The pre-malignant lesion: the adenomatous polyp
There is abundant evidence that virtually all colorectal carcinomas begin as adenomatous polyps.
In a number of studies, colonic polyps have been left in situ and the follow up of these patients showed variable natural history from complete regression, increase in size or progression to carcinoma11-13.
Histological studies have revealed a spectrum of dysplasia within adenomatous polyps up to carcinoma-in-situ and it is not uncommon for true invasive carcinomas to have associated adenomatous tissue14. In a study of post mortem examinations of the colon, the population with the highest proportion of adenomas was observed in the area with the highest incidence of colonic cancer. Also, the segmental distribution of adenomas within the colon was found to be similar to the site distribution of cancer15.
The transition from benign adenoma to colorectal cancer is thought to have a long natural history of between 10 and 35 years 13,16. It is estimated that the annual conversion rate of a polyp to a cancer is approximately 0.25%17.
The adenoma / carcinoma sequence
Colorectal carcinogenesis has long been thought to be due to a stepwise accumulation of cellular mutations18. Studies of adenoma and carcinoma cell types have revealed that there is a monoclonal expansion of a single or small number of colonic epithelial cells19,20. Much research has been done to identify mutations in oncogenes, tumour suppressor genes or DNA repair genes that confer a growth advantage in these neoplastic cells21.
A genetic model for the sequence of adenoma transformation to carcinoma was proposed by Vogelstein22 which in light of recent advances in molecular genetics has become modified to include additional genes that contribute (Figure 3).
Figure 3. Genetic model of colorectal carcinogenesis
It is thought to be the accumulation rather than the order of genetic mutations that is critical to the development of colorectal cancer23.
Cellular hyperproliferation is a preceding step to adenoma formation and is associated with loss or mutation of both alleles of the adenomatous polyposis coli (APC) gene on chromosome 5q24. Inherited mutation in this gene gives rise to familial adenomatous polyposis (FAP) which is typified by hundreds and occasionally thousands of adenomatous polyps25. The APC gene is a tumour suppressor gene which prevents uncontrolled epithelial cell proliferation. Mutation results in a truncated APC protein that fails to bind to ß-catenin, which in turn fails to promote cell adhesion via the calcium dependent cell surface adhesion molecule E cadherin 26.
The over expression of the cyclo-oxygenases (COX 1 and COX2) catalyses the conversion of arachidonic acid to prostaglandin H2 and other derivatives, e.g. malondialdehyde, which is itself mutagenic, promoting further polyp proliferation 27. This explains why the non-steroidal anti-inflammatory drugs, which inhibit the cyclo-oxygenases, have been postulated as possessing a potential therapeutic role in the prophylaxis of colorectal cancer 28.
A significant loss of DNA methyl groups has been shown to occur early in colorectal tumourogenesis29. Hypomethylation interferes with chromosome precipitation and mitotic separation30 resulting in increased frequency of genetic alterations.
Approximately 50% of colorectal cancers31,32 and adenomas larger than 1cm22 have been found to exhibit mutation in the K-ras oncogene. This mutation is present from the intermediate stage (>1cm, mild & moderate dysplasia) of adenoma formation and therefore probably represents an initiating stage for adenoma progression21.
Allelic and chromosomal losses occur frequently in colorectal cancer33,34. This can result in loss of regions that code for tumour suppressor genes. Allelic loss of chromosome 18q occurs in more than 70% of carcinomas22 and 50% of late adenomas. In this area, the tumour suppression gene DCC (deleted in colorectal cancer) is located. This gene encodes a cell surface-localized protein35 and is thought to be involved in cell adhesion36 and its preservation is associated with the majority of mucinous colorectal tumours37 suggesting a function in cellular differentiation or phenotype modulation.
Similarly, the p53 gene located on chromosome 17p38 frequently exhibits allelic loss (also termed loss of heterozygosity). This occurs in approximately 75% of cases of colorectal cancers22,39 but infrequently at the adenoma stage40. In addition, somatic mutations in the remaining p53 allele have been regularly observed in keeping with the proposed function of p53 as a tumour suppressor gene38,41. Thus, mutation in one allele coupled with loss of the other appears to be tumourogenic and an important step in the transformation of adenoma to carcinoma.