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.