criteria or Bethesda guidelines and in whom tumor tissue is available
gene analysis is the first and only molecular evaluation
If there is a family history of a known specific
genetic mutation, this same known gene is sequenced
in the patient. Testing for an already known mutant gene
avoids having to laboriously analyze all MMR genes. In
patients with no available tissue for study and in whom
there is no available genetic information, analysis of
all MMR genes is performed. If a mutation is found, a
diagnosis of HNPCC is made and surveillance proceeds
accordingly (figure 2).
FAMILIAL ADENOMATOUS POLYPOSIS
Familial adenomatous polyposis (FAP), an inherited
disorder, is responsible for one percent of all colorectal
malignancies. Caused by a mutation in a single gene,
the Adenomatosis Polyposis Coli (APC) gene, FAP can
lead to a radical change in the structure and functioning
of the body.
In both FAP and sporadic colorectal cancers, a
mutation of the APC gene is one of the earliest events
leading to polyp formation and subsequent malignant
degeneration. This is known as the adenoma-carcinoma
sequence. ( 10) The APC gene mutation has a high
penetrance rate, meaning that individuals with the
mutated gene (the genotype) will almost surely develop
polyps (the phenotype).
80% of patients will have a family history of FAP
or AFAP, with a known, precisely located mutation,
heightening diagnostic suspicion and making the
diagnosis of FAP straightforward. However, 20% of
Figure 2: Evaluation of HNPCC in patients meeting the Amsterdam- 2
criteria or Bethesda guidelines and in whom no tumor tissue is
available for analysis.
patients will have a de-novo mutation in an unknown
Attenuated Familial Adenomatous Polyposis
Attenuated Familial Adenomatous Polyposis (AFAP) is
characterized by the formation of fewer, more proximal
polyps developed at a later age. Clinically, AFAP has
been recognized relatively recently. It may be a variant
of FAP, or may be a disease in its own right.
Securing a diagnosis of AFAP is more challenging
but must be considered in younger patients with
between ten and 100 proximally located colonic polyps.
The polyps are often flat. An upper gastrointestinal
examination must be performed in patients with FAP
or AFAP, as 80% to 90% will develop duodenal or
periampullary adenomas. The polyps are commonly
flat. They are diagnosed at an average age of 44 years.
The carcinomas in AFAP develop at age 56 compared
with FAP in which the average age at diagnosis is 10 or
15 years earlier. It is possible that the differential in age
of onset of the polyposis and malignant transformation
between FAP and AFAP is due to a lack of earlier
recognition of AFAP by physicians and patients, rather
than being a true difference in the age of onset.
It is often difficult to distinguish between FAP and
AFAP based solely on the number of polyps seen on
examination. In a single family with a single mutation,
the number of colonic polyps in each family member
may vary widely. In fact, there is evidence that AFAP
and FAP may not be separate diseases, but different
manifestations of a single entity. Extracolonic disease is