Genetic Alterations in Colorectal Cancer, Comparative Analysis of Deletion Events, and Point Mutations

Although data on genetic alterations leading to the development of colorectal cancer are abundant, no specific genetic alteration, as has been demonstrated for certain rare tumors such as lymphoma, leukemia, or sarcoma, has been shown to be responsible for the development of colorectal carcinomas. The colorectal cancer phenotype undoubtedly originates from an accumulation of different genetic alterations. The nature of these alterations, their order of appearance, and their associations vary greatly from one tumor to another, suggesting that the concept of a unique model of carcinogenesis is not applicable to these tumors. We studied a panel of 40 colorectal tumors in an attempt to identify different carcinoma subsets distinguishable by the pattern of genetic alterations. We examined a series of genetic anomalies frequently implicated in the development of colorectal cancer, including genetic material loss, demonstrated by loss of heterozygosity on chromosome arms 1p, 17p, and 18q; mutations of proto-oncogene K-RAS codons 12, 13, and 61; and gene TP53 mutations, identified by studying the accumulation of the corresponding immunohistochemically detectable protein. Our findings showed an important correlation between the genetic material loss events and an independent distribution of point mutations, which favors the hypothesis of a specific type of genetic instability characterized by the recurrent loss of chromatin fragments implicated in a subset of colorectal cancers.