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The Molecular Edge

Micro-satellite Instability and Cancer

Vol. 20 • Issue 7 • Page 12

Molecular Diagnostics

Micro-satellite instability has been associated with some common cancers and has been especially well studied in hereditary nonpolyposis colorectal cancer. Molecular tests for micro-satellite instability play an important role in cancer patient care.

What is Micro-satellite?

Micro-satellite is a segment of DNA in our genome consisting of variable numbers of short tandem nucleotide repeats, e.g., TAA-TAA-TAA-TAA-TAA. In this case, the "TAA" is a basic unit of the nucleotide repeats. The basic units can consist of one or more nucleotides. For example, it can be "A" or "AATT." Thousands of different micro-satellites are randomly distributed in our genome. For each individual, a specific microsatellite has a certain number of repeated nucleotide units, hence a certain length. For example, one of Mr. Smith's micro-satellites may have 20 TAA units. Therefore, the length of this micro-satellite is 60-nucleotides long.

What is Micro-satellite Instability?

During DNA replication, errors can happen. Like any part of DNA in our genome, micro-satellites can have errors during DNA replication, which includes deletions and insertions of one or more repeats. In fact, micro-satellites are often more prone to DNA duplication errors. These deletions and insertions will change the length of that micro-satellite.

On the other hand, a mechanism-the DNA mismatch repair system-is in our body and able to identify and fix some of these errors in DNA replication. The result is to restore the original length of that micro-satellite so that the micro-satellite is stable. Such repairs are carried out by a group of enzymes, coded by DNA mismatch repair genes, which are represented by MSH2, MLH1, MSH6 and PMS2. When one or more such enzymes lose their function due to mutation, the mismatch repair system will fail to repair the DNA errors in micro-satellites. As a result, the sizes of micro-satellites will deviate from its normal sizes. This is called micro-satellite instability. Therefore, micro-satellite instability (size variation in micro-satellites) reflects the loss of the DNA mismatch repair system function.

The Relationship to Cancer

The DNA mismatch repair system not only fixes the DNA errors in micro-satellites, but also fixes the errors in other parts of the genome, including the errors in some genes that are critical in carcinogenesis. Therefore, the existence of micro-satellite instability, which indicates malfunctions of the DNA mismatch repair system, implies higher risks of having cancer.

Micro-satellite instability has been seen in some common cancers. It has been especially well studied in a tumor predisposition syndrome, Lynch syndrome, also called hereditary nonpolyposis colorectal cancer. Patients with Lynch syndrome usually inherit heterozygous mutation in one or more mismatch repair genes. The gene with heterozygous mutation may still be functional. Later in life, a somatic mutation hits the other allele of this mismatch repair gene in a certain cell, and now this cell has homozygous mutation of the mismatch repair gene. A homozygous mutation may result in the loss of mismatch repair function. As well, a tumor may be developed from this cell.

In a Lynch syndrome family, a family member who has inherited heterozygous mutation of mismatch repair gene has a higher risk to develop cancer. The most common cancer seen in Lynch syndrome is colorectal carcinoma. However, not every colorectal cancer is due to Lynch syndrome. It is important to distinguish Lynch syndrome-related colorectal carcinoma from other colorectal carcinomas for two reasons. One is for the sake of the patient since, apart from colorectal carcinoma, Lynch syndrome patients may also develop other cancers, e.g., endometrial carcinoma or ovarian cancer, etc. The establishment of a Lynch syndrome diagnosis will give indication of closely monitoring other possible tumors so that an early diagnosis is possible if other tumors develop.

The other reason is for the sake of family. Lynch syndrome patient family members may potentially inherit the same heterozygous mutation. Such mutations may be identified through molecular tests. The carriers can have a more stringent surveillance for colorectal cancer. For example, the colonoscopy screen starts at the age of 25 and at every two years. In general population, colonoscopy screen usually starts at age 50 and at every 10 years afterwards if the first one is negative.

How Micro-satellite Instability is Diagnosed

Micro-satellite instability can be diagnosed using molecular tests, the micro-satellite instability (MSI) test. A unique feature of micro-satellite instability is the variation of the micro-satellite length. Taking advantage of this feature, a multiplex PCR molecular assay was developed, which will amplify multiple micro-satellites. ICG-HNPCC (The International Collaborative Group on Hereditary NonPolyposis Colorectal Cancer) Bethesda recommendation includes five microsatellites (BAT25, BAT26, D5S346, D2S123 and D17S250) as targets of the multiplex PCR. The PCR primers labeled with different fluorescent dyes will flank each micro-satellite so that each micro-satellite will be amplified by PCR.

The PCR product will be run in a gel electrophoresis and each PCR product will be identified by its sizes and tagged fluorescence. In individuals, each micro-satellite has a certain number of short tandem repeats of nucleotides, hence a certain length. In a tumor with micro-satellite instability, the length of micro-satellites may deviate from the normal length. In other words, the length of that certain micro-satellite from that tumor will be different from the length of the patient's normal tissue. Therefore, for each patient, the tumor and normal tissue will be tested and compared.

If a tumor micro-satellite deviates from the corresponding normal one, it is registered as positive. Among five micro-satellites tested, if two or more are positive, the result will be MSI-H (highfrequency MSI). If one out of five is positive, the result will be MSI-L (low-frequency MSI). When no positive is found, the result will be MSS (micro-satellite stable). MSI-H in combination of other clinical features will give a diagnosis of Lynch syndrome. MSS will help to rule out Lynch syndrome.

The biological significance of MSI-L is still in discussion. Generally speaking, its biological properties appear more like MSS tumors than MSI-H tumors.

Dr. Qin is assistant professor, Department of Pathology, Moffitt Cancer Center, Tampa, FL.


1. Coleman WB, Tsongalis GT. Molecular Diagnostics For the Clinical Laboratorian. 2nd Edition. © 2006 Humana Press Inc., Totowa, New Jersey

2. Tubbs RR, Stoler MH. Cell and Tissue Based Molecular Pathology. © 2009 Churchill Livingstone Elsevier, Philadelphia, PA.


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