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."

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