Three decades after a surgeon general's report linked smoking to human cancers, researchers at the Johns Hopkins School of Medicine have traced one of the genetic pathways by which tobacco does its harm.
Scientists studying people with head and neck cancer found that tobacco damages a gene, known as p53, that works as a natural brake against a developing cancer. Without this repair mechanism, malignant cells can multiply and flourish into full-blown tumors.
Although the mutation has been blamed for many cancers, the research by Dr. David Sidransky and colleagues at Hopkins is the first time the genetic defect has been tied specifically to tobacco smoke in a large number of human patients.
What's worse, the scientists also found that the mutation occurs with even greater regularity among people who both smoke and drink alcohol. Although the reasons are not completely understood, Dr. Sidransky said alcohol may cause a cell's genetic material to act like a sponge, soaking up carcinogens more readily than it otherwise would.
Some studies, he said, have suggested that alcohol may also damage the protective lining of the mouth and other tissues, allowing carcinogens to pass more easily into the underlying cells.
"What we saw was phenomenal," said Dr. Sidransky. "If you smoke and drink, you had a much, much higher rate of the p53 mutation than if you were a nonsmoker and a nondrinker."
The findings, reported in today's New England Journal of Medicine, grew out of a study of 129 people who had cancers of the lip, mouth, tongue, jaw and other tissues of the head and neck. More than three-quarters of the patients were smokers.
When the scientists studied the genetic makeup of the patients' tumors, they found that one-third of the patients who smoked carried the defects of the tumor suppressor gene. Among the smokers, the mutation showed up twice as frequently as it did in the small number of cancer patients who did not smoke.
The mutation, however, was found in 58 percent of the cancer patients who both smoked and drank -- suggesting that alcohol enhances the cancer-causing power of tobacco smoke.
Smokers were defined as people who consumed at least a pack of cigarettes a day for at least 20 years, and drinkers as individuals who consumed at least an ounce of hard liquor a day for any length of time.
Specific gene targeted
Taken together, the findings suggest that tobacco smoke in many cases targets a specific gene -- and hits it with greater frequency when alcohol is added. Although scientists at the National Institutes of Health several years ago found the p53 mutation in some patients with lung cancer, the defect could not be tied specifically to tobacco.
Dr. Sidransky said tobacco probably causes the same type of genetic damage in the lungs as it does in tissues of the head and neck.
"The damage starts at the lip, goes to the voice box, and if you drop one inch from that, you're in the lung," he said.
The National Cancer Society estimates that 169,900 new cases of lung cancer will be diagnosed in 1995. Head and neck cancers are about a third as common.
Several years ago, researchers with the National Cancer Institute discovered in a statistical study that people who smoked and drank were more likely to get oral cancers than were people who only smoked. They did so by studying the lifestyle patterns of 1,000 people with oral cancers.
"It's a very strong risk factor," said Dr. William Blot, one of the scientists involved in the study. He said the odds of developing oral cancer are four times greater for smokers than for nonsmokers. But people who both smoke and drink increase their odds 35 times, he said.
It remains unclear whether alcohol also compounds a smoker's odds of developing lung cancer, he said.
Case against tobacco
The Hopkins findings are merely the latest chapter in the scientific community's evolving case against tobacco.
One of the first warnings was sounded in 1938 by Dr. Raymond Pearl, a Hopkins biologist who published tables showing that people who smoked generally lived shorter lives than did nonsmokers. The longer people smoked, he said, the shorter their life span.
Subsequent studies showed that monkeys who were forced to inhale tobacco developed lung cancer at a greatly increased rate. Surveys of human populations showed that smokers were predisposed to lung cancer.
Such studies led to the landmark 1964 report by U.S. Surgeon General Luther Terry, who warned smokers that tobacco causes cancer. Further studies of cancer patterns implicated smoking in cancers of the head and neck, pancreas, esophagus, bladder and cervix.
The new tools of molecular biology have enabled scientists to study the cellular changes that trigger cancer.
Yesterday, Maryland Health Secretary Martin P. Wasserman said he might use the new findings to bolster the state's efforts to lower its cancer death rate, which is among the highest in the nation.
"It's a great story to be coming up right now," he said. "We'll try to look at how it could be used to influence social policy."