Researchers have moved a significant step closer to proving a molecular connection between tobacco smoke and one of the key factors associated with some cases of lung cancer: specific mutations in the p53 tumor-suppressor gene of lung cells.
The finding requires further study, says lead author John Wiencke, PhD, a UC San Francisco associate professor of epidemiology. However, it lays the groundwork for developing a means of determining whether a given individual has developed lung cancer as a result of exposure to tobacco smoke--even second-hand smoke. The investigation, conducted by UCSF's Wiencke and colleagues at Harvard Medical School and Massachusetts General Hospital, was presented here today (March 31) at the American Association for Cancer Research meeting.
Scientists have known for several years that there is a strong "association" between the specific pattern of mutations often seen in the p53 tumor-suppressor gene of lung cancer cells and exposure to tobacco smoke. But until now they have not had hard evidence that tobacco smoke actually caused these mutations.
Previous studies in lab cultured cells have demonstrated that the carcinogens in tobacco smoke known as polynuclear aromatic hydrocarbons (PAHs) physically bind to the p53 gene in so-called "hot spots," forming physical complexes, or chemical modifications, called DNA adducts. Adducts are one of the first steps in the carcinogenic pathway that ultimately leads to tumor formation.
Given these findings, scientists have suspected that DNA adducts were the actual cause of the p53 mutations. However, because they could not literally peer into the human lung and document cigarette carcinogens creating mutations in the p53 gene, they could not prove it.
In the current study, the researchers have worked around this roadblock--and have done so in humans.
In a study of 137 currently smoking, non-small cell lung cancer patients at Massachusetts General Hospital, the scientists examined whether increased levels of PAH DNA adducts, were associated with the occurrence of p53 mutations.
They did so by assessing the DNA adduct levels in each of the patients' non-cancerous lung tissue, and scrutinizing the same patients' tumors for evidence of p53 mutations. They found that people with increased adduct levels in their lungs were three times more likely to have p53 mutations in their lung cancer cells. This group accounted for 38 of the patients.
While the researchers still have to demonstrate that the p53 mutations identified in the patients have the specific pattern, or "fingerprint," associated with the PAH tobacco carcinogen, the immediate finding is itself compelling, says Wiencke.
"Until now, the only association between PAH DNA adducts and p53 mutations had been demonstrated in cultured cells in the laboratory," says Wiencke. "This is the first strong evidence that DNA adducts are the causal link between the tobacco smoke and the mutation. Our study supports the proposal that p53 fingerprinting may be useful for identifying specific causes of cancer."
The researchers also observed that DNA adduct levels varied in the 137 patients by as much as 30-fold, and the disparity could not be explained by levels of exposure to cigarette smoke (e.g., number of cigarettes smoked per day or number of years smoked).
"This enormous variation in DNA adduct levels observed between patients suggests that people respond very differently to the different carcinogens in tobacco," says Wiencke.
"There are likely to be several distinct mechanisms, or pathways, by which smoking causes lung cancer," he explains, "one involving PAHs and the p53 gene, and others involving different classes of carcinogens (e.g., nitrosamines), which may target genes other than p53. Different parts of the smoking carcinogens affect different people."
"Our findings," says Wiencke, "suggest that measuring the adduct levels in lung cancer patients is superior to taking a smoking exposure history in predicting which patients will develop p53 abnormalities."
The researchers have subsequently found a close correlation between DNA adduct levels in the lung and white blood cell levels. Eventually, says Wiencke, it may be possible to predict DNA adduct levels in the lung--and thus the likelihood of a person developing p53 mutations--by assessing the blood.
"Such a test may allow us to predict which smokers are at greatest risk for developing lung cancer," he says.
"We only expect this research on DNA adducts to get stronger and better," says Wiencke. "We already have an association that is very significant, so it will be hard for this to go away."