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Genetic Risks Shape Cancer Prevention Options

By Jennifer Michalowski

Speaking recently at the second annual Advances in Cancer Prevention Lecture, Dr. Frederick P. Li addressed the topic of identifying and caring for high-risk individuals. His focus was the impact of genetics on cancer risk.

"There is a lengthy chain of events that has to precede any successful intervention," said Li, vice chair for population sciences in the department of adult oncology at the Dana Farber/Harvard Cancer Center, professor of clinical cancer epidemiology at Harvard School of Public Health, and professor of medicine at Harvard Medical School.

The first essential step leading to intervention, he said, is an understanding of the causes of disease. He emphasized that while recent discoveries have helped in the identification of persons at high risk, determinants of which individuals will develop cancer often remain unknown.

Dr. Frederick Li (r), who gave the second annual Advances in Cancer Prevention Lecture recently, accepts plaque from NCI's Dr. Douglas Weed.

"Cancer is a complex topic, and it's going to get more complex," he said.

Comparing the potency of hereditary and environmental risk factors for cancer, Li made clear the hazards of some cancer susceptibility genes. Those born with defects in genes associated with colon cancer or retinoblastoma (a childhood eye cancer) have a 90 percent chance of developing cancer in their lifetime. In comparison, environmental factors such as prenatal exposure to the carcinogen DES or exposure to 1 gray of radiation translates into a risk of only 0.1 percent each year.

Li told of his own studies of Li-Fraumeni syndrome, which played a key role in the understanding of the risk associated with such genes. In 1969, Li documented cancer cases in four families. These families had an unusually high incidence of six types of cancer: soft tissue sarcoma, breast cancer, osteosarcoma, brain tumor, acute lymphocytic leukemia, and adrenocortical carcinoma. Many of the family members developed cancers at a young age.

Li and his colleague Dr. Joseph Fraumeni (now chief of NCI's Division of Cancer Epidemiology and Genetics) published a paper in the Annals of Internal Medicine proposing a hereditary component of these cancers, and immediately began to receive calls about similar cases across the country. Eventually, they identified 24 cancer-prone families that fit the description of Li-Fraumeni syndrome. Li also began to hear from the patients in his original report, who called to tell him that additional cancers had been diagnosed in their families.

"By this time it was very obvious that the cancer occurrences were not due to bad luck," Li said. "There was something terrible going on." Further evidence of an alarming phenomenon came when Li followed patients who survived their primary cancers and learned that those individuals had an extraordinary propensity to develop second and third cancers.

Convinced that there was a hereditary component to these families' cancers, the researchers' next step was to search for the responsible gene. In the face of a seemingly endless pool of cancer-related genes, the task appeared overwhelming. However, when the search was narrowed down to genes involved with all of the six cancers, the p53 tumor suppressor stood out.

Investigation of patients with Li-Fraumeni syndrome revealed that they had been born with a mutated copy of the gene.

Many years of further studies yielded even more surprises. The most recent of these, Li said, was the finding that inherited mutations in the p53 gene appear to predispose individuals to an even wider range of cancers than previously thought. Although the frequencies of these additional cancers — lung, stomach, colorectal, lymph and ovarian — are not necessarily higher in Li-Fraumeni patients than in the general population, those born with p53 mutations developed these cancers at an unusually young age.

How can knowledge of heritable susceptibility affect patient care? Li is studying how genetic testing influences patients' health care decisions. In a study following women who have been tested by their local physician for inherited mutations in the genes BRCA1 and BRCA2, which increase breast and ovarian cancer risk, Li has found that 90 percent of the participants are satisfied with their decision to undergo testing. After learning the results of their tests, more than half of the women said they were considering prophylactic surgery, and a similar number were considering chemoprevention.

Prophylactic surgery, chemoprevention, and targeted screening are all interventions that can be employed once individuals have been identified as having a high risk, but Li cautioned that these strategies are not appropriate for every cancer. "The opportunities for intervention vary considerably with the gene involved," he said. For example, surgery and chemoprevention are possibilities for those at risk of breast or colon cancer, whereas heightened surveillance is currently the best option for those at risk of kidney cancer. For those with p53 mutations, Li said, even surveillance is difficult, as the increased cancer risk pertains to many organs.

Li concluded his talk by noting the last century's successes in disease control. Defeat of polio, rubella, and malaria in the U.S. and other developed nations, he asserted, could all be attributed to successful prevention campaigns.

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