HEALTH

Frederick P. Li, Who Proved a Genetic Cancer Link, Dies at 75

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Frederick P. Li was one of the doctors who discovered a genetic condition in which cancer was passed on from generation to generation.Dana-Farber Cancer Institute 

Dr. Frederick P. Li, who helped prove to a doubting medical establishment that heredity and genetics play a major role in some forms of cancer, died on June 12 at his home in Brookline, Mass. He was 75.
His wife, Dr. Elaine Shiang, confirmed his death and said the probable cause was Alzheimer’s disease. Dr. Li had dementia for a number of years and retired in 2008 from the Dana-Farber Cancer Institute in Boston, where he had worked for more than 30 years.
Dr. Li, who was also a professor at Harvard’s medical school and its school of public health, was best known for research that he began in the 1960s at the National Cancer Institute with Dr. Joseph F. Fraumeni. They discovered four families that, Dr. Fraumeni said in an interview, were “loaded with cancer.” Generation after generation, family members were struck down by different forms of the disease, often when they were children or young adults. Some who survived one type of cancer later developed another.
“It was devastating,” Dr. Fraumeni said, adding that in that era “we knew almost nothing about the cause of cancer.”
As the two researchers gathered information, the detailed family trees they drew were dotted with grim, shaded symbols indicating people living with cancer and those who had died of it. The same pattern of disease emerged again and again, suggesting that a dominant gene, passed from parent to child, was predisposing family members to various cancers.
The doctors first described their findings in the journal Annals of Internal Medicine in 1969. The title of their report included the phrase “A Familial Syndrome?” Dr. Li insisted on the question mark, Dr. Fraumeni said, because he did not think they had enough data to state their hypothesis as a fact.
They found more families like the first four, and confirmed their suspicions. The condition they described, which came to be called the Li-Fraumeni syndrome, is rare and dreaded, because people who have it are almost sure to develop cancer.
When the researchers identified the syndrome, they did not know which gene caused it. They stored blood samples from the affected families in the hope that future research would find the answer.
“We thought genetic factors were involved,” Dr. Fraumeni said. “We thought it was an opportunity to search for an underlying mechanism that might apply to a wide variety of cancers.”
Initially, their findings were met with skepticism, Dr. Fraumeni said. Viruses and environmental factors like air pollution, occupational exposures and diet received more attention than genetics as potential causes of cancer.
But the scientific landscape was changing fast.
“In the 1980s, the technology became available to look for susceptibility genes,” Dr. Fraumeni said.
In 1990, researchers collaborating with Dr. Li and Dr. Fraumeni identified the genetic defect responsible for many cases of the syndrome. It was an inherited mutation in a gene called TP53 — a gene that, in its normal state, acts as a “tumor suppressor” and helps to prevent cancer. It is sometimes called the guardian of the genome. 
Mutations in the same gene are also involved in many types of cancer that are not part of the Li-Fraumeni syndrome, so studying families that have the syndrome can yield information about cancer biology that may have broad implications, Dr. Fraumeni said.
Dr. Li had great compassion for people with a genetic predisposition to cancer, and worked to find ways to help them prevent the disease or detect it early. He tracked cancer patients carefully to gauge the risk of subsequent tumors. He helped determine that people with the Li-Fraumeni syndrome were particularly sensitive to radiation, and that using it to treat their tumors could increase their risk of developing additional cancers.
“He was also very sensitive to the medical and ethical aspects of how genetic discoveries would impact patients and families,” said Dr. Kenneth Offit, chief of the clinical genetics service at Memorial Sloan Kettering Cancer Center in New York.
Dr. Li quickly recognized that once a genetic test for Li-Fraumeni syndrome became available, families would face tough questions. Did they want to know? Should children be tested? If they got bad news, what could they do about it? If a health insurer got the results, would the family be denied coverage? The same questions came up when other cancer-related genes were found, like the BRCA mutations that increase the risk of breast cancer.
“Fred Li was a true pioneer in the field of cancer genetics who anticipated most of the challenges we later faced,” Dr. Offit said.
Dr. Li was also a founder of a clinic for immigrants in Boston’s Chinatown, and he sometimes worked there at nights, taking care of patients for no money.
Frederick Pei Li was born in Canton, China, on May 7, 1940. He had three sisters and a brother. His father, Han Hun Li, was a general in the Chinese Army and fought in the Second Sino-Japanese War. His mother, Chu Fang Wu, organized schools and orphanages for war widows and children in China. The family immigrated to the United States when Dr. Li was 7, and opened a Chinese restaurant in White Plains, N.Y.
Besides his wife, Dr. Li is survived by a son, Andrew; two daughters, Margaret and Irene; three sisters, Virginia Li, Angela Li-Scholz and Tina Li; and two grandchildren.
Dr. Li left high school early and enrolled at New York University when he was 16, earning a degree in physics. He studied medicine at the University of Rochester, earned a master’s degree in demography from Georgetown University and went to work at the National Cancer Institute in 1967. In the early 1970s, still employed by the institute, he was sent to Dana-Farber as a medical officer in epidemiology.
Dr. David G. Nathan, a former president of Dana-Farber, said Dr. Li had been sent there as part of an effort by the institute to bring more scientific rigor to cancer research.
“We’re all sitting there rather stupidly at Dana-Farber, and in walks Fred Li,” Dr. Nathan said. “And he says: ‘I’m for free. You don’t have to pay me.’ ”
Dr. Li transformed the institute, Dr. Nathan said. He taught doctors how to conduct studies, how to assess risk, how to recognize patterns of disease.
“He had a high gut instinct about what might be,” Dr. Nathan said. “Some people don’t do science very well because they don’t really know what to study. They kind of wander around, but they don’t go to the core. Fred Li liked to go to the core.”