations that also can lead to cancer. CCND1, one of the key cell cycle regulators, is important in cell cycle control and is central to the repair of DNA damage before cell division.

A difficult cancer to treat due to its advanced stage at diagnosis, lung cancer will be newly diagnosed in more than 170,000 people in the United States in 2003.
The study is funded by a grant from the National Cancer Institute. Co-investigators include Shama Buch, Ph.D., Bing Zhu, M.D., S. Lerdtragool, Ph.D., A. Gaither Davis, Dominic Odom, Jill Siegfried, Ph.D. and Jennifer Grandis, M.D., all with the University of Pittsburgh.

Clare Collins
Jocelyn Uhl
PHONE: 412-647-3555
FAX: 412-624-3184

University of Pittsburgh Medical Center

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