From Early Research Themes to the Present

On a door in the office of Joseph F. Fraumeni, Jr., M.D., is a poster containing a Chinese proverb attributed to Confucius. This proverb roughly translates as “When you drink the water, remember who dug the well.”

Dr. Fraumeni is one of those rare individuals who always remembers and honors the mentors and scientific leaders who paved the way. And yet, for the more than 300 people currently in DCEG, Dr. Fraumeni is the one “who dug the well” that initiated their research. For a majority of scientific themes under study across the Division, Dr. Fraumeni conducted seminal work showing the promise of that particular line of research for yielding clues to cancer etiology and prevention. Under his guidance, these research themes have flourished and expanded.

The well-known work on what is now called Li-Fraumeni syndrome laid the foundation for the many studies of familial cancer that Dr. Fraumeni and others have conducted in DCEG. These projects have had a significant impact not only on scientific discovery but also on the clinical management of hereditary cancer syndromes and related conditions. For example, by studying families at high risk for melanoma, DCEG researchers and their collaborators established that dysplastic nevi are precursors to familial and sporadic melanoma, identified the first major susceptibility genes for melanoma, published a clinical pathology atlas for melanoma and nevi, created training videos on how to manage high-risk families and individuals, and developed the first calculator to estimate an individual’s risk of developing melanoma.

Special emphasis is now being placed on determining the biological mechanisms of melanoma susceptibility through genome-wide association studies, exome sequencing, high-resolution array-based comparative genomic hybridization (array-CGH), chromatin immunoprecipitation (ChIP) sequencing (used to analyze protein interactions with DNA), and molecular profiling. The search for high-risk susceptibility genes is under way for several other familial cancers and precancerous syndromes, both common and rare, such as lymphoproliferative disorders; bone marrow failure syndromes; chordoma; osteosarcoma; and cancers of the ovary, lung, testis, and bladder.

In 1967, in the first published report of familial bladder cancer, Dr. Fraumeni described what might be viewed as a forerunner to DCEG’s interdisciplinary investigations of familial cancer. In striving to explain why bladder cancer developed in a man and his three sons, all of whom were smokers, Dr. Fraumeni brought the affected and unaffected family members to the NIH Clinical Center for a study of tryptophan metabolism, which was suspected at the time to play a role in bladder carcinogenesis.

Although the findings proved to be unremarkable, echoes of this approach reverberate in DCEG’s portfolio of studies that use molecular biomarkers to identify mechanisms of cancer susceptibility, including gene-environment interactions in familial and non-familial forms of cancer.

Although studies of genetic susceptibility to cancer remain a major focus in DCEG, Dr. Fraumeni and his colleagues began, in the 1960s, a series of investigations designed to identify the role of environmental and occupational exposures in cancer etiology. Most informative was the landmark report in 1969 of a study of copper smelter workers in Montana that revealed a significant dose-related excess risk of lung cancer associated with exposure to inorganic arsenic. This was the first indication that inhaled arsenic is a respiratory carcinogen, and the finding was sufficiently robust to prompt the Occupational Safety and Health Administration to set new federal occupational exposure limits.

In 1975, interest in environmental cancer was further sparked by the publication of the first NCI cancer mortality atlas, which mapped the death rates for cancer across the United States at the county level. In view of the earlier report that occupational arsenical exposure is carcinogenic, it was not surprising to find elevated rates of lung cancer in counties with arsenic-emitting smelters, but further studies with fellow NCI researcher Dr. William Blot revealed that the elevated risk extended beyond the workforce to the residential population exposed to arsenical pollution emitted by the plants.

The most dramatic geographic pattern for lung cancer was seen in the string of U.S. counties with markedly elevated rates along the southeast Atlantic coast. In a series of case-control studies conducted in this area with Dr. Blot and Robert N. Hoover, M.D., Sc.D., Director of the Epidemiology and Biostatistics Program, the researchers found that the excess lung cancer was due to asbestos exposures associated with short-term shipyard work that took place during World War II.

In recent decades, the expanding portfolio of occupational and environmental studies in DCEG has been strengthened by increasingly sophisticated methods of exposure assessment to identify specific carcinogens and quantify the risks involved. The studies continue to have an impact on regulatory and public health policies, as illustrated by recent studies of workers exposed to diesel exhaust, formaldehyde, benzene, trichloroethylene, and agricultural pesticides.

The initial publication of the U.S. cancer maps was soon followed by similar atlases from other countries. Most remarkable was geographic clustering of various cancers in China, motivating Drs. Fraumeni and Blot, along with their colleagues, to collaborate with Chinese scientists in a series of epidemiologic studies in high-risk populations of various cancers. In efforts to explain the elevated rates of lung cancer among nonsmoking women in northern China, case-control studies implicated indoor air pollution from coal-burning stoves and cooking oil volatiles in poorly ventilated homes.

More recent studies have focused on Xuan Wei province, which has the highest incidence of lung cancer in China, providing evidence for the International Agency for Research on Cancer to classify coal-combustion products as an established carcinogen. The research has extended to other high-risk populations in China and Asia, where genetic susceptibility markers for lung cancer have been identified through collaborative genome-wide association studies. Other ongoing studies instigated by geographic patterns include investigations of bladder cancer in northern New England; gallbladder cancer in Chile; and esophageal cancer in high-risk areas spanning the globe, including China, Iran, Kenya, and Brazil.

When Dr. Fraumeni arrived at NCI in 1962, he was asked to evaluate the potential cancer risk associated with exposure to polio vaccine that had been inadvertently contaminated with simian virus 40 (SV40), known to be carcinogenic in laboratory animals. Public health concern was intense, but Dr. Fraumeni’s report in JAMA in 1963 revealed no evidence of excess cancer risk among children who were exposed to those early batches of vaccine that contained SV40. When concern over SV40 resurfaced in the 1990s due to its apparent detection in human mesothelioma, brain, and other tumors, DCEG studies found that cancer risks did not increase among newborns and others who had received the SV40- contaminated vaccine.

In addition to studies of the role of infectious agents in cancer risk, most notably HIV/AIDS and human papillomavirus, recent attention has centered on the impact of immunological alterations and inflammatory processes in cancer susceptibility.

A series of epidemiological studies was launched to evaluate the cancer risk following immunosuppression related to underlying medical conditions and their treatments, including the first study, with Dr. Hoover, that quantified the excess risk of lymphoma and other cancers among solid organ transplant recipients. This report, published in The Lancet in 1973, became a forerunner of current record-linkage studies of transplant-related cancers that encompass the majority of the U.S. population.

Another long-standing interest of Dr. Fraumeni and his colleagues has been the risk of cancer following chemotherapy, hormonal therapy, and radiotherapy, including their interactions with genetic, immunological, and lifestyle factors. These studies became the cornerstone of the expanding portfolio of DCEG research in radiation and hormonal epidemiology.

The studies described here represent only a few of Dr. Fraumeni’s early wide-ranging research projects that, in retrospect, anticipated the next half century of cancer epidemiology in DCEG and elsewhere. His interdisciplinary approach to studies of high-risk populations continues to inspire lines of research across DCEG and around the world.