Genetic Changes May Persist in Former Smokers

Current and former smokers may not be not so different after all. Although the appearance of lung tissue in smokers returns to normal fairly rapidly once they cease smoking, molecular changes in their DNA do not.

Dr. Adi Gazdar, professor of pathology at the Southwestern Medical Center in Dallas, and his colleagues detected genetic changes commonly found in lung cancer tumors in noncancerous lung tissue from both current and former smokers. In fact, they could not distinguish between the two groups. Lung tissue from nonsmokers showed no genetic changes. Results of the study, conducted by investigators at Southwestern and the British Columbia Cancer Agency in Vancouver, were recently published in the Journal of the National Cancer Institute.

The researchers believe that lung cancer is the culmination of a multistep process in which genetic lesions progressively accumulate in lung cells. They want to identify the early molecular changes, or markers, that may indicate risk of lung cancer development.

In the present study, the investigators examined lung epithelial tissue from 63 current smokers, former smokers, and nonsmokers. After microscopically isolating multiple normal and suspicious areas from each patient, they examined the samples for the loss of genetic material at eight chromosomal regions frequently deleted in lung-cancer tumors. They also looked for signs of genetic instability by checking for microsatellite alterations.

Lung specimens were assigned to one of five pathologic categories from normal to precancerous. Smokers had the entire range of pathologic changes seen prior to the development of a lung cancer tumor. Only 4% of specimens from current smokers were normal, and 25% of former smoker specimens were normal. Of the specimens from nonsmokers, 97% were normal or only slightly abnormal.

Eighty-six percent of smokers had genetic loss at one or more chromosomal regions. Even in specimens with a normal appearance, about half showed loss of genetic material. The most common losses were found on the short arms of chromosome 3 and chromosome 9, thereby indicating that genetic loss in these regions may be relatively early events in the development of lung cancer. At least one microsatellite change was detected in 64% of smokers. Not a single specimen from nonsmokers showed any genetic change.

The authors found genetic changes present throughout the lungs of the vast majority of smokers. These results indicate that such changes, which are not present in lifetime nonsmokers, persist for many years after smoking cessation.

“It is apparent from these studies that the vast majority of heavy smokers, both current and former, have sustained extensive molecular damage to their lungs, and that these changes persist for many years, perhaps for life. We are currently exploring whether these changes can be reversed by various chemoprevention agents such as retinoids These changes may also be useful for risk assessment, so as to determine which smokers are at highest risk for developing lung cancer,” said Gaadar, holder of the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.