A question of heredity and environment
Frederick Li, MD, had an early lesson in the difficulties of connecting cause and effect in human disease. Working at the National Cancer Institute (NCI) in the late 1960s, he was involved in a study of cancer in chemists. The question was whether they had higher-than-normal cancer rates because of their frequent exposure to chemicals.
Fredrick Li, MD, is exploring the connection between genetic mutations and cancer.
Li and his colleagues found that while the chemists developed certain kinds of tumors more frequently than the general population, the discrepancy couldn't be conclusively linked to chemicals. "I found that lack of definitiveness very unsatisfying," says Li, now director of Population Sciences at the Institute. "With a disease as complex as cancer, it's not always possible to identify all the factors that contribute to its development."
Trying another approach, Li learned of a family in which two children had sarcomas, cancers of connective tissue that are very rare in children. One such case in a family would have been unusual enough; two cases was a true anomaly. The cancers had to be the result, as he puts it, of either "bad luck, a bad environment, or a bad gene." He wanted to know whether a gene was responsible.
He asked one of his mentors, Joseph Fraumeni, MD, of the NCI what he thought about the case; Fraumeni advised him to find other families with the same pattern of sarcomas in children. He arranged for Li to visit hospitals around the country, including Dana-Farber, and review their records for such cases. He found three additional families that had more than one child with a sarcoma. Each family also had several members who had developed breast cancer at an early age.
To Li, four examples seemed too few on which to base an epidemiological study to find a genetic link to disease. (The Nurses' Health Study run by Harvard Medical School, for example, involves many thousands of participants.) He was reluctant to announce such meager data, but, with encouragement, the two researchers published a scientific paper on their findings in 1969. More cases began to trickle in, and soon 24 families were identified.
"Within these families, we found six rare types of cancers that occur at markedly excessive rates," recalls Li, who joined Dana-Farber in 1969. "This was a strong indication that we were dealing with an inherited condition." But which gene or genes were to blame? And, more to the point, how to find those genes amid the 30,000 or so others within the human genome?
Joining the research effort, Steven Friend, MD, a Dana-Farber pediatric oncologist, wondered which gene could be responsible for all the different types of cancers associated with the condition, which had been named Li-Fraumeni syndrome for its discoverers. The most likely candidate was p53, sometimes called the "guardian of the genome."
"It's an exciting time in science when two fields grow independently, and a discovery is made that leads investigators to realize they're working on the same problem."
— Alan D'Andrea, MD
Whenever a cell divides, p53's job is to inspect the genetic material and order repairs if any damage is detected. If such repairs are not made, p53 initiates the cell's death. If p53 itself is damaged, however, that quality control function is partially lost, and the cell may forge ahead with division — damaged DNA or not. When enough of these flaws accumulate, the result can be cancer.
The identification of p53 as the culprit for Li-Fraumeni syndrome made it possible to test members of affected families to determine if they carry an abnormal p53 gene and are therefore at elevated risk for certain cancers. While most families with a history of Li-Fraumeni have an inherited mutation in p53, not all of them do, suggesting other genes may play a role in the condition.
More recently Li and his colleagues have discovered that Li-Fraumeni families are not only at higher-than-normal risk for the six cancers, they appear to be at increased risk for a range of other types of cancers at an early age.
As the understanding of the genetic roots of Li-Fraumeni syndrome has grown, Li and his associates are increasingly driven to find ways of helping people who might develop the condition. If p53 errors could be counteracted by medications, the risk for these rare cancers would drop dramatically.
"Historically, studies of cancer causation focused almost entirely on the environment; it's relatively simple to measure the number of cigarettes a person smokes," Li remarks. "But, until recently, few researchers focused on clinical cancer genetics because the tools, such as DNA chips, didn't exist to probe individual genes.
"A condition like Li-Fraumeni, where the environment is not the major trigger, provides a very clean model for studying the link between genetic mutations and cancer," he continues. "We can generalize and perhaps gain a better understanding of the complex interplay between genes and environment in causing most types of cancers."
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