Only over the past two to three decades has direct evidence been obtained to support the proposal that cancer is a genetic disease, although a genetic basis for the development of cancer has been hypothesized for over a century. A present view is that cancers arise through a multistep evolution driven by somatic mutation of cellular genes and clonal selection of variant progeny with increasingly more aggressive growth properties. While molecular genetic studies have provided insights into the pathogenesis of many different tumor types, our understanding of cancer at a genetic level is probably most advanced in colorectal cancer.

Approximately 160,000 cases of colon and rectal cancer were diagnosed in 1994, and more than 45% of these patients will die from their disease, often despite the apparent complete surgical resection of their local disease. These statistics reflect the unfortunate fact that limited progress has been made in the treatment of advanced colorectal cancer with chemotherapeutic agents. In addition, relatively little is known about specific dietary or pharmacologic strategies that will prevent or at least delay the development of colorectal cancer. Nevertheless, despite the present difficulties in the prevention and treatment of colorectal cancer, colorectal tumors have proven to be a rich experimental system for study of the nature, role, and origins of mutations in a common human cancer because of their natural history and the inherited syndromes predisposing to cancer development. The insights gained from these studies have not only shed light on the pathogenesis of colorectal and other cancer types, but should provide a basis for important future advances in our ability to prevent, detect, and treat the disease. Because of the enormous progress that has been made in the study of the genetic alterations present in cancer in general and colorectal cancer in particular, the principal aims of this review will be limited to the following:(i) to summarize the general properties of the genes that are mutated in colorectal cancer, including oncogenes, tumor suppressor genes, and DNA damage recognition and repair genes;(ii) to describe some of the genetic defects present in the germline of those with inherited predisposition to colorectal cancer;(iii) to review some of the somatic mutations that are frequently seen in colorectal tumors; and (iv) to outline the means by which the information gleaned from the molecular genetic studies may be applied to improve the prevention, detection, and treatment of colorectal cancer.