Smoking, Cancer Deaths Linked at p53 Gene By Karin Twilde Researchers at the School of Medicine have uncovered the most conclusive evidence to date linking cigarette smoking to cancer. Their findings, reported in the March 16 issue of the New England Journal of Medicine, represent the strongest molecular link between cigarette smoking, the most common cause of cancer-related death, and mutation of the p53 gene, the most common cancer-related genetic mutation. The research team, led by David Sidransky, associate professor of otolaryngology and oncology, studied tumor samples of 129 head and neck cancer patients for p53 mutations. They found that patients who smoked were twice as likely as nonsmokers to have mutations of the p53 gene. Patients who used alcohol in addition to cigarettes were 3.5 times as likely as those who neither smoked nor drank to have the mutation. Thirty-three percent of patients who smoked and 58 percent of patients who smoked and drank had p53 mutations. In contrast, only 17 percent of patients who neither smoked nor drank had mutations. The researchers defined smokers as those who smoked at least one pack of cigarettes per day for 20 years or more, and alcohol users as those who drank more than one ounce of hard alcohol per day. Dr. Sidransky believes that the p53 gene, a tumor suppressor gene that normally helps to prevent the formation and growth of cancers, is a specific target of carcinogens in cigarette smoke. "Carcinogens from cigarette smoke bind to the DNA and selectively inactivate the gene. Alcohol further facilitates mutations by increasing the absorption of carcinogens," Dr. Sidransky said. The researchers isolated DNA from surgically removed head and neck tumors and used polymerase chain reaction to amplify and isolate the p53 gene. They cloned and sequenced the gene to identify the mutations. Their results were confirmed with repeated amplification, cloning and sequencing of the tumor DNA. The researchers also found that smokers had mutations in different regions of the p53 gene than nonsmokers. In the nonsmoking group, all the mutations occurred in an area of the gene known as a CpG site, Dr. Sidransky said. Scientists call these areas mutational "hotspots" because they are the site of frequent cellular errors that lead to genetic mutations. Only 23 percent of the mutations in the smoker/drinker group occurred in these sites. "This new data is preliminary evidence that the genetic pattern of some patients' tumors might enable us to identify smoking as the specific cause of their cancer," said Steven Goodman, assistant professor of oncology and biostatistics. Though this study included only head and neck cancer patients, Dr. Sidransky and Dr. Goodman believe it has implications for all smoking-related cancers. Experts believe that one-third of all cancers are smoking-related. The American Cancer Society estimates that cigarette smoking is responsible for almost 90 percent of lung cancer deaths. Smoking is also associated with cancers of the mouth, pharynx, larynx, esophagus, pancreas, cervix, kidney and bladder. According to the World Health Organization, 2.5 million people die worldwide each year as a result of smoking. "This study provides strong evidence that abstinence from smoking is important to preventing these cancers," Dr. Sidransky said.
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