Benign adenomatous polyps (adenomas) of the lower gastrointestinal tract are clinically important because about 5% develop into carcinoma. In fact, many colorectal cancers are believed to begin as benign polyps that undergo malignant transformation over periods ranging from years to decades. Large-bowel polyps may also be clinical clues to inherited forms of colorectal cancer. The commonest of such polyps are those of familial adenomatous polyposis, in which typical cases with wall-to-wall polyps have a lifetime risk of colorectal cancer approaching 100%. Hamartomatous polyps (ie, those in juvenile polyposis and Peutz-Jeghers syndromes) are associated with rare inherited forms of colorectal cancers.

The gradual transformation of benign adenomatous polyps into dysplasitic lesions and ultimately to invasive cancer is known as the adenoma-carcinoma sequence. Colorectal cancers are believed to develop through two molecular pathogenetic pathways--- ie, chromosomal instability and microsatellite instability. About 80% of all colorectal cancers are aneuploid---ie, they have extra or missing chromosomes. The remaining tumours are diploid but have DNA microsatellite instability, the result of acquired or inherited DNA mismatch repair deficiency. The visible changes that appear when a benign polyp becomes malignant accompany a sequence of underlying genetic mutations that results ultimately in unbridled cell proliferation and metastatic behaviour. The genetic changes in colorectal cancer are not random. Instead, in most cases only a small number of genes are mutated. These are shown in the accompanying table.

Gene	Class	Frequency in colorectal cancer
APC	Tumour suppressor	75 - 80%
p53	Tumour suppressor	60 - 70%
K-Ras	Oncogene	40 - 50%
	Tumour suppressor	25 - 30%
MLH1 & other DNA mismatch repair genes	Tumour suppressor	15% (often silenced by methylation)
Smad4	Tumour suppressor	10 - 30%
DCC	Tumour suppressor	> 10%
	Oncogene	2 - 10%
Smad2	Tumour suppressor	< 5%
N-Ras	Oncogene	< 5%
HER-2/NEU	Oncogene	< 5%

There seems to a temporal sequence in which genes mutate in colon carcinogenesis. APC gene mutations occur early and can be detected even in small, clinically benign polyps. Mutations in the intermediate part of the temporal sequence include mutations of K-Ras, which are common in larger polyps, which in turn are at higher risk of malignant change than are small polyps. Loss of p53 gene function occurs even later. These genetic mutations enable cells to embark on unregulated proliferation (through activated oncogenes and/or inactivated tumour-suppressor genes), to escape apoptosis, and to generate malignant clones that commonly have the capacity to metastasise to other tissues.

The molecular biology of colorectal cancer illustrates several principles of basic cancer biology. Several (possibly >10) mutations are required for cancer to develop. These mutations take many years to accumulate. The cancer-cell genome is unstable. Each type of cancer has a characteristic repertoire of genetic lesions (i.e., cancers are molecularly distinct). Identification of cancer-critical genes is essential for developing superior methods of diagnosis and treatment of cancer.

Benign adenomatous polyp of the colon: tubular glands lined by epithelium with low-grade dysplasia, confined to the mucosa.

Adenocarcinoma of the colon: irregular complex glands lined by severely dysplastic epithelium with invasion into the submucosa (arrow)

A/Prof. Kon Oi Lian Head Division of Medical Sciences

Dr Priyanthi M. Kumarasinghe Consultant Histopathology/Clology Dept of Pathology, SGH