| HNPCC |
| Microsatellite
Instability Testing |
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By
Miriam Komaromy,
MD
Reviewed
by Peggy
Conrad, MS, CGC and Jonathan
Terdiman, MD
Last
updated August 4, 2000
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Mutations
in genes that repair damaged DNA cause regions called
microsatellites to get longer or shorter, a phenomenon
that scientists call microsatellite instability (MSI).
Testing for microsatellite instability helps doctors
determine whether a person is likely to have a gene
mutation that causes hereditary nonpolyposis colorectal cancer (also known
as HNPCC or Lynch Syndrome).
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What
Does Microsatellite Instability Have to Do With HNPCC?
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| If
a tumor is found to have microsatellite instability,
scientists are more likely to find a mutation in
one of the known DNA mismatch repair genes during
genetic testing. |
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The genes that cause HNPCC are DNA
repair genes. Everyone has two copies of each gene —
one from their mother and one from their father. However,
every cell in people with HNPCC has
inherited one mutated copy of a DNA
repair gene. If the remaining nonmutated copy of that
DNA repair gene is deactivated in any cell, that cell's
ability to repair DNA is impaired. When a cell can't repair
damaged DNA, many mutations accumulate, and a tumor can
result. In addition to making tumors more likely, the
cell's difficulty in repairing DNA causes another phenomenon
called microsatellite instability.
Microsatellites are repeated sequences of DNA. Although
the length of these microsatellites is highly variable
from person to person, each individual has microsatellites
of a set length. These repeated sequences are common,
and normal. In cells with mutations in DNA repair genes,
however, some of these sequences accumulate errors and
become longer or shorter. The appearance of abnormally
long or short microsatellites in an individual's DNA is
referred to as microsatellite instability.
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| Testing
a tumor sample for microsatellite instability can
often provide a helpful way to determine whether
genetic testing for HNPCC is appropriate. |
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About
ninety percent of tumors from people who have HNPCC show
microsatellite instability. Tests are available that detect
microsatellite instability in tumor cells, and finding
numerous longer or shorter microsatellite regions in these
cells suggests the presence of a mutated DNA mismatch
repair gene — and that in turn points to HNPCC. Thus,
testing a tumor sample for microsatellite instability
can often provide a helpful way to determine whether genetic
testing for HNPCC is appropriate. If a patient's tumor
cells show no evidence of microsatellite instability,
it's unlikely that he or she has a mutated mismatch repair
gene — and that's precisely what genetic tests for
HNPCC are looking for. In such cases, genetic tests are
unlikely to yield useful information and are rarely worth
the time and money they entail.
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What
are They Really Looking for?
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Usually a laboratory that does MSI testing will
look at five different microsatellite regions of
the DNA. A tumor is considered "unstable-high"
if changes are found in two or more regions, "unstable-low"
if changes are found in one region, and stable if
no changes are found between the patient's tumor
cells and normal cells. Tumors that are unstable-high
are considered suggestive of HNPCC. If the tumor
is stable or unstable-low, it is unlikely (though
not impossible) that a subsequent genetic test will
show a mutation in a mismatch repair gene. |
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When Is Microsatellite Instability
Testing Appropriate?
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Sometimes
genetic specialists will perform microsatellite instability
testing on colon, endometrial, or other cancer tissue
as the first step in genetic testing for families with
medical histories suggestive of HNPCC. Because about ninety
percent of HNPCC-related colon cancers have high-frequency
microsatellite instability, few HNPCC patients will be
overlooked if they are screened for microsatellite instability
before having blood drawn for genetic testing.
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| Genetic
testing for DNA repair gene mutations may be necessary
even if microsatellite instability testing is negative. |
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However,
if your family history is strongly suggestive of HNPCC,
genetic testing for DNA repair gene mutations may be necessary
even if microsatellite instability testing is negative.
In addition, MSI-positive colon tumors can occur in about
10 percent of people without HNPCC. Thus, having an MSI-positive
tumor is not proof that HNPCC is present, but it can be
suggestive. |
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One situation in which microsatellite instability testing
can be particularly useful is when all affected family
members have died, leaving no affected family member who
can provide blood for testing DNA repair gene mutations.
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| Microsatellite
instability testing can be particularly useful is
when all affected family members have died. |
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In such scenarios, labs can perform microsatellite instability
testing on tumor tissue that has been removed while the
patient was still alive (hospitals routinely save tumor
tissue for several years after cancer surgery). With written
permission from the next of kin, a physician or genetic
counselor can request tissue samples by contacting the
pathologist at the hospital where the surgery was performed.
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Another
Type of Tissue Test
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| Recently,
another form of tissue testing, called protein immunostaining,
has become available to help determine which patients
have HNPCC. When the DNA repair genes are functioning
normally, colon cells produce a protein that is a product
of those genes. Protein immunostaining is a way to visualize
whether this protein is present. If a test on colon tissue
doesn't produce evidence of this protein, there's a greater
chance that this person has inherited a DNA repair mutation
and thus HNPCC. |
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References
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Boland,
C. et al. (1998). A National Cancer Institute workshop
on microsatellite instability for cancer detection and
familial predisposition: development of international
criteria for determination of microsattelite instability
in colorectal cancer. Cancer Res 58: 5248-57.
Aaltonen, L. A et al. (1998). Incidence of hereditary
nonpolyposis colorectal cancer and the feasibility of
molecular screening for the disease. New England
Journal of Medicine 338: 1481-1487.
Loukola, A, et al. (1999). Strategies for screening
for hereditary non-polyposis colorectal cancer. J
Med Genet 36: 819-822.
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