Seeking Clues to Genetic
Susceptibility and Cancer Risk
Dr. Margaret R. Spitz, Dr. Stephen D. Hursting (left) and Dr. J. C. Shen
are studying genetic susceptibility and cancer development.
Why do some people who are exposed to a carcinogen develop cancer and others do not?
And, in those individuals who are predisposed to getting certain cancers, can changing
their diet help offset that risk?
These were two key questions scientists in M. D. Anderson's Department of Epidemiology
set out to answer this past fiscal year. According to Dr. Stephen D. Hursting,
assistant professor of epidemiology, in reference to dietary changes, the answer appears
to be yes - at least in mice.
Dr. Hursting and his colleagues have examined whether dietary interventions alone can
alter the disease process in "p53 knockout mice," or those who lack the p53
tumor suppressor gene. When present, this gene guards against uncontrolled cell growth - a
key characteristic of cancer development and progression.
The p53 gene has been shown to be either mutated or absent in more than one-half of
human tumors, and mice with this gene inactivated appear to develop normally but are
highly susceptible to spontaneous tumor development at a young age.
According to Dr. Hursting, his group's research - in collaboration with investigators at
the National Cancer Institute - shows that placing these mice on a calorie-restricted
diet, subjecting them to a one-day per week fast, giving them antioxidant food components
or anti-inflammatory agents can increase the length of time before cancer develops
compared to mice who had no dietary modifications.
"This was the first demonstration that one could alter tumor development in
p53-deficient mice through dietary intervention," he says. "With this knowledge,
we are now focusing on understanding the molecular mechanisms of these cancer preventive
effects and how they can offset people's susceptibility to cancer."
Other studies provided new clues to the question concerning genetic susceptibility to
cancer-causing agents and disease development. Several faculty members in epidemiology are
studying why only a fraction of smokers develop lung cancer.
In two separate studies involving lung and head and neck cancer patients, the ability to
repair DNA damage was found to affect the disease process in cancer, say study
investigators Dr. Qingyi Wei, Dr. Xifeng Wu and Dr. Margaret R. Spitz, chair of the
Department of Epidemiology and holder of the Mesa Petroleum Co. Professorship in Cancer
Prevention.
Their research demonstrated that the capacity for DNA correction was reduced in patients
with these diseases, but was not affected in healthy people.
"The DNA structure must be intact to function properly," says Dr. Wei,
assistant professor of epidemiology. "Through our research, we've found that this
lessened ability of DNA to repair itself results from either an inherited genetic
abnormality or an acquired genetic defect, which can result from exposure to various
carcinogens such as tobacco or alcohol."
The epidemiology research teams collaborated with Dr. Waun Ki Hong, chair of the
Department of Thoracic/Head and Neck Medical Oncology; and Dr. Susan Eicher, assistant
professor of head and neck surgery, for these investigations. Dr. Hong holds the Charles
A. LeMaistre Chair in Thoracic Oncology given by W. A. "Tex" and Deborah
Moncrief, Jr.
Other efforts to answer this question also were pursued last year, with Dr. Hursting and
his team capitalizing on the susceptibility of the p53 knockout mice to low-dose, chronic
carcinogen exposure to develop chemically induced models that more closely mimic the human
carcinogenesis process.
"The body's responses to carcinogens depend largely on the individual's genetic
susceptibility to that agent," Dr. Hursting says. "These mice provide a useful
system for studying this type of gene-environment interaction."