Inherited Colorectal Cancer

Introduction

Colorectal cancers develop from the accumulation of mutations of a variety of genes within cells of the gut lining. This usually starts with a single abnormal cell which multiplies, first becoming an early (small) polyp progressing to a late (large) polyp and finally to a cancer according to the increasing number of mutations occurring within the cells. Although this usually occurs by chance in the majority of people, a small number have inherited an abnormal gene from one of their parents which has already started along the pathway to develop a cancer. It is by no means certain that these people will develop colorectal cancer, their likelihood of doing so is higher than the rest of the population and they benefit from careful surveillance and in some cases preventative surgery.

inherited cancer diagram

The accumulation of genetic mutations leads to the transition from normal tissue to a polyp or adenoma and finally to a cancer (Vogelstein et al)

Risk Assessment

Colorectal cancer develops in around 1 in 20 people in the UK. Since it is a common condition many, people will be related to some one with such a tumour. These people are at no greater risk for developing this form of cancer. The risk of having as predisposition to develop colorectal cancer increase with the number of relatives with this condition, the absolute risk is best assessed by doctor taking a careful family history. This is time consuming and accuracy is greatly aided by patients finding a much about this as possible using an appropriate family history sheet. Although generally effective, the family history may be inaccurate if there is a lack of knowledge about other members of the family, if families are small or if there is a chance clustering of cancer within a family. It should also be remembered that family history changes with time and the development of cancer in another member may move the family to a higher risk group.

Assigning Risk and Subsequent Management

Generally speaking people can be assigned into one of three risk categories; low, moderate and high risk. A number of patients do not fall neatly into these groups and should be managed as if in the higher risk group.

Low Risk

This includes the majority of the population who have no first degree relative (parent, sibling or child) with bowel cancer or one first degree relative with a bowel cancer diagnosed after they were 45 years of age. This group may be reassured and offered entry into the national population screening programme.

Moderate Risk

This includes those with: a single first degree relative with bowel cancer diagnosed before the age of 45 or 2 first degree relatives diagnosed with bowel cancer at any age (providing they do not fall into the high risk group). This group has an increased risk compared to the population of 1:6 and 1:10 respectively. Current guidelines suggest a colonoscopy between the ages of 35-40 and if normal, a further colonoscopy at 55 years old.

High Risk

This includes those from a family known to have a familial polyposis syndrome e.g. Familial Adenomatous Polyposis (FAP), Peutz-Jeghers Syndrome, Juvenille Polyposis Syndrome or those fulfilling the Amsterdam criteria for the diagnosis of Hereditary Non Polyposis Colorectal Cancer (HNPCC). These patients should undergo genetic assessment and enter into a formal surveillance programme under the guidance of a clinical geneticist.

Specific High Risk Syndromes

The likelihood of having a high risk syndrome is very small. Those with a known inherited genetic mutation account for less than 5% of all the bowel cancers in the UK. It should be remembered that even patients from a high risk family only have a 1 in 2 chance of inheriting the damaged gene. The following gives a very brief overview of the major inherited syndromes.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

This condition accounts for the majority of inherited colorectal cancers and is caused by a mutation in one of the genes responsible for repairing faulty DNA known as mismatch repair genes. It may be difficult to diagnose HNPCC since there are no clear features such as multiple polyps as seen in other syndromes. In addition a variety of other cancers including endometrial, ovarian, small intestinal and urinary tract are all seen in this condition. An exacting set of guidelines, the Amsterdam criteria have been developed to help identify people in this group.

Familial Adenomatous Polyposis

This condition accounts for around 1% of all bowel cancer and is caused by a mutation in the APC gene. Patients develop hundreds of colonic polyps in their teens and twenties and generally require surgery to remove the bowel to prevent almost certain development of cancer. Further polyps may also develop in the duodenum which requiring regular surveillance.

Peutz-Jeghers Syndrome

This is an extremely rare condition characterised by pigmentation around the mouth and multiple polyps of the gastrointestinal tract. It is caused by a mutation in the STK11 gene. Patients commonly develop bowel obstruction due to intussusception (the bowel folding in on itself) and may form cancers particularly of the colon and stomach.

Juvenille Polyposis

This is another very rare condition characterised by the presence of multiple polyps occuring throughout the whole gastrointestinal tract. It is caused by mutations of the SMAD 4 or BMPRA1A genes. Those affected tend to develop colorectal cancers but may also develop cancers of the stomach and small intestine.

Patients who are thought to be at an increased risk of having an inherited bowel cancer should be referred to a clinician with a particular interest in this field and make every effort to identify all the members of their family who developed a cancer. Family history clinics are only for asymptomatic individuals and NOT those with symptoms suggesting bowel disease who should be referred urgently to a colorectal surgeon via the usual pathway. I must be reiterated that family histories are constantly changing and the development of new cancers in family members after the assessment should be reported since they may change the risk group.