It is not intended to give a comprehensive overview of colorectal cancer genetics on these pages; instead links are provided to relevant websites for further information.

The development and progression of colorectal cancer can involve several factors, such as environmental, lifestyle, reproductive, and genetic factors.

A significant family history

Colorectal cancers that have occurred in a family are more likely to be significant if:

• There is more than one case of colorectal cancer in the family
• The cancers were diagnosed at a young age
• The people who have had colorectal cancer are closely related (first and second-degree) blood relatives of the patient - such as mother, aunt, grandmother, sisters.
• Diagnosis of other, associated cancers in relatives.

An example of a moderate risk colorectal cancer family can be seen here.

Only a small percentage of colorectal cancer family histories are associated with hereditary colorectal cancer syndromes, such as hereditary non-polyposis colon cancer (HNPCC) or familial adenomatous polyposis (FAP).

Hereditary non-polyposis colon cancer (HNPCC)

Familial adenomatous polyposis (FAP)

This condition accounts for about 1% of all colorectal cancers and is an autosomal dominant genetic condition in which almost all individuals who carry the gene develop hundreds of adenomatous polyps and if untreated colorectal cancer. The average of development of colon cancer is about 30 and by the age of 14 most gene carriers will have some polyps. In most gene carriers (70-80%), the causative gene, adenomatous polyposis coli (APC) can be identified. Other tumours and features can occur within FAP and include upper GI polyps, brain tumours, hepatoblastoma, desmoid tumours, adrenal adenomas, and benign craniofacial and long-bone tumours, papillary thyroid cancer, periampullary carcinoma, CHRPE (congential hypertrophy of the retinal pigment epithelium).

A variation of FAP, attenuated FAP accounts for fewer polyps, later onset of cancer and lower penetrance (not all individuals with the gene fault will develop cancer.)

If FAP is identified, an extensive family history should be taken although in 30% of cases new mutations will be identified and thus no other family members will be obviously affected. Cole (2002) et al recommend that the parents of newly identified affected individuals should undergo a single colonosocopy to ascertain if they may be affected by attenuated FAP. Surveillance recommendations for potentially affected individuals include annual flexible sigmoidoscopy (because the polyps occur obviously in the left sided colon) or colonoscopy from the age of 12 until 40 or until the individual undergoes genetic testing to detect if they carry the mutated gene.

Several studies have shown that morbidity and mortality in FAP can be reduced by identifying gene carriers, bowel surveillance and surgery. Vasen et al 1990). If the surveillance reveals that the individual has polyps, prophylactic surgery may be recommended. This includes ileo-rectal anastamosis or reconstruction of the rectal pouch using the small bowel. Evidence is available to illustrate that mutations in the second half of the gene may result in earlier cancer development and therefore in this group restorative colectomy is recommended. Following surgery there is still a risk of other tumours, especially periampullary and papillary tumours and there are issues regarding the potential need for upper gastrointestinal surveillance to observe for upper duodenal polyps. However the benefit of surveillance is difficult to assess as indeed the mortality and morbidity rates associated with major pancreaticoduodenal resection when duodenal polyps have been detected are high (Dunlop 2002), although the polyps can be individually removed. In families where there is a known gene mutation controversy exists over the timing of identifying the gene fault in children (molecular analysis), but is usually undertaken at around the age that surveillance should begin.In a family where an APC gene fault has been identified and an individual does not carry the gene fault, that person is then at near-population risk of developing a colorectal cancer and thus on-going bowel surveillance is not required.

MYH-associated polyposis

This inherited bowel cancer syndrome has recently been identified. Fewer polyps may develop in an individual than in classic FAP. The condition is recessively inherited and genetic testing is available.

References:

Cole T, Weiner C, Sleightholme HV (2002) in The Effective Management of Colorectal Cancer (2nd edition) edited by Cunningham D, Topham C and Miles Aesculapius Medical Press: London.

Dunlop MG (2002) Guidance on gastrointestinal surveillance for hereditary, non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis and Peutz-Jeghers syndrome: Gut : 51 (Supplement 5), 21-27.

Vasen HFA, Griffioen G, Offerhaus GJA et al (1990): The value of screening and central registration of families with familial adenomatous polyposis: A study of 82 families in the Netherlands: Diseases of the colon and rectum 33, 227-230.