Microsatellite instability

Micrograph showing tumor-infiltrating lymphocytes in a case of colorectal cancer with evidence of MSI-H on immunostaining. H&E stain.

Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA Mismatch Repair (MMR). In other words, MSI is the phenotypic evidence that MMR isn't functioning normally. DNA MMR corrects errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions. The proteins involved in MMR form a complex that binds to the mismatch, identifies the correct strand of DNA, then subsequently excises the error and repairs the mismatch.^[1] Cells with abnormally functioning MMR tend to accumulate errors rather than correcting those errors. As a result, gene sequences are not preserved faithfully through DNA replication, and novel Microsatellites fragments are created. Microsatellite instability is detected by PCR based assays that reveal these novel microsatellites.

There are two mechanisms that cause impaired MMR: 1. MMR gene mutation that results in a malfunctioning gene product 2. MMR gene product underproduction (for example by promoter hypermethylation).

Microsatellite instability detects that MMR is functionally impaired, but does not imply the mechanism by which it is impaired. MSI-PCR can be used as a less expensive screening tool for MMR gene mutations that are confirmed by gene sequencing.

Microsatellites are repeated sequences of DNA. These sequences can be made of repeating units of 1-6 base pairs in length. Although the length of these microsatellites is highly variable from person to person (part of DNA "fingerprint"), each individual has microsatellites of a set length. The most common microsatellite in humans is a dinucleotide repeat of CA, which occurs tens of thousands of times across the genome. Microsatellites are also known as simple sequence repeats (SSRs).

Example of Microsatellite Instability in a DNA Electropherogram Trace

Microsatellite Instability at the US National Library of Medicine Medical Subject Headings (MeSH)</ref> Sections of DNA called microsatellites, which consist of a sequence of repeating units of 1-6 base pairs in length, become unstable and can shorten or lengthen.

Clinical significance

Abnormal function of the MMR gene products increases the risk of many cancers including colorectal, endometrial, ovarian, gastric cancers.

Colorectal cancer studies have demonstrated two mechanisms for MSI occurrence:

• The first is in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch Syndrome, where an inherited mutation in a mismatch-repair gene causes a microsatellite repeat replication error to go unfixed. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...).^[2]

• The second mechanism whereby MSI is a marker for colorectal cancer is an epigenetic change that silences an essential mismatch-repair gene. Hypermethylation of a promoter may lead to gene under-expression.

Markers

Five markers have been recommended by the National Cancer Institute to screen for MSI in HNPCC tumors (often called Bethesda markers). Generally, MSI detection in two of the markers is considered a positive result or high probability of MSI (MSI-H).

MSI-High MSI-Low MSI negative

See also

• Adenomatous polyposis coli, or APC
• Chromosome Instability

References

Jiricny 2006, PMID 16612326

External links

Software for analyzing AFLP data

• SoftGenetics GeneMarker fragment analysis software