Abstract
There has been enormous progress in defining structural alterations of genes common in colonic cancer. Accumulation of mutations and deletions in APC, p53, DCC, and Ki-ras are the sine qua non of the disease, although the roles and interactions of these genetic alterations in the biological and clinical heterogeneity of the disease are not understood. Of even greater interest from the point of view of disease prevention are inherited mutations found in the APC gene and in genes which encode mismatch repair functions, which lead to the high frequency of colonic cancer in familial polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) families, respectively1–6. However, unlike inherited childhood cancers, such as retinoblastoma and Wilm’s tumor, inherited colon cancer takes decades to develop. This can be partially understood in the context of what has been learned regarding genetic alterations in sporadic cancers. For example, one may assume that the inherited mutation supplies the first of a series of genetic alterations, and by so doing reduces the overall time and elevates the probability of accumulating the necessary number of alterations in genes such as those cited above. In the case of FAP, the inheritance of a mutant allele for APC provides one of the key events directly, since mutations in the gene occur somatically in over 70% of human colon tumors, and the mutation is sufficient to initiate development of intestinal tumors in mice7,8. In HNPCC, the situation is more complicated, in that the inherited mutations in genes responsible for DNA mismatch repair fail to repair errors which arise during DNA synthesis at tens of thousands of loci throughout the genome, and it must be presumed that among this plethora of changes there are key genes, again perhaps coincident with some of those mentioned above, which are eventual targets that lead to tumor formation.
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Augenlicht, L.H., Velcich, A., Heerdt, B.G. (1995). Short-Chain Fatty Acids and Molecular and Cellular Mechanisms of Colonic Cell Differentiation and Transformation. In: Diet and Cancer. Advances in Experimental Medicine and Biology, vol 354. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0949-7_12
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