Genetic Basis of Cancer Progression

Abstract

The current paradigm for the development of cancer is that it is a genetic disease, with the malignant phenotype resulting from an accumulation of genetic alterations. This model was first postulated by Cavenee et al. (1) and further developed by Fearon and Vogelstein (2). In the simplest situation of a hematologic neoplasm, such as chronic myeloid leukemia (CML), neoplasia arises as a direct result of the formation of the Philadelphia chromosome (1). This primary aberration is observed recurrently in CML, and the onset of the more aggressive acute phase of the disease is usually heralded by the acquisition of secondary chromosomal changes (3). Many hematologic neoplasms and sarcomas are characterized by the presence of consistent primary chromosomal rearrangements. However, for most carcinomas, a more complex pattern of acquisition of genomic aberration takes place. An advanced carcinoma may have undergone multiple genetic alterations involving both simple mutations in tumor suppressor genes and oncogenes, as well as extensive karyotypic aberrations. Genetic changes are accompanied by a spectrum of phenotypic changes, and, as the number of genetic aberrations increases, there appears to be a more marked histologic phenotype. Through studies of colon cancer, we understand that colorectal neoplasia arises as a result of the mutational activation of oncogenes coupled with the mutational inactivation of tumor suppressor genes (for a review see ref. 2). It is believed that the total number of genetic changes, rather than the sequence in which they occur, is a primary factor in the development of malignancy. Vogelstein and coworkers found that at least five distinct genetic events were required for colon cancer to develop (2). In this malignancy, the specific genetic changes that lead to the production of invasive carcinoma have been clearly identified: the combination of adenomatous polyposis coli (APC) gene mutations; methylation status alterations; K-ras mutations; DCC (deleted in colon cancer) gene mutations; and p53 mutations. Invasive carcinoma has more genetic alterations than a benign lesion like an adenoma, and, in turn, an adenoma has more genetic alterations than histologically normal epithelium (Fig. 1). This particular model has guided much of our current thinking about how cancer arises.