Clinical Review

ABC of colorectal cancer

Molecular basis for risk factors

BMJ 2000; 321 doi: 10.1136/bmj.321.7265.886 (Published 7 October 2000)
Cite this as: BMJ 2000;321:886

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  1. Robert G Hardy,
  2. Stephen J Meltzer,
  3. Janusz A Jankowski

    Evidence for the molecular basis of colorectal cancer comes from genetic analysis of tissues either from patients with a family history of the disease or from patients with sporadic adenomatous colorectal polyps or extensive ulcerative colitis. The traditional view is that background rates of genetic mutation, combined with several rounds of clonal expansion, are necessary for a tumour to develop. It has recently been argued, however, that inherent genetic instability not only is necessary but may also be sufficient for cancer to develop.

    Proposed adenoma to carcinoma sequence in colorectal cancer. Adenomatous polyposis coli (APC) gene mutations and hypermethylation occur early, followed by k ras mutations. Deleted in colon cancer (DCC) and p53 gene mutations occur later in the sequence, although the exact order may vary

    Sporadic colorectal adenomas

    More than 70% of colorectal cancers develop from sporadic adenomatous polyps, and postmortem studies have shown the incidence of adenomas to be 30-40% in Western populations. Polyps are asymptomatic in most cases and are often multiple. Flat adenomas, which are more difficult to detect at endoscopy, account for about 10% of all polyps and may have a higher rate of malignant change or may predispose to a more aggressive cancer phenotype.

    Key molecular events in colorectal premalignancy: comparisons between the adenoma carcinoma sequence and ulcerative colitis associated neoplasia

    Family history

    Recognised familial syndromes account for about 5% of colorectal cancers. The commonest hereditary syndromes are familial adenomatous polyposis and heredity non-polyposis colon cancer. Patients with these syndromes usually have a family history of colorectal cancer presenting at an early age. Attenuated familial adenomatous polyposis, juvenile polyposis syndrome, and Peutz-Jeghers syndrome are rarer, mendelian causes of colorectal cancer. In familial adenomatous polyposis (a mendelian dominant disorder with almost complete penetrance) there is a germline mutation in the tumour suppressor gene for adenomatous polyposis coli (APC) on chromosome …

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