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HNPCC
  Microsatellite Instability Testing

By Miriam Komaromy, MD

Reviewed by Peggy Conrad, MS, CGC and Jonathan Terdiman, MD


 

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).

 
 
 

What Does Microsatellite Instability Have to Do With HNPCC?

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.
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.

Testing a tumor sample for microsatellite instability can often provide a helpful way to determine whether genetic testing for HNPCC is appropriate.
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.

 

What are They Really Looking for?

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?

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.

Genetic testing for DNA repair gene mutations may be necessary even if microsatellite instability testing is negative.
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.

 

 


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.
Microsatellite instability testing can be particularly useful is when all affected family members have died.
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

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

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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