Microsatellite Instability Testing

About 5% of colorectal cancer is believed to be hereditary, meaning caused by an inherited mutation (change) in a specific gene. To date, several hereditary syndromes are known to be associated with an increased risk of colorectal cancer.One such syndrome is hereditary nonpolyposis colorectal cancer (HNPCC).

Genetic testing for HNPCC is currently available, and takes place in two steps. The first involves testing the actual tumor. When HNPCC is suspected in an individual or a family, the tumor tissue is obtained so that microsatellite instability (MSI) testing may be performed.Colorectal tumor tissue is typically preserved in a substance called paraffin, thus testing can be done years after the tumor was removed.

Microsatellites are short repeated sequences of DNA. DNA is the chain of chemical bases that make up our genes. Some bases are normally repeated a specific number of times in a sequence.However, sometimes the number of repeats is increased in tumor tissue, and this is called "instability." Normally, instability is "corrected" by DNA proofreading mechanisms. In individuals with HNPCC, the genes involved in the proofreading process are mutated so that they don’t work properly and instability develops. By comparing the number of repeats found in normal tissue with the number of repeats found in tumor tissue, it is possible to determine if the tumor demonstrates instability.

Researchers have discovered that MSI testing is a good first step in determining whether or not a particular individual has HNPCC. Evidence suggests that approximately 90% of tumors associated with HNPCC will show instability, while only 20% of sporadic (non-hereditary) tumors will be unstable. Since both hereditary and sporadic tumors can demonstrate instability, MSI testing is referred to as a "screening" test. It is important to recognize that MSI test results do not prove or disprove a diagnosis. Generally, if a tumor is tested for MSI and shows instability, there is a greater likelihood of HNPCC as a diagnosis. However, direct gene testing is still needed to actually prove HNPCC as a diagnosis. Likewise, if the tumor does not show instability, HNPCC is much less likely, but it cannot be ruled out. Therefore, MSI testing is used to determine if direct gene testing should be performed. [Of note, direct gene testing is performed on a blood specimen, and thus far, five genes have been shown to be associated with HNPCC.]

There are two important benefits of MSI testing: it costs less than direct gene testing, and it provides the opportunity to test tumors of relatives who are no longer living in an attempt to sort out the diagnosis in a family. A major disadvantage is that not every HNPCC tumor will be MSI-positive.

If an individual suspects hereditary colorectal cancer in his or her family, an appointment with a genetic counselor and a physician specializing in hereditary cancer is recommended. A review of the person’s family history will determine if it is appropriate to consider genetic testing.

Jennifer E. Sollenberger, MS, is a genetic counselor with the Cancer Risk Assessment Program at The Johns Hopkins Hospital.