Inherited Colorectal (Bowel) 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.
Risk Assessment
Colorectal cancer develops in 5% (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 around 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 known as 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 which occur predominantly within the colon but also
the rest of the 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.
Summary
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 dynamic and the development of new cancers in
family members after the assessment should be reported since they may
change the risk group.
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