The role of clinical genetics in management
Before 1990 the role of inherited factors in the aetiology of
adult cancer was relatively poorly understood and aroused little
interest among doctors and the public alike—although familial
adenomatous polyposis (the autosomal dominant colon cancer
syndrome) was an exception in this respect. In the past decade,
however, interest has increased markedly. In the West Midlands,
for example, familial cancer referrals constituted < 1% ( < 20
cases) of all clinical genetic referrals in 1991, whereas now they
represent over 30% of cases ( > 1000).
Despite the estimate that 5-10% of colorectal cancer has an
inherited basis, only a small percentage of referred families
have mutations in one of the currently identified genes.
Furthermore, mutation studies are usually possible only if DNA
is available from an affected patient, so molecular investigation
will facilitate the management of only a small minority of cases.
The remaining referrals must be managed with clinically
derived strategies. This article discusses the clinical features and
management of dominant colon cancer syndromes and
provides referral guidelines and screening protocols for more
common familial clusters.
Genetic counselling for families with a history of cancer
requires a full and accurate family history. When possible,
histological confirmation of the reported tumours should be
obtained. It should then be possible to recognise the specific
cancer syndromes. It is important to emphasise to families that
however extensive the family history of cancer (unless present
on both sides), a person will always have a greater than 50%
chance of not developing that particular tumour. This may
surprise but greatly reassure many families.
Familial adenomatous polyposis
Familial adenomatous polyposis, previously called polyposis coli
(or Gardner’s syndrome if extra colonic manifestations were
present), is the best recognised of the colorectal cancer
syndromes but accounts for less than 1% of all colorectal
cancers and has an incidence of 1 in 10 000. It is characterised
by the presence of 100 or more tubovillous adenomas in the
colon, with intervening microadenoma on histological
examination. The mean age of diagnosis of polyps is during
teenage years, and almost all of gene carriers have polyps by the
age of 40. If these polyps are left untreated, malignant
transformation is inevitable, with a mean age of colorectal
cancer occurring during the patients’ mid-30s, often with
synchronous tumours.
This condition is an autosomal dominant disorder, with the
offspring of affected individuals at 50% risk of being gene
carriers. The diagnosis of familial adenomatous polyposis
should always result in a careful and full evaluation of the family
history. Wherever possible, parents should have at least one
colonoscopy, irrespective of age. In most cases without a family
history, parental examination will be negative and the proband
will probably be one of 30% of cases that represent new
mutations. The siblings of all probands, however, should be
offered annual flexible sigmoidoscopy up to the age of 40 or
until proved to be non-gene carriers.
The cloning of the causative gene (APC) on chromosome 5
in 1991 dramatically changed the management of familial
adenomatous polyposis. If DNA is available from an affected
individual, mutation detection is possible in about 70% of
families. In these families first degree relatives should be offered
predictive testing with appropriate genetic counselling. In
families with no identified mutation, linkage studies to identify
the “high risk” chromosome 5 are possible in many cases.
Non-gene carriers should be reassured and surveillance
stopped. Gene carriers should be offered annual flexible
sigmoidoscopy from the age of 12. Once several polyps have
been identified, the timing and type of surgery available should
be discussed (a sensitive issue in teenagers and young adults).
The two most common options are ileal-rectal anastomosis with
annual surveillance of the remaining rectal tissue; and ileal-anal
anastomosis with reconstruction of a rectal pouch using
terminal small bowel.
Molecular testing is usually offered to “at risk” children at
age 10-14 before starting annual sigmoidoscopy. However,
parental pressure for earlier testing (before the child can give
consent) is not uncommon, and ongoing studies may help to
clarify when to proceed with testing.
Cloning APC explained several clinical features and aided
studies of genotypes and phenotypes. For example, congenital
hypertrophy of the retinal pigment epithelium, an attenuated
phenotype (that is, fewer than 100 polyps or late onset), and
non-malignant but debilitating and potentially lethal desmoid
disease each show an association with mutations in specific
exon regions. The cloning also confirmed clinical findings that
familial adenomatous polyposis and Gardner’s syndrome were
different manifestations of the same disease spectrum that
could coexist within the same family.
With greater clinical awareness, regular surveillance, and the
advent of molecular investigation, almost all colorectal cancer
deaths in inherited cases of familial adenomatous polyposis can
be avoided. Increased survival has revealed later complications,
in particular periampullary or duodenal adenocarcinoma
(present in about 12% of postcolectomy cases). Also important
are aggressive desmoid disease and other rare malignant
disease.
Chemoprophylactic approaches to reduce polyp growth (for
example, aspirin and non-digestible starch) are the subject of
multicentre trials.
Hereditary non-polyposis colon cancer
Hereditary non-polyposis colon cancer (also known as Lynch
syndrome) became more widely recognised about 30 years ago
in families manifesting mainly colorectal cancer segregating in
an autosomal dominant fashion. Many families also exhibit
extracolonic tumours, particularly gynaecological, small bowel,
or urinary tract carcinomas, and these became known as Lynch
type 2 to distinguish them from site specific colorectal cancers,
designated Lynch type 1. The subsequent name change to
hereditary non-polyposis colon cancer is potentially misleading
as many gene carriers will develop a small number of
tubovillous adenomas, but not more than 100, as seen in
familial adenomatous polyposis. The proportion of colorectal
cancers due to hereditary non-polyposis colon cancer is
controversial, and estimates range from 1% to 20%; most
observers, however, suggest about 2%.
