Microsatellite instability – MSI

Microsatellite instability (MSI) is the mutational signature found in colorectal cancers (CRCs) that evolve as a result of inactivation of the DNA mismatch repair (MMR) system. Genes in the MMR pathway are responsible for identifying and repairing single nucleotide mismatches and insertion or deletion loops that occur as cells grow and divide [1]. Defects in the genes involved in mismatch repair lead to an accumulation of somatic mutations in a cell, which may result in the cell becoming malignant.

Microsatellites are repeating sequences of nucleotide bases (e.g., AAAAA or CGCGCGCG) of unknown function within the genome. The length of  microsatellites is highly polymorphic in human populations, but appear stable during the life span of an individual. Microsatellites do not cause a malignancy to develop, but fluctuations in the length of microsatellites (termed instability) can mean that mismatch repair genes are not functioning correctly. MSI can be found in approximately 15% of all CRCs. Approximately 3% of all CRCs are a consequence of Lynch Syndrome, and nearly all Lynch Syndrome CRCs have MSI [2].

Microsatellite instability testing can be performed to determine if a tumor exhibits microsatellite instability (MSI) by comparing the microsatellites in the tumor specimen to a normal tissue of the same individual. If the tumor specimen exhibits alterations within the microsatellite regions, it is indicative of a probable defect in the mismatch repair genes. MSI testing demonstrating instability in the tumor specimen is suggestive of HNPCC, although not diagnostic since 10-15% of sporadic colon cancers will also exhibit MSI.

For the determination of MSI, we are using fragment analysis based test of six markers: five microsatellite markers of the Bethesda consensus panel (BAT25, BAT26, D5S346, D2S123, and D17S250) [3] one additional mononucleotide marker (BAT40) [4]. The panel of six markers is used to assess microsatellite instability in tumor tissue and normal tissue.

Patterns of normal and tumor genotypes are compared for each marker and scored as:

>> MSI-high if more than 30% of the markers show instability
>> MSI-low if fewer than 30% of the markers show instability
>> MSI-stable if 0% of the markers show instability

Patient with a microsatellite instability-high (MSI-H) tumor may be further tested for germline mutation in a mismatch repair gene and, if found, the patient and blood relatives may be counseled about strategies for early cancer detection and risk reduction. On the other hand, the majority of MSI-H tumors will be identified as sporadic by further testing, which greatly reduces the likelihood of developing new malignancies.

[1]    Boland CR: Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4:211-218, 2005.
[2]    Dietmaier W, Wallinger S, Bocker T et al. Diagnostic microsatellite instability: Definition and correlation with mismatch repair protein expression. Cancer Res 1997; 57: 4749–56.
[3]     Boland C.R., Thibodeau S.N., Hamilton S.R., Sidransky D., Eshleman J.R, Burt R.W., Meltzer S.J., Rodriguez-Bigas M.A., Fodde R., Ranzani G.N., Srivastava S. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998; 58: 5248–57.
[4]    Samowitz W.S., Slattery M.L., Potter J.D., Leppert M.F. BAT-26 and BAT-40  Instability in Colorectal Adenomas and Carcinomas and Germline Polymorphisms. American Journal of Pathology. 1999;154:1637-1641.