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Frederick P. Li, M.D., pioneer in genetic causes of cancer, including Li-Fraumeni Syndrome, who had his start at the NCI, dies

, by DCEG Staff

by Jennifer K. Loukissas, M.P.P.

Frederick P. Li, M.D., a pioneer in establishing genetic risk factors for cancer, and long-time collaborator with the Division of Cancer Epidemiology and Genetics (DCEG), passed away on June 10, 2015, at his home in Brookline, MA. As a young clinician Dr. Li joined the Epidemiology Branch of the National Cancer Institute, what is now DCEG, as a Commissioned Officer in the U.S. Public Health Service.

Frederick Li and Joseph Fraumeni.

Dr. Li is perhaps most widely known for his contribution to the discovery of the cancer predisposition syndrome named for him and his collaborator, former DCEG Division Director Joseph F. Fraumeni, Jr., M.D. The two identified what came to be known as Li-Fraumeni Syndrome (LFS) from the study of a group of families with an unexpected constellation of tumors occurring at very young ages.

In 1990, using biological samples carefully collected from those families, colleagues of Li and Fraumeni discovered that germline mutations in the TP53 tumor suppressor gene cause LFS. This finding aroused considerable interest in the condition, particularly since mutations of TP53, the so-called guardian of the genome, were known to occur in a high percentage of cancers in the general population. Dr. Li took the lead in planning the next generation of studies, which included organizing a series of workshops in which the syndrome served as a prototype for developing recommendations about predictive genetic testing and interventions in cancer-prone families.

Their first description of LFS families was published in 1969 in the Annals of Internal Medicine. The title of the article was “Soft-tissue sarcomas, breast cancer, and other neoplasms: A familial syndrome?” According to Dr. Fraumeni, the two spent more time debating the title than writing the paper, “Fred thought we should be conservative and insert a question mark, and he prevailed. But he was more confident later that year when we presented more data in The Journal of the National Cancer Institute. The paper was called ‘Rhabdomyosarcoma in children: Epidemiologic study and identification of a familial cancer syndrome’ (with no question mark).”

Reflecting upon his first meeting with Dr. Li, Dr. Fraumeni recalled, “Fred was different from the many young physicians who were flocking to NIH at that time. His background in clinical medicine was matched by a passionate interest in public health. He seemed a natural for epidemiology, and his intellectual curiosity and productivity were evident from the very start.”

In recognition of their discovery of LFS and the identification of the gene responsible, Li and Fraumeni were jointly awarded the Charles S. Mott General Motors Prize in 1995.

Among his many efforts at NCI, he successfully mapped a gene in kidney cancer families, identifying a chromosomal translocation associated with elevated risk for the disease. He was instrumental in launching the study of cancer survivorship, leading efforts on risk for second malignancies after childhood cancer. Dr. Li was a key member of the original Late Effects Study Group and later the Childhood Cancer Survivor Study. He also initiated the NCI Retinoblastoma Follow-up Study, a cohort of retinoblastoma survivors that DCEG investigators continue to follow.

As surprising as it may seem in today’s era of precision medicine, which often relies on an analysis of genetic factors in the patient and in tumor tissue, at the time of the discovery of LFS genetics was outside mainstream cancer research, and family studies were on the fringe. During that period the research priority was on the study of tumor viruses. In addition, there was also a prevailing dogma that any familial tendencies to cancer were site-specific, so that families with different forms of cancer were thought to represent the play of chance, or referral bias, or possibly an environmental factor.

“Fred had a knack for making important clinical and epidemiological observations, and taking them to the next level. This often meant overcoming the considerable challenge of bringing together experts from multiple disciplines. [We] were drawn not only to the scientific ideas he generated, but also by his friendly, calm, and thoughtful demeanor, as well as his generosity of spirit,” said Dr. Fraumeni.

Dr. Li helped found a free clinic in Boston’s Chinatown in the late 1960’s where he worked for years. “He was very concerned about social justice issues and felt it important to ‘give back’ to those with fewer resources,” said Margaret Tucker, M.D., another of Dr. Li’s DCEG collaborators. “He was also involved in the early delegations to China, the ‘opening up’ of U.S.-China relations, and helped to develop their cancer research programs.”

As Dr. Li’s career blossomed at Dana-Farber and Harvard, his focus extended to several other hereditary cancer syndromes, the study of late effects of cancer and its treatment, issues of cancer survivorship, preventive strategies in high-risk populations, and, more recently, cancer control research in Asian-American and other minority populations.

Read more about Dr. Li

New York Times: Frederick P. Li, who proved a genetic cancer link, dies at 75

Boston Globe: Dr. Frederick P. Li, 75; helped prove genetic cancer link