When Dr. Peggy Tucker talks of "funny looking moles," she's not complaining about vermin in her yard. Rather, she's using shorthand for what dermatologists and melanoma experts call dysplastic nevi. In the 1970s and early 1980s, Dr. Tucker, chief of the Genetic Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics (DCEG), and colleagues discovered in studies of melanoma-prone families that this previously unrecognized class of pigmented lesions was strongly related to melanoma risk. Subsequently, Dr. Tucker and colleagues conducted a large-scale case-control study of melanoma risk in the general population. The result: Half of the people with melanoma had dysplastic nevi.

"What we found as a risk marker in families translated directly to the general population," Dr. Tucker says. The finding now has even more import: Annual melanoma incidence in the United States exceeds 50,000 cases, and has tripled in men and doubled in women over the last 30 years. "We still don't have a population estimate of the prevalence of dysplastic nevi," she adds, but the risk conferred by these misshapen moles "gives important information about potential screening for an epidemic cancer."

The discovery of dysplastic nevi is an excellent example of the enormous impact that high-risk families have had on cancer research. According to DCEG Director Dr. Joseph Fraumeni, Jr., a pioneer in family studies research and co-discoverer of Li-Fraumeni syndrome (LFS), the influence of family studies has been far-reaching, especially in the booming area of genomics. "There has been a sea change in the recognition of genetics' importance in cancer induction and progression," Dr. Fraumeni says. "And discovery of the genetic underpinnings of familial cancer syndromes has fueled that shift."

The clinical and epidemiologic patterns that distinguish the hereditary and nonhereditary forms of retinoblastoma (a rare eye cancer in children) provided the foundation for one of the bellwether moments in cancer genetics. In 1971, Dr. Alfred Knudson reported his "two-hit" mathematical model indicating that one genetic mutation is inherited and the second is acquired in the target tissue of hereditary tumors, whereas both mutations of the same gene are acquired in nonhereditary tumors.

Guided by this model, laboratory scientists in 1986 uncovered the first identified tumor-suppressor gene, RB1, in retinoblastoma. That was followed by family-based studies that made it possible, for example, to identify the p53 gene in LFS, the p16 gene in hereditary melanoma, the BRCA1 and 2 genes in hereditary breast/ovarian cancer, the APC gene in familial polyposis, and the mismatch repair genes in familial colon cancer. In line with Knudson's hypothesis, the genetic mutations inherited in familial cancer syndromes have proven to be mechanistically important in the nonhereditary cancers that are much more common in the population. "The observations made in high-risk families," says Dr. Mark H. Greene, chief of DCEG's Clinical Genetics Branch, "have given us a window into the molecular pathogenesis of many cancers."

A Team Effort
Family studies at NCI and other centers were forerunners to the recent wave of collaborative studies linking epidemiology with clinical and laboratory approaches to uncover the causes of cancer and the means of prevention. While this interdisciplinary strategy has provided insights into many hereditary syndromes, adds Dr. Greene, there are questions about some familial tumors that can't be answered by a single group of investigators. "It requires increasingly large numbers of patients," he says, "which means creating collaborations between research groups willing to pool information and resources."

That realization has led the NCI intramural program to participate in a number of coalitions of investigators involved, most recently, in family-based studies of testicular cancer and chronic lymphocytic leukemia.

In the end, Dr. Fraumeni says, "The application of genomic and other emerging technologies to clinical and epidemiologic studies of familial cancer has paid huge dividends in understanding the mechanistic pathways that inform preventive, diagnostic, and therapeutic approaches toward cancer in the general population. At the same time, the findings are providing new clinical options and realistic hope to those high-risk families that have been so devastated by cancer."