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Microsatellite Instability


Microsatellite instability (MSI), also known as simple sequence repeats, is a condition of DNA damage due to defects in the normal DNA repair process. Microsatellites are repeated sequences of DNA consisting of a sequence of repeating units of 1-6 base pairs in length. 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. The most common microsatellite in humans is a dinucleotide repeat of cytosine and adenine, which occurs tens of thousands of times across the genome. When a germ-line microsatellite allele undergoes somatic changes that result in gain or loss of the repeat units, microsatellites become unstable.  The appearance of abnormally long or short microsatellites in an individual's DNA is referred to as microsatellite instability (MSI).  Normally, this is prevented from happening by a DNA repair process.  A group of DNA mismatch-repair genes are responsible for correcting the abnormality. When mutation occurs in DNA repair genes, however, these abnormally long or short sequences accumulate and eventually result in errors in encoding genes. MSI plays a key role in several cancers including colorectal, endometrial, ovarian and gastric cancers. Colorectal cancer studies have demonstrated two mechanisms by which MSI causes cancer.

• The first is in hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome, where an inherited mutation in a mismatch-repair gene causes a microsatellite repeat replication error to go unfixed. The replication error results in a frame-shift mutation that inactivates or alters major tumor suppressor genes, which in turn result in malignant transformation.  About ninety percent of tumors from people who have HNPCC show microsatellite instability

• The second mechanism whereby MSI causes colorectal cancer is an epigenetic change that silences an essential mismatch-repair gene.

In both cases, microsatellite insertions and deletions of microsatellite within tumor suppressor gene coding regions result in uncontrolled cell division and tumor growth.  Mismatch repair genes encodes protein products that perform an essential cellular function by repair DNA mismatches that may occur during cellular replication.  A number of these genes have been identified in the human genome, including human MLH-1, MSH-2, MSH-3, MSH-6, PMS-1 and PMS-2.  MLH-1, MSH-2, MSH-6 and PMS-2 proteins are normally expressed in the nucleus of cells. The absence of nuclear expression of these proteins is correlated with the presence of a defect in the respective mismatch repair gene. Patients with HNPCC syndrome have an 80-90% lifetime risk of colorectal carcinoma, and typically have an early onset (mean age of onset 42 versus 65 years for conventional colorectal carcinoma).

Protein products of five of these mismatch repair genes have been recommended as biomarker by the National Cancer Institute to screen for MSI in HNPCC tumors (often called Bethesda markers). Generally, absence of two of the markers in the tumor cells is considered a positive result that is reported as high probability of MSI (MSI-H).  However loss of MLH-1 expression is most commonly due to methylation of the promote region of the MLH-1 gene.  About 50-70% patients with HNPCC have a defect in one of these DNA mismatch repair genes. 


E. Vilar et al: Microsatellite instability in colorectal cancer—the stable evidence. Nature Rev Clin Oncol  (2010) 7:153-162.

S. Popat et al: Systematic Review of Microsatellite Instability and Colorectal Cancer Prognosis. J Clin Oncol. (2005)  23 (3): 609-618.