The diagnosis of hereditary non-polyposis colon cancer is
made on the family history as the appearance of the bowel,
unlike in familial adenomatous polyposis, is not diagnostic. To
improve the recognition of hereditary non-polyposis colon
cancer, diagnostic criteria were devised in Amsterdam in 1991
and were subsequently modified to include non-colonic
tumours.
In 1994 the first of the genes for hereditary non-polyposis
colon cancer (hMSH2 on chromosome 2) was cloned, and since
then four further genes have been identified; all are mismatch
repair genes. If both copies of the genes are mutated, as
postulated in Knudson’s “two hit” hypothesis, that cell and all its
daughter cells are missing a vital mechanism for repair of DNA
in somatic tissue. Failure to repair mutations in tumour
suppressor genes will in some instances result in initiation of
the adenoma carcinoma sequence. Molecular studies showed
that about 30% of colorectal cancers with early onset (under age
35) are due to the mismatch repair genes, and the typical age of
onset and the spectrum of tumours in families with hereditary
non-polyposis colon cancer were revised.
The limited available evidence suggests that screening for
colorectal cancer in hereditary non-polyposis colon cancer is
beneficial. In 1999 Vasen et al published figures showing clinical
benefit and cost effectiveness of screening in hereditary
non-polyposis colon cancer after a Finnish study reporting
reduced morbidity and mortality in a non-randomised
observational study of colonoscopy versus no screening.
The optimal surveillance frequency has not yet been defined
in families with hereditary non-polyposis colon cancer. The
method of choice, however, is colonoscopy rather than flexible
sigmoidoscopy as 80% of cancers are proximal to the rectum
(compared with only 57% in sporadic colorectal cancer). The
screening interval should be at most three years and probably
every 18-24 months in gene carriers. Failure to reach the
caecum should be followed by barium enema examination,
although surveillance using radiological techniques should
probably be used sparingly owing to the theoretical mutagenic
consequences in patients with DNA repair defects. Patients
should understand that the strategy of colonoscopy is the
removal of polyps and prevention of tumours or early
diagnosis, but that complete prevention is impossible.
Familial clusters with no recognisable
single gene disorder
Families whose cancers do not meet the diagnostic criteria of
familial adenomatous polyposis, hereditary non-polyposis colon
cancer, or rarer colorectal cancer syndromes (such as
syndromes related to the PTEN gene, Turcot’s syndrome,
Peutz-Jeghers syndrome, or juvenile polyposis) make up the
largest and most difficult group of patients requesting
management. There is rarely any indication of the aetiological
basis of the cluster of colorectal cancer, and many instances will
be coincidental occurrences. Other tumours clusters may be
due to common environmental exposures, the effect of multiple
low penetrance genes, or an interaction of both these elements.
The risk of colorectal cancer may be assessed with empirical
risk figures. These figures are estimates, however, and do not
take into account factors such as the number of unaffected
relatives. Further enquiry is usually justified if features such as
multiple relatives with the same tumour or early onset of
tumours are present in a family.
Concerns about not having precise risk figures may be
misguided as many patients have difficulty interpreting risk
figures and are often requesting only general guidance on risk
and a discussion of management options. Many different
screening protocols have been suggested in the past, however,
and the lack of consistency and long term audit in these
families is a problem.
To manage familial cancer in the West Midlands (population
5.2 million), a protocol has been developed that builds on the
Calman-Hine model for cancer services and maximise the role
of primary care. The protocol provides clear inclusion and
screening guidance for cancer units and centres. This has
promoted a consistency of management in and between
families and is now allowing data collection for audit.
It may be wise for general practitioners to use a reactive
approach to patient enquiries until evidence exists to support a
proactive approach. In the West Midlands, patients requesting
advice are asked to complete a data collection sheet at home.
This form and the inclusion criteria are available at
www.bham.ac.uk/ich/clingen.htm. Completion of the form in
the patient’s own time, at home, facilitates discussion with
relatives to clarify the relevant information and has saved time
in primary care if a referral is required.
After histological confirmation in suspected familial
cases, the data are evaluated centrally to identify high risk
families requiring specialist investigation or referral to a cancer
unit.
In a pilot study (population 200 000) the protocol reduced
referrals from primary care by 50%, with a greater reduction in
screening owing to a fall in low risk referrals to cancer units.
This was associated with an increased referral rate for high risk
referrals to clinical genetics departments. Central coordination
prevents unnecessary investigations for different branches of
any one family and facilitates audit.
Reports from general practitioners and patients suggest that
individuals at no or minimal increased risk of cancer avoid
unnecessary outpatient appointments and screening and for
the most part are reassured by standardised protocols with
explanations on the data collection forms. Such systems need to
be studied further but seem to be preferable to continuing the
current exponential rise of ad hoc responses from individual
clinicians without long term audit.
