What is hereditary non-polyposis colorectal cancer?

Genetics

• Hereditary non-polyposis colorectal cancer accounts for two to seven per cent of cases of colorectal cancer.
• The risk of an individual developing hereditary non-polyposis colorectal cancer is increased by mutations in a set of genes normally responsible for repairing DNA.
• Only one inherited copy of a mutated gene is sufficient to raise an individual’s risk of cancer.
• Mutations in the MLH1, MSH2, MSH6 or PMS2 genes all increase an individual’s risk of developing hereditary non-polyposis colorectal cancer.
• Mutations in the MSH2 and MLH1 genes are most common (90 per cent of cases).
• Mutations in the EPCAM gene can also indirectly increase an individual’s risk of developing the disorder. The EPCAM gene lies next to the gene MSH2 on chromosome 2 and some mutations in the EPCAM gene can switch the MSH2 gene off.
• Hereditary non-polyposis colorectal cancer also increases the risk of other cancer types including cancers of the ovary, stomach, small intestine, brain and skin.

Biology

• The genes MLH1, MSH2, MSH6 and PMS2 are all involved in repairing the mistakes that occur when DNA is copied in preparation for cell division.
• Mutations in these genes mean that mistakes made during DNA replication are not properly repaired and the cells continue to divide, copying the mistakes over and over.
• This can then lead to uncontrolled cell growth and possibly cancer.
• However, not all individuals with these mutations will develop cancerous tumours.

Symptoms

• The average age of onset is 44 years old.
• Hereditary non-polyposis colorectal cancer may not present with any symptoms (asymptomatic).
• It can present with rectal bleeding, stomach pain and cancer-related symptoms like unexplained weight loss and fatigue.
• Despite the name, hereditary non-polyposis colorectal cancer does cause the formation of polyps but far fewer than seen in familial adenomatous polyposis. These polyps are generally not cancerous at first but can become cancerous within two to three years.
• The lifetime risk of hereditary non-polyposis colorectal cancer patients developing colorectal cancer is estimated to be about 70 to 80 per cent.
• Female patients have a significantly higher risk of endometrial and ovarian cancer (39 and 9 per cent respectively, by the age of 70).

Diagnosis

• Hereditary non-polyposis colorectal cancer is usually suspected in individuals with a family history of the disease.
• A colonoscopy is used to confirm the diagnosis. This involves a doctor inserting a small camera up the bottom of the patient to view the colon and identify the presence of any potentially cancerous polyps.
• Patients with a family member who has tested positive for hereditary non-polyposis colorectal cancer can undergo genetic testing to see if they have the same genetic mutation as their family member. They can also undergo regular colonoscopies to check for colorectal cancer.

Treatment

• Predisposition to cancer means that regular reviews by a specialist doctor are essential to catch the formation of polyps early and arrange for their removal before they become cancerous.
• Monitoring often involves a colonoscopy every two years either:
  • from the age of 25, or
  • from an age five years younger than the earliest colorectal cancer case seen in the family.
• Although not routinely tested for in the UK, certain drugs have been shown to be more effective in patients with specific mutations. This raises the possibility of personalised treatment where a genetic test determines the best treatment for a patient.
• Screening is also showing promise.
  • One study has looked at testing all newly diagnosed colorectal cancers in patients under the age of 50 for evidence of mutations in the genes that repair DNA.
  • Those who were identified to be in the ‘high’ group for these tests were then offered additional testing for hereditary non-polyposis colorectal cancer.
  • Those found to have hereditary non-polyposis colorectal cancer were then made aware of their increased risk of cancer so that they, and their family members, could be screened more regularly to hopefully prevent future cancers.