| FAP |
| The Testing Process for FAP |
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By
Miriam Komaromy,
MD
Reviewed
by Peggy Conrad,
MS, CGC and Jonathan
Terdiman, MD
Last updated August 10, 2000
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If
you believe you may have inherited FAP (familial adenomatous
polyposis), a medical condition that puts people at
extreme risk for colon cancer, one of the first things
you might do is ask your doctor if you can get an immediate
DNA test so that you can "know for sure."
Although this is a logical (and increasingly common)
request, you need to understand that your doctor
will only give you a genetic test under some very specific
circumstances. In fact, investigating your family's
medical history is almost always the first step in understanding
how your genetic inheritance is likely to affect your
health.
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If
your doctor does decide that you are a good candidate
for genetic testing, here are some things you will want
to know about the test:
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Testing
the APC Gene
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| FAP
is caused by inheriting a defective copy of a specific
gene (the adenomatous polyposis coli, or APC, gene). When
working properly, this gene produces a special substance
(a protein) that keeps polyps from developing in the colon.
When this gene is defective, the protein no longer functions
properly, and polyps begin to appear. Without treatment,
colon cancer almost inevitably develops from one or more
of these polyps. |
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The
Most Common Method: Protein Truncation Testing
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Commercial
laboratories employ a variety of methods to detect potentially
cancer-causing mutations in human genes. However, detecting
a FAP mutation is difficult because the APC gene is
very large, and a mutation can occur anywhere in the
gene. Current APC gene tests involve successive steps
depending on what is found in any given diagnostic test.
Today, the most widely available FAP genetic test is
protein truncation testing, or PTT. Researchers have
discovered that when the APC gene is defective, or mutated,
it usually produces a protein that is shorter than those
created by normal versions of the gene. Thus, one way
to test for a genetic mutation that causes FAP is to
look for evidence that APC gene proteins are truncated,
or shorter.
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| Other
types of APC gene tests can also be performed and may
soon be widely available. However, it's important to understand
that none of the gene tests is perfect (see below), and
a gene mutation can be present but missed. |
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The
Drawbacks of Protein Truncation Testing
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| Currently
available tests are not capable of detecting all
of the mutations in the APC gene that can cause
FAP. |
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You
should also know that even if a defective APC gene is
indeed the culprit for FAP in your family, APC gene testing
may not be able to help you sort out which individuals
have (or haven't) inherited the condition. This is because
currently available tests are not capable of detecting
all of the mutations in the APC gene that can cause FAP.
Take the case of PTT: Not all APC gene alterations that
cause FAP will be detected when this test is administered.
Indeed, positive PTT gene test results are only found
in roughly eighty percent of FAP families tested. However,
if a member of your family has been clinically diagnosed
with FAP and also has a positive PTT test, this
test will subsequently serve as an extremely reliable
way of determining whether you or any other members of
your family carry that mutation.
Unfortunately, if the PTT tests of clinically proven
FAP patients in your family come back "normal,"
the news is not necessarily good. It simply demonstrates
that this particular test has not detected the genetic
cause of your family's FAP. (And remember, twenty percent
of all FAP families will have defective APC genes that
do not produce positive PTT results when tested.)
If this is the case for your family, you must assume that
you are at high risk for FAP (and therefore colon cancer)
since this test cannot help your particular family sort
out which individual members are (and are not) genetically
predisposed to the disease.
In other words, the absence of a positive gene test in
a family that appears to have FAP does not mean that the
family does not have FAP. It only means that the currently
available testing technology was unable to detect the
gene alteration in the family. |
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Further
Ways to Test the APC Gene
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As
we learn more about the APC gene and FAP, it may become
increasingly important to perform additional genetic tests
to reveal the precise alteration that's present in the
gene in a particular family.
This is often done by sequencing
the portion of the gene that is suspected to harbor the
alteration. It's important to realize, however, that few
laboratories will proceed to sequencing without first
identifying a potential mutation via PTT or another preliminary
blood test. When a gene is sequenced, doctors are able
to learn the exact order of the nucleotide bases that
make up the gene, and how that order was changed by the
mutation.
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| Researchers
have already indentified a few specific APC mutations
that appear to cause very sever polyposis. |
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Pinpointing the precise mutation has the
potential to provide extremely valuable information about
the specific nature of a family's FAP condition. Although
this area of genetic medicine is rapidly evolving (and
constantly changing), scientists believe that understanding
the exact nature of the mutation may help them predict
how severe the FAP will be. For example, the number of
polyps that may develop, where in the colon they are likely
to appear, and what other FAP-associated conditions are
more likely to occur. Researchers have already identified
a few specific APC mutations that appear to cause very
severe polyposis (the extreme proliferation of polyps).
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Children
and Testing
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| While
doctors do not normally recommend that children receive
genetic testing for most adult-onset inherited diseases,
they make an exception with FAP because it can produce
polyps and cancer in very young patients. Because of this
high risk, doctors recommend that children from families
in which FAP is known to exist undergo annual clinical
screening via sigmoidoscopy
starting as early as age 10. If you are able to determine,
through genetic testing, which specific children do and
do not carry the mutation(s), you may be able to
spare your child these regular invasive screenings. (If,
however, your child is found to carry the genetic mutation,
he or she will have to undergo these screenings, plus
perhaps take other preventive measures.) |
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