Hereditary colon cancer

FAMILIAL ADENOMATOUS POLYPOSIS Clinical features: FAP has an incidence of one in 5000 to one in 7500. Average age of onset of polyps is 25 years, of symptom manifestation is 33 years and of diagnosis is 36 years. Average age of cancer is 42 years. Penetrance, ie, the presence of polyps, is close to 100% by 40 years. The name ‘familial adenomatosis polyposis’ is derived from the presence of hundreds of polyps, with less in the right than in the left colon. Three-quarters of individuals with FAP have inherited the gene from one affected parent; 20% to 25% have a new mutation. Genetics: The gene for FAP, apc, is located on 5q21. The abnormal gene functions as an autosomal dominant; in its normal state it is a tumour repressor, ie, its natural function is to

facilitate the removal of unwanted or damaged cells.Most apc alleles have point mutations or small deletions which result in protein truncation.Individuals with FAP have mutations in both the germline and tumour.Somatic mutations to apc are frequently found in sporadic tumours.Genotype-phenotype correlations: Colonic manifestations may be severe or mild, but most cases are intermediate.Extracolonic manifestations may include adenomatous polyps elsewhere, particularly at the ampulla of Vater or in the gastric mucosa; ocular, cutaneous and skeletal abnormalities in the subset known as Gardner's syndrome (congenital hypertrophy of retinal pigment epithelium [CHRPE] is diagnostic for this condition); and malignancy in other organs, such as mesenteric fibromatosis, thyroid cancer or hepatoblastoma.

HEREDITARY NONPOLYPOSIS COLON CANCER Clinical features:
The name 'hereditary nonpolyposis colon cancer' is misleading because there may be polyps, but these are much fewer in number than in FAP and are more numerous in the right versus left colon.Mean age of onset is 44 years.In HNPCC type I, only tumours of the colon occur.In HNPCC type II, tumours occur in the colon and elsewhere, especially the endometrium.Genetics: HNPCC is also an autosomal dominant.Four genes have been implicated.Mutations to hMSH2 at 2p22 are associated with HNPCC type I; mutations to hMLH1 at 3p21 are associated with HNPCC type II.Each accounts for approximately 45% of affected families.Mutations of hPMS1 and hPMS2 are rare.
The normal genes are responsible for DNA mismatch repair.Mutated genes lose this function -it is as if the 'spellcheck' for DNA is off-line.
Mutations to the HNPCC genes are also seen in sporadic tumours.
OTHER HEREDITARY POLYPOID SYNDROMES Turcot syndrome: Turcot syndrome involves colonic polyps, colon cancer and primary brain tumours (1).This is likely a recessive condition, and mutations have been shown in apc and HNPCC genes.The former is associated with medulloblastoma; the latter with glioblastoma.Muir-Torre syndrome: In Muir-Torre syndrome, polyps and colon cancer are associated with skin tumours including basal cell and squamous cell cancer, as well as sebaceous adenoma (4).This is a dominant syndrome and mutations have been demonstrated in MSH2.Hamartomatous polyposis: Peutz-Jeghers syndrome is a dominant syndrome of mucocutaneous pigmentation and gastrointestinal polyposis with an increased risk of gastrointestinal tumours (1).Juvenile polyposis is also a dominant syndrome, with increased risk of colon tumours.Cowden's disease is yet another dominant syndrome delineated by mucocutaneous growths, breast and thyroid cancer, and gastrointestinal polyps, but with no increased risk of gastrointestinal tumours.

ONCOGENIC THEORY
The first theory of oncogenesis was proposed by Knudson (5) as a two-hit mechanism best exemplified by retinoblastoma.In this model, the individual inherits a germline mutation in a tumour repressor and then its normal counterpart is independently deactivated.
The multihit model of oncogenesis from Vogelstein et al (6) was first described in FAP.The first hit is a mutation to the apc gene, followed by K-ras oncogene activation and then loss of tumour repressors on 18q and 17p (the latter, p53).
HNPCC has become the model for the third mechanism of tumour genesis (2), ie, altered control of DNA fidelity.
In all cases, individuals at risk for hereditary cancer have a germline mutation that may subsequently be important at a somatic level.In many sporadic tumours the same genetic mutations are seen, although just in somatic tissue.For example, 30% to 40% of sporadic colon cancers shown mutations to apc, and 15% to HNPCC genes.

PREDICTIVE TESTING
Recommendations for monitoring (1) known or suspected FAP/HNPCC individuals and their families are outlined in Table 1.This is an onerous schedule for both patients and their physicians, as well as an expensive one.Optimally, genetic testing may allow the ruling in or ruling out of individuals at risk for hereditary colon cancer.
Unfortunately, predictive testing for at-risk individuals is far from easy.First, it is not always possible to identify individuals at true increased genetic risk.Because of the frequency of colon cancer in the North American population, many individuals may have one or more relatives with colon cancer of a sporadic nature.Second, one gene does not equal one mutation.Colon cancer can be caused by several genes, and there are multiple known mutations in each.This complicates molecular diagnostics and exponentially increases cost.Third, testing procedures often require blood from multiple affected family members.If the family is small or those affected have died, then testing may not be possible.Finally, individuals may not wish to be tested.Negative consequences may accrue to those at risk for a disorder even though it may not manifest for many years.Insurance or emigration may be denied and social or employment discrimination may occur.
As well, the psychological response to knowing that one is likely to develop cancer may be devastating to individuals and families; this may be particularly true for testing of children.
When molecular diagnosis of hereditary colon cancer is successful, the at-risk individual becomes either at very high risk or at very low risk.Those at very low risk may avoid a lot of unpleasant and expensive testing.Those at very high risk (and their physicians) may feel more motivated to follow surveillance protocols.Many patients undergo prophylactic surgery.Unfortunately, reliable preventive treatment for colon cancer does not exist nor are there existing treatment modalities more specific to hereditary (versus sporadic) cancer.

WHAT IS AVAILABLE NOW?
Linkage and common deletion testing in FAP is available as a service in many molecular diagnostic laboratories throughout Canada.Linkage and replication error repeats for HNPCC are approaching service in some laboratories but are still done mostly on research protocols.Queries regarding assessment of individuals/families at risk for hereditary colon cancer should be made through the medical genetics clinics or specialized hereditary cancer clinics in each province.The Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital in Toronto, Ontario is also an excellent resource for information.

SUMMARY
Most of our knowledge of hereditary colon cancer has accumulated in this decade, and our understanding of molecular mechanisms in cancer is rapidly improving.Predictive testing for at-risk individuals is available in very limited circumstances; genetic screening on a population basis is not possible.Management in terms of surveillance and prophylactic surgical intervention is also improved but specific treatment, both clinical and genetic, is a goal for the future.

TABLE 1 Recommendations for monitoring known or suspected familial adenomatosis polyposis/hereditary nonpolyposis colon cancer individuals and their families Familial adenomatosis polyposis
422Can J Gastroenterol Vol 11 No 5 July/August 1997GilchristCHRPE Congenital hypertrophy of retinal pigment epithelium