Cancer control in susceptible groups: opportunities and challenges.

Cancer mortality rates in the United States have risen throughout most of this century, and a downward trend has just emerged in recent years. Nevertheless, it is predicted that cancer will soon be the leading cause of death among Americans. To gain new knowledge of etiology, we have studied persons at highest risk as human models of cancer susceptibility. Clinical observations at the bedside are used to generate etiologic hypotheses that are tested in epidemiologic studies. Companion laboratory studies can identify biologic mechanisms of predisposition. Data show that inborn mutations in cancer-predisposing genes, such as BRCA1 and BRCA2, markedly increase the risk of cancers at unusually early ages. Increasing numbers of these highly penetrant genes are being identified. These discoveries have created new opportunities for genetic testing to identify cancer-prone individuals. Individuals found to be carriers can be offered counseling to avoid environmental exposures that further elevate risk, intensive medical surveillance for early detection, participation in chemoprevention trials, and prophylactic surgery to remove at-risk tissues. However, genetic knowledge can have adverse effects, including psychologic distress, social stigmatization, and loss of health insurance. Research is needed to maximize benefits and minimize risks to the susceptible populations. Professional and public education can promote appropriate use of genetic data, and legislation may be required to prevent discrimination. Knowledge of these highly penetrant genes can be extended to common polymorphisms that modify cancer risk associated with exposures to environmental carcinogens.