Hereditary non-polyposis colorectal cancer 23/11/05. By Chrissie Giles. Reviewed by Jules Harvey and Robin Phillips Hereditary non-polyposis colorectal cancer is the commonest inherited syndrome that predisposes sufferers to early-onset colorectal cancer, but is still rare.

Hereditary non-polyposis colorectal cancer (HNPCC, also known as Lynch syndrome) affects roughly 1 in 5000 people, accounting for 3-10 per cent of all colorectal cancer cases. In HNPCC, colorectal cancer occurs earlier than in sporadic cases, on average, between the ages of 40 and 50.

Genetics

HNPCC is caused by a mutation in one of the DNA mismatch repair (MMR) genes. The most commonly mutated MMR genes in HNPCC are hMSH2 and hMLH1, but others include hMSH6, PMS1 and PMS2. Microsatellite instability (MSI) occurs when DNA mismatch repair systems do not operate properly and cause microsatellites (naturally occurring, highly repeated short DNA sequences) to get shorter or longer than expected.

Microsatellite instability is seen in more than 90 per cent of HNPCC tumours, and is detected by looking at five microsatellite regions in DNA from normal and cancer cells and scoring the instability as absent, low or high. MMR gene mutations cause abnormal DNA repair, so high microsatellite instability is seen in most cases of HNPCC, except for cases involving MSH6, which may show low instability.

Clinical features

HNPCC may be totally without symptoms, especially if the patient is being investigated at a young age because of a positive family history of the disease. However, it can present with rectal bleeding, stomach pain or symptoms related to the variety of cancers associated with it.

Although the name suggests otherwise, HNPCC does cause the formation of polyps (less than 100) – but still far fewer than seen in familial adenomatous polyposis (FAP). In HNPCC, the polyps themselves are not cancerous, but they can rapidly degenerate to cancer within two to three years – quicker than the eight to ten years taken in sporadic cases.

The lifetime risk of HNPCC patients developing colorectal cancer is estimated to be about 70–80 per cent and female patients have a significantly higher risk of endometrial and ovarian cancer (39 and 9 per cent, respectively, by the age of 70). HNPCC also increases the susceptibility of patients to other cancers, including the stomach, intestine, hepatobiliary system (liver), urinary system, skin and brain.

Diagnosis

Today, HNPCC is suspected by doctors following a thorough history (especially family history) and examination. If indicated, the patient may have a gene test or colonoscopy to confirm the diagnosis. HNPCC was initially diagnosed according to a set of rigid guidelines called The Amsterdam criteria (decided in 1990). To ensure that all patients diagnosed with HNPCC actually had HNPCC, they were very strict and excluded many patients who actually had HNPCC, but didn't meet all the criteria.

However, when the causative MMR gene mutations were discovered in 1993, more relaxed criteria were created, known as the Amsterdam II and the Bethesda.

Patients from affected families can undergo genetic testing if the HNPCC mutation in their family is known.

Background: Genetic testing for colorectal cancer

Treatment

The predisposition to cancer seen in HNPCC patients means that they need regular reviews by a specialist doctor. To help prevent colorectal cancer, patients from affected families (positive family history) or those with a proven MMR mutation are recommended to have a colonoscopy (looking inside the colon using a bendy camera up the bottom) every two years, from the age of 25, or from an age five years younger than the earliest colorectal cancer case seen in the family (whichever is the lowest).

See Colorectal cancer for details on the treatment of CRC.

Chrissie Giles is a freelance writer based in London. Dr Jules Harvey and Professor Robin Phillips are at the Colorectal Cancer Research Unit, St Mark's Hospital, Harrow.

Links

Cancer Research UK: About Cancer

CancerBACUP: Cancer of the large bowel

Beating Bowel Cancer