Microsatellite instability

Microsatellites are short, tandem sequences of mononucleotide, dinucleotide, or higher-order nucleotide repeats that are scattered throughout the human genome.

Microsatellites hard defined as short, repeating DNA sequences that are prone to slipage during DNA replication.

Microsatellites are prone to DNA replication errors as a result of DNA polymerase slippage, leading to missmatched DNA strands.

Normally, these replication errors can be repaired by DNA mismatch repair (MMR) system.

Defects in MMR (dMMR) proteins can lead to accumulation of mutations in microsatellite sequences resulting in MSI.

Microsatellite mutations located within coding sequences can produce abnormal proteins involved in DNA repair, apoptosis, or cell growth, which can ultimately lead to development of cancer.

MSIis an important biomarker to guide immunotherapy.

High level of microsatellite instability (MSI-H)  is the genetic feature of a sub group of cancers characterized by a deficient mismatch repair (dMMR) system and resulting in inability to correct damage to DNA that primarily derives from single base repair insertions or deletions that may occur during DNA replication by DNA polymerases.
Errors in bass-pair of matching during DNA replication are normally  correctly, but a faulty mismatch repair process can result in the accumulation of insertions or deletions that predisposed to malignant tumors.

Because of the high  immunogenicity of these tumors, microsatellite instability-high (MSI-H) or deficiency MMR cancers respond well to immunotherapy in contrast to their  microsatellites stable counterparts.

Each time a cell divides, approximately 100,000 polymerase errors occur, and polymerase attempts to correct them through its proof reading activity.

Some areas escape proofreading and are corrected through the MMR system, which is responsible for surveillance and correction of errors during DNA replication, repair , and recombination.

Although MSI-H tumors can elicit an immune response, MS-H tumors also Express checkpoint inhibitors such as PD-1, CTLA – 4 aT higher rates which suppress the immune response and immune mediated tumor lysis.

MLH1, MSH2, MSH6, and PMS2 are the main proteins involved in the MMR system.

Loss of function of any of these proteins leads to a state of MMR-D and high instability in microsattelite repeats.

Found in many different malignancies and characterized by a change in length of DNA microsatellites secondary to insertion or deletion of repeating units.

The condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR).

The presence of MSI is phenotypic evidence that MMR is not functioning normally.

MMR corrects errors that spontaneously occur during DNA replication, such as single base mismatches or short insertions and deletions.

The proteins involved in MMR correct polymerase errors by forming a complex that binds to the mismatched section of DNA, excises the error, and inserts the correct sequence in its place.

Cells with abnormally functioning MMR are unable to correct errors that occur during DNA replication and consequently accumulate errors, causing the creation of microsatellite fragments.

Polymerase chain reaction-based assays can reveal these novel microsatellites and provide evidence for the presence of MSI.

Microsatellites are repeated sequences of DNA, and can be made of repeating units of one to six base pairs in length.

Thevlength of microsatellites is highly variable from person to person and contributes to the individual DNA “fingerprint”.

Each person has microsatellites of a set length.

The most common microsatellite is a dinucleotide repeat of the nucleotides C and A, which occurs tens of thousands of times across the genome.

Microsatellite instability structure consists of repeated nucleotides, most often seen as GT/CA repeats.

Microsatellites are repeat sequences, the lengths of the sequences remain in question.

Longer sequences are called minisatellite, and even longer sequences are called satellite DNA sites.

Microsatellites make up approximately three percent of the human genome, or more than one million fragments of DNA.

Microsatellite density increases with genome size and is seen twice as much at the ends of chromosome arms than in the chromosome bodies.

The first human disease attributed to MSI was xeroderma pigmentosum.

MSI results from the inability of the mismatch repair (MMR) proteins to fix a DNA replication error.

DNA replication occurs in the “S” phase of the cell cycle.

The event creating an MSI region occurs during the second replication event.

The original DNA strand is unharmed, but the daughter strand experiences a mutation due to DNA polymerase slippage.

DNA polymerase slips, creating a temporary insertion-deletion loop, which is usually recognized by MMR proteins.

When the MMR proteins do not function normally, as in the case of MSI, this loop results in frame-shift mutations, either