Oncogenes

In 1971 Alfred Knudson Jr. proposed that retinoblastoma resulted from at least two separate genetic defects. In families with a high risk of retinoblastoma, the first defect is inherited and the second occurs sometime during childhood. This came to be known as Knudson's "two-hit theory." Subsequent research has shown that most, if not all, cancer arises from multiple genetic events, or "hits."

In many cancers, more than two hits are required. Bert Vogelstein and coworkers first showed this in colon cancer in the late 1980s. Colon cancer begins with a precancerous stage, called a benign polyp. Left untreated, this will progress through successively more cancerous stages until it becomes an aggressive carcinoma. Vogelstein's group found that progression of colon cancer through these different stages was associated with the acquisition of genetic changes in oncogenes such as Ras, as well as in a number of different tumor suppressor genes, including p53. Together, sequential activation of different oncogenes along with inactivation of various tumor suppressor genes drive the step-wise progression of precancerous cells to highly malignant tumors.