Smokers' Damaged Genes Point the Way to Lung Cancer Screening

AURORA, Colo., Aug 31 -- High-risk smokers have "tremendous" genetic damage in their bronchial endothelium even before lung cancer develops, which may provide clues in the search for a genetic screening test.

Smokers at high risk of lung cancer based on their smoking history and cytology findings had nearly 15 times more bronchial chromosomal abnormalities than people who had never smoked (P=0.01), according to a study in the Sept. 1 issue of the American Journal of Respiratory and Critical Care Medicine.

The damage appeared to be more common at certain chromosomes, such as chromosome 18, reported Wilbur A. Franklin, M.D., of the University of Colorado Health Sciences Center here, and colleagues.

This suggests that the recently developed chromosome analysis technique used in the study can find targets for use in a genetic screening test for lung cancer risk, they said.

The technique, spectral karyotyping (SKY), gives a comprehensive profile of irreversible chromosomal changes caused in the airways by tobacco smoke exposure, but it requires a tissue sample.

Another technique, fluorescence in situ hybridization (FISH) offers a more limited view of genetic changes with less sensitivity, but requires only a sputum sample.

"Thus, whereas SKY is not a practical tool to directly apply to sputum, it does identify candidate chromosomal sequences that could improve the sensitivity of a FISH probe set for sputum screening and risk assessment," they wrote.

"Improvement in sensitivity and perhaps automated processing and analysis could move a FISH-based assay forward to clinical application," they added.

The researchers gathered benign bronchial epithelial samples from 71 patients. This included 43 from endobronchial biopsies of high-risk smokers in a clinical trial, 14 from the margins of surgical resection for lung cancer, and 14 from healthy never-smoker volunteers who served as controls.

SKY testing revealed that 14% of those who had never smoked, 82% of high-risk smokers, and 100% of lung cancer patients had chromosomal abnormalities.

The overall extent of chromosomal damage as measured by the proportion of cells with numerical or structural anomalies was significantly different between groups (P=0.012). The percentages were:

• 0.7% for never-smoker controls.
• 10.1% for high-risk smokers (P=0.01 versus controls).
• 15.8% for lung cancer patients (P=0.003 versus controls, P=0.21 versus high-risk smokers).

Clonal abnormalities-those seen in more than a single cell, indicating damage replicated in daughter cell clones-appeared in biopsies of 50% of lung cancer patients, 40% of high-risk smokers, and none of the never-smokers.

All but two of the 14 controls had purely normal diploid biopsies without abnormalities in the number of chromosomes, such as monosomy, trisomy, tetrasomy, or tetraploidy.

Single cell abnormalities were seen in the two never smokers (14%) as well as in 50% of the lung cancer patients and 42% of the high-risk smokers.

A gain in chromosomes-typically trisomy-was the most common clonal abnormality and second most common single cell abnormality. Clonal gains "did not appear to be entirely random" and were seen most often at chromosomes 7 and 18 with a cluster of cases also affected at chromosome 8 or 5. Single cell gains were more widely distributed among the chromosomes.

Clonal gains were found in 26% of lung cancer and high-risk patients overall, which the researchers said was probably an underestimate.

Chromosomal losses -- monosomies -- were seen in 65% of lung cancer and high-risk patients overall, although the researchers said the single-cell losses were likely overestimated. Clonal losses were seen on chromosomes 21, 10, and 22.

The researchers also confirmed the results using FISH assays for 16 high-risk smokers, four lung cancer patients, and one control who had chromosomal losses or gains identified by spectral karyotyping.

Agreement in findings between the two methods was 88% overall, 100% for clonal abnormalities, and 82% for single-cell changes.

Thus, "SKY FISH is a feasible technique for comprehensive evaluation of the chromosomal changes in nonmalignant bronchial epithelial cells of high-risk individuals," the investigators concluded.

But, further study is needed to determine whether the chromosomal abnormalities found are predictive of eventual cancer, they cautioned.