Genetic Testing and Counseling in Familial Adenomatous Polyposis
Genetic Testing and Counseling in Familial Adenomatous Polyposis
Over the past decade, we have made major discoveries about the
molecular genetic basis of colorectal cancer, including the identification
of genes that cause certain colorectal cancer syndromes [1-4].
There is little doubt that these discoveries will lead not only
to a better understanding of etiology but also to improvements
in the clinical management of colorectal cancer patients and their
One of the best examples of how basic research has made the transition
to clinical application is in familial adenomatous polyposis (FAP).
As a result of the discovery and characterization of the gene
for FAP, predictive genetic testing can now be offered to family
members in FAP kindreds . However, the new technology carries
an important responsibility for the clinician to help at-risk
individuals who may choose genetic testing to understand the implications
of the test.
We will briefly review the genetics of FAP, and discuss the various
issues related to the genetic counseling and management of FAP
patients, at-risk persons, and their families. Our paper represents
a body of experience drawn from work with families in the FAP
registry at The Johns Hopkins Hospital . The Hopkins registry,
which originated in 1973, has followed hundreds of FAP patients
from over 300 families, many of them large and multigenerational.
We will present several case reports to illustrate the breadth
of the issues that may arise in the context of predictive genetic
testing for FAP.
The clinical features of FAP have been well documented [7-9].
As its name implies, familial adenomatous polyposis is a condition
characterized by numerous adenomatous polyps (100) in the colon,
which exhibits autosomal dominant inheritance in families. This
means that affected persons are heterozygous, such that each offspring
of a patient with FAP has a 50% chance of inheriting the disease
gene. The gene responsible for FAP is known as APC (for adenomatous
polyposis coli) and is located on chromosome 5q2l [1-2,10].
Mutations of the APC gene have been found in patients with FAP
(eg, 2,11). These are often insertions, deletions, and nonsense
mutations that lead to frameshifts and/or premature stop codons
in the resulting transcript of the gene. It is not yet clear how
the subsequent truncated protein product causes adenomas to form.
Capitalizing on the nature of these mutations, however, has led
to the development of a molecular genetic test for FAP . Unlike
genetic linkage analysis, this test is useful with spontaneous,
or "new mutations" (the first occurrence of FAP in a
kindred), which may account for as many as one-third of incident
Recent evidence suggests that there is genetic heterogeneity of
FAP. Several kindreds have been described that do not appear to
be linked to the gene region on chromosome 5q . Also,
in some FAP patients, there has been an apparent inability to
detect APC mutations [12,14].
On the other hand, clinical variability of FAP has been manifested
by the appearance of the adenomas in some families that do have
an APC mutation. A variant entity of FAP with attentuated polyps
has been called the hereditary flat adenoma syndrome [15,16],
and in the reported kindreds appears to be due to mutations in
the APC gene. Other workers have suggested, however, that diminutive
adenomas will progress to larger, ordinary adenomas .
Individuals who inherit a mutant APC gene have a very high likelihood
of manifesting colonic adenomas; penetrance has been estimated
to be over 90% [7-9]. The age at onset of adenomas in the colon
is variable. Cumulative age-at-onset curves suggest that by age
10 years, only 15% of FAP gene carriers manifest adenomas; by
age 20, the probability rises to 75%; and by age 30, 90% will
have presented with FAP [7-9,18].
Without any intervention, most persons with FAP will inevitably
develop colon or rectal cancer by 40 years of age. Thus,
the medical goal in patients with FAP is to prevent colon cancer.
Conventional management of persons at 50% risk of developing FAP
has been to initiate annual colon surveillance by flexible sigmoidoscopy
in late childhood and to perform subsequent colectomy when numerous
polyps are present [19,20]. While it is not unusual to find FAP
patients under age 12 who have dozens of polyps, colon cancer
has been reported in children as young as 10 years of age [7-9].
Under no circumstances, however, is preventive colectomy indicated
in FAP patients prior to the appearance of polyps.
Genetic counseling of FAP patients and their family members can
occur in several contexts: at the time of diagnosis of FAP, at
the time that an FAP patient is considering reproductive options,
at the time that the FAP patient is having his or her children
screened, and at the time that an at-risk person is considering
genetic testing. In the following sections, each of these contexts
will be discussed in light of new information and risks that can
be conveyed during counseling at that particular time.
When FAP Is Diagnosed
This is the most common, conventional context in which FAP patients
are told about the condition and its genetic implications. Not
only are these patients coping with the disease and its medical
implications, they are also told that it is hereditary and that
their offspring may inherit the condition. For newly diagnosed
patients, this can be the most stressful time, as they deal with
the clinical sequelae, medical tests, and eventual surgery. Often,
patients with "new mutations" may have been diagnosed
when symptoms and possibly colon or rectal cancer have presented.
Thus, they may not be ready to absorb the genetic implications
of FAP until they have dealt with the requisite medical procedures.
Genetic counseling of newly diagnosed FAP patients and their families
is essential. Since many patients may be learning for the first
time about the hereditary nature of FAP, referral to a clinical
geneticist or genetic counselor is optimal, although we have observed
that this often does not occur in practice. The genetic counselor
obtains detailed information about the family history, including
health and cancer histories of blood relatives; family structure;
and social support within and outside the immediate family. Once
this information has been collected, pedigrees are drawn and recurrence
and other risks assessed.
Genetic counseling generally serves two functions: (1) to help
the patient and family understand medical and genetic information
about FAP, and (2) to provide emotional and psychological support
as the family copes with the new information and burdens that
such information can impose. This process is best accomplished
by a series of discussions over time. Because so much has been
learned about the genetic basis and management of FAP, patients
can be given reasons to be hopeful about future prospects in prevention
and treatment of this condition.
When Starting or Continuing a Family
Increasingly more often, FAP patients are being diagnosed in late
childhood or adolescence [7,20]. When such patients mature and
decide to start their own family, the genetic counselor or health
professional needs to review and discuss with both the patient
and his or her partner many of the issues related to inheritance
and the latest technological developments. Specific issues to
be reviewed include the mode of inheritance of FAP, the recurrence
risk for offspring, and the fact that the risk of FAP for each
offspring is independent of the others.
After a careful, sensitive exploration and discussion of the goals,
values, and wishes of the couple, reproductive options can be
sifted, including the feasibility of prenatal genetic diagnosis,
adoption, and artificial insemination. Prenatal genetic diagnosis
of FAP is a technically feasible option, as is in vitro preimplantation
diagnosis, but neither has ever been performed, to the authors'
knowledge. Anecdotally, during the course of pregnancy, several
couples have inquired about prenatal genetic diagnosis, but after
thinking through the consequences (ie, what would they do should
the gene test indicate that the fetus had inherited the mutant
APC gene?), this option was not elected. These experiences underscore
the importance of careful, thoughtful discussion of all the issues.
A related, but different situation occurs when a couple may already
have one or two children and wish to have more, but the decision
depends on whether those already born have inherited the FAP gene.
Couples may have different, often valid rationales for seeking
this information about children who may be quite young and for
whom intervention may be years away. These reasons may include
burden of caretaking, insurance coverage, or financial obligations
for which the couple may want to appropriately plan.