Genetic events in the development of colon cancer
Colon cancer has been shown to progress through a series of well defined pathological stages. Initially, there is widespread hyperplasia in the colonic epithelium followed by the development of tumours in hyperplastic areas. Progressive stages of small, intermediate and late non-malignant adenomas have been identified leading to malignant carcinoma and finally metastasis.
Oncogenes are activated by genetic changes, mutations or translocations, to an aberrant function, which contributes to cancer development. In cancer process the tumour suppressor genes become inactive, thus losing their “suppressor” function. Tumour suppressor genes are recessive and need to lose both copies by deletion (LOH, loss of heterozygosity), mutation or a combination of both. Familial adenomatous polyposis (FAP) is an inherited disorder predisposing to colorectal neoplasm.
A tumour suppressor gene, adematous polyposis coli (APC) has been isolated from the long arm of chromosome 5 (5q21) and individuals who inherit germ-line mutations in this gene develop hundreds of colonic polyps at an early age. Mutation of one APC allele, resulting in a truncated protein, is thought to be the initiating event in these colon cancers. Sporadic colorectal cancer arises mainly through two distinct pathways. In this pathway, chromosome instability, the initial inactivation of the APC tumour-suppressor gene (chromosome 5q), is followed by the accumulation of alterations in additional oncogenes (k-ras, v-ki-ras Kirsten rat sarcoma viral oncogene, on chromosome 12p) and tumour-suppressor genes (chromosome 18q: DCC, deleted in colorectal cancer; chromosome 17p: TP53, p53 gene).
The second pathway, associated with microsatellite instability (MSI), occurs in 15–20% of sporadic colorectal cancer cases. Alterations have been found to cluster in genes encoding enzymes involved in the repair of DNA mismatches (in particular, hMLH1 and hMSH2). These alterations provide growth advantage and lead to clonal expansion of distorted cells.
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