Skip to main content
An official website of the United States government

How a Hereditary Multicancer Syndrome Was Discovered

, by DCEG Staff

Frederick Li and Joseph Fraumeni

Frederick Li and Joseph Fraumeni, 1991

In the 1960s, Joseph F. Fraumeni, Jr., M.D., and Dr. Robert W. Miller, in what was then the Epidemiology Branch of NCI, began an exploration into the epidemiologic patterns of childhood and familial cancer about which little was known. Their search began with a systematic multicenter study of childhood cancer that suggested an excess of certain congenital anomalies (e.g., aniridia with Wilms tumor) and multiple primary cancers in the same individual (e.g., adrenocortical and brain tumors). At the same time, Dr. Fraumeni began to investigate a series of cancer-prone families that he identified while making rounds at the NIH Clinical Center. These families became the foundation for the DCEG familial cancer registry, which continues to this day. As expected, most of the familial aggregations were confined to a single type of cancer, but a few families were found to have an unusual diversity of tumors that was difficult to explain.

Soon thereafter, a remarkable familial occurrence came to the attention of Dr. Frederick P. Li, a research colleague at NCI. In an almost explosive manner, several members of one family developed a variety of tumors, notably childhood rhabdomyosarcoma and breast cancer, but also other forms of cancer among children and young adults in the line of descent. This observation prompted Drs. Li and Fraumeni to return to the multicenter survey of childhood tumors and expedite completion of a study of children diagnosed with rhabdomyosarcoma. In 1969, they reported their findings in two landmark papers that appeared in the Annals of Internal Medicine and the Journal of the National Cancer Institute. The striking diversity of tumors was at variance with the prevailing notion that familial susceptibility to cancer is usually site- or tissue-specific (see Figure 1).

Pedigree of Family A from the first paper documenting the constellation of tumors in what would later be known as Li-Fraumeni syndrome.

The spectrum of early-onset cancers was clarified in 1982, when Drs. Li and Fraumeni published in JAMA a 12-year prospective study of members of the original four families. There were 16 new cases of cancer, far exceeding expectations based on general population rates. The array of new cancers closely resembled the familial pattern that was initially reported. By the late 1980s, Drs. Li and Fraumeni had assembled 24 families with similar, well-documented manifestations of a multiple-cancer syndrome. A prospective study of all families provided epidemiologic evidence of an excess risk of diverse cancers affecting young people in a dominantly inherited pattern. Breast cancer and soft tissue and osteogenic sarcomas were especially prevalent, but the risks of acute leukemia, brain tumors, and adrenocortical neoplasms were elevated as well. As interest increased in this familial disorder, it generally became known as Li-Fraumeni syndrome (LFS).

As time passed, Drs. Li and Fraumeni collected biospecimens and collaborated with laboratory investigators using a variety of biomarkers to search for an underlying mechanism that might explain the familial susceptibility to multiple tumors. Success was limited, however, until collaboration with Dr. Stephen Friend and Dr. David Malkin at Harvard, along with Dr. Louise Strong at the MD Anderson Cancer Center, uncovered germline mutations of the p53 tumor suppressor gene in five consecutive families. The finding was quickly confirmed and intensified clinical and molecular interest in LFS, particularly because somatic mutations of p53 also were reported in a large proportion of cancers arising in the general population.

The discovery of inherited p53 mutations provided an opportunity for predictive genetic testing and clinical intervention aimed at the early detection and management of tumors in LFS. The finding also brought into sharp focus a series of clinical, psychological, legal, and ethical problems that would likely extend to other cancer susceptibility genes that seemed on the verge of isolation at that time. The issues prompted a series of NCI-sponsored workshops that published recommendations about predictive genetic testing in cancer-prone families.

Participants in the 2010 Li-Fraumeni syndrome workshop included researchers, clinicians, patient families, and advocates.

Over the next two decades, LFS work continued mainly outside of NCI until 2010, when Sharon Savage, M.D., and Phuong Mai, M.D., both of the Clinical Genetics Branch, organized a workshop that brought together researchers, clinicians, and members of affected families. An international consortium was formed to develop effective cancer prevention and risk-reduction strategies for LFS families, provide a platform for developing a support group for LFS families, and pool resources for further research into the biology and genetics of the syndrome. Working with other clinical investigators in the consortium, Drs. Savage and Mai launched a feasibility study to recruit LFS families into a new screening protocol study at NIH designed to identify effective methods for early cancer detection without the use of radiation, which is known to magnify the risk of cancer in p53 gene carriers. Efforts also are being made to understand and manage the psychosocial aspects of this disease among LFS patients as well as their relatives and caretakers. So far, the study has enrolled 118 families at NIH, with many additional families being seen at extramural locations. “Clearly, there is a desire across the LFS community for this type of study,” Dr. Savage said. “Families really want to do something to help understand and ultimately prevent this devastating disease.”

At the end of the workshop, Dr. Strong commented, “In the 1960s, studies of familial cancer generally focused on a single site, such as hereditary breast cancer. The initial description of a familial syndrome involving so many tumor types raised questions about the possibility of referral bias, chance events, or an environmental factor such as an oncogenic virus. It was the perseverance of Drs. Li and Fraumeni over 20 years; the prospective findings; and the convergence of clinical, epidemiological, and biological observations that convinced the medical and scientific community that there was, indeed, a distinctive syndrome of cancer susceptibility. The work of Drs. Li and Fraumeni reflects the power of the multidisciplinary approach of genetic epidemiology and its potential contribution toward a better understanding of cancer etiology and prevention.”