Familial Factors Frederick P. Li, M.D., a Mary C. Fraser, R.N., M.A. b	Most cancers are caused by a variable mix of heredity and environment (Knudson, 1985). While an inherited defect can lead to cancer clusters in multiple members of certain families, the age at which cancers first appear will differ among these relatives, due in part to environmental triggers (Li et al, 1989). Other cancers, such as lung cancers in cigarette smokers, while caused primarily by external factors, are still influenced by genes which modify an individual's risk of disease. To further our understanding of cancer etiology and risk factors, scientists are currently studying the complex ways in which genes and environment interact. Some ethnic groups apparently possess traits that protect them against specific cancers. For example, chronic lymphocytic leukemia is extremely rare among Asians; Ewing's sarcoma, skin cancers, and testicular cancer are very rare among blacks. Family clusters have been reported for virtually every form of cancer (Li, 1988). In general, close relatives of a cancer patient have twice the usual risk for developing the same type of cancer, but among different cancer families the level of excess risk can vary widely. Familial cancer clusters are often due to inherited factors, but environmental influences, chance association, or a combination of these factors also must be considered. The effect of chance is considerable; within the U.S. population there is approximately a 45 percent lifetime risk of developing cancer, including the common nonmelanoma skin cancers (Li, 1990). Thus, it is not unusual for most families to have at least some individuals with a history of cancer (Mulvihill, 1985). An inherited susceptibility often becomes apparent when cancers of the same body site or organ occur in multiple blood relatives (Lynch and Lynch, 1993). These cancers tend to occur at earlier ages than usual, and often develop in more than one site in a particular organ, e.g., two primary breast cancers in the same breast or one in each breast. Hereditary cancers can also arise in multiple organs, as seen in the Li-Fraumeni syndrome, a disorder characterized by the early onset of breast cancer in mothers of children with leukemia and/or bone and soft tissue sarcomas (Srivastava et al, 1990). In addition, cancer can occur as part of a non-cancerous hereditary disease with diverse features, such as neurofibromatosis. In familial cancers that are triggered by environmental carcinogens, patient education regarding the avoidance of harmful exposures can help prevent or delay the onset of cancer. For example, members of melanoma-prone families who avoid significant ultraviolet radiation exposure can reduce substantially their risk of melanoma. Recent laboratory findings have emphasized the importance of studying cancer-prone families (Benz, 1990). New methods in molecular biology have been used to identify several human cancer genes and to reveal a new class of cancer genes, called tumor suppressor genes or antioncogenes (Friend et al, 1988). These genes normally function by inhibiting the development of cancer. However, when they are damaged they lose their protective effect and cancer arises with greater frequency. The first such inherited cancer susceptibility gene to be discovered was that for retinoblastoma (RB1), a malignant eye tumor which occurs in children (Friend, 1988). Several additional tumor suppressor genes have been identified, predominantly through studies of cancer-prone families with hereditary cancers (Li, 1993). For example, inherited alterations in the p53 gene have been found in the Li-Fraumeni Syndrome (Srivastava et al, 1990). The WT1 gene for Wilms' tumor, the APC gene for colon cancers associated with familial adenomatous polyposis coli, the NF1 and NF2 genes for neurofibromatosis, types 1 and 2, the p16 gene found in some melanoma families and the VHL gene for renal cancer and other tumors associated with von Hippel-Lindau disease have all been recently identified and characterized (Li, in press). Major discoveries within the last year include the identification of BRCA1, a gene for hereditary breast and ovarian cancer, the localization of BRCA2, another breast cancer gene, and mismatch repair genes--such as MLH1 and MSH2 for heriditary nonpolyposis colorectal cancer (Bronner, et al., 1994, Futreal, et al., 1994, Miki et al., 1994). (The function of mismatch repair genes is to prevent DNA from making errors during replication.) Approximately 5 percent of breast or colon cancer patients might carry one or more inherited susceptibility genes. The discovery of these genes has increased greatly the numbers of cancer susceptibility gene carriers who can possibly be identified (Peters, 1994, Offit and Brown, 1994). The primary purpose of identifying gene carriers would be to promote earlier detection of cancer and, since prognosis is correlated closely with stage of disease at diagnosis, increased survivability (Parry et al. 1987, Wattenberg, 1993). However, identifying gene carriers in cancer-free populations is a new concept with many clinical, ethical, legal and psychosocial implications yet to be explored (Lerman et al. 1991, American Society of Human Genetics, 1994, Li et al. 1992). Predisposition testing presents certain advantages when prevention and early detection measures are available. On the other hand, there is a great potential for harm--from loss of insurability and employability, psychological stress, social stigmatization and other adverse consequences. As more and more inherited susceptibility genes are identified, their clinical relevance will require careful evaluation. The challenge to research is to identify testing procedures and guidelines that maximize benefits while minimizing harm (Loescher, 1995).
continue

^a From the Dana Farber Institute, Boston, Massachusetts

^b From the Department of Nursing, Warren G. Magnuson Clinical Center, and the Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Maryland