Mary B Daly

As we enter the 21st century, we are witnessing a historic transition in science that will reveal the genetic basis of common medical conditions and have an enormous impact on biology, medicine, health care, and society. The role of genetics in understanding and treating cancer has traditionally been limited to the observation of cytogenetic abnormalities in certain tumor types. With the recent stimulus of the Human Genome Project, new opportunities to define all cancer in genetic terms are emerging. Efforts to characterize the several classes of genes involved in the transformation and growth of cancer cells have not only advanced knowledge of the genetic basis of cancer but also stimulated the development of sophisticated high throughput technologies that open a new generation of opportunities for the next decade of clinical research and application. Molecular genetic analysis will permit the identification of cancer susceptibility patterns decades before the onset of symptoms or the appearance of disease. The impact of this genetic revolution will shape the practice of medicine, and in particular, the practice of oncology, in many ways. The growing appreciation of the molecular basis of carcinogenesis will have clinical applications in understanding cancer etiology and assigning more precise estimates of risk; in tailoring screening and prevention approaches to populations at defined levels of risk; in improving accuracy of diagnosis and prognosis based on molecular profiles; and in the rational design of therapeutic modalities based on molecular targets.

Although the grouping of site-specific cancer clusters in some families has been recognized for decades, it was not until the past few decades, with the identification of genes such as BRCA1 and BRCA2, that hereditary patterns of cancer could be definitively linked to discrete germ-line mutations. Although hereditary cancers account for only 10% of all cancers, the identification of these genes and the attention devoted to these discoveries have heightened awareness of the genetic contribution to cancer in general among both the medical profession and the lay community and have provided a means to begin to recognize individuals and families with an increased genetic risk of cancer.

Because deleterious mutations in genes associated with hereditary cancer syndromes diagnose a risk for cancer, not the disease itself, knowledge of germ-line cancer susceptibility genes has stimulated intense interest in preventive strategies that may be employed to alter an individual's risk and that of his or her family members. Studies are under way to understand the functions of cancer susceptibility genes and how their alteration contributes to carcinogenesis. Gene-gene and gene-environment interactions are being explored to understand the significant variation in penetrance of these genes. This work is likely to elucidate the causal mechanisms of the traditional epidemiologic factors associated with cancer that will have implications for the more common sporadic forms.

This chapter explores the application of the rapidly expanding field of genetics to genetic screening and counseling for hereditary cancer syndromes in the clinical setting.

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