Epidemiologic analyses have shown that four to six rate-limiting events must occur before a tumor becomes clinically apparent (4,5). The changes that must occur are genetic and/or epigenetic in nature. Most of these events result from somatic mutations that occur infrequently or are induced by carcinogen exposure, and only in aggregate do they lead to the tumorigenic state.
In a seminal series of studies, Vogelstein and his colleagues described a stepwise genetic history of colorectal tumors (6). Since colorectal carcinoma develops intraluminally and tissue is readily available for examination, specific histopathological alterations that occur in cancer development are readily observed in different stages. By studying tissue derived from specific histopathologic stages, ranging from normal colonic epithelium to frank carcinoma, they catalogued genetic alterations specific for each stage, thereby developing a model that dissected an accumulation of separate genetic mutations that could in combination lead to malignancy (7,8).
A vast majority of early adenomatous polyps were found to exhibit an inactivated mutant form of the tumor suppressor gene, adenomatous polyposis coli (APC) (9). Alterations in this gene had been previously shown to be responsible for Familial Adenomatous Polyposis (FAP) (10,11). However, patients with germline mutations of APC have a greater risk for but do not necessarily develop colorectal cancer. In addition to the germline mutation, somatic mutation of the wild-type APC allele must also occur (9,12).
When they investigated intermediate size adenomas, they found that approximately half carry activating mutant RAS oncogenes (6,13). Interestingly, normal colonic epithelium harboring RAS mutations alone, do not lead to neoplasia (14), and these cells may eventually succumb to apoptosis (15), suggesting that other genetic alterations are necessary for RAS mutation to contribute to tumor formation. In a subset of larger
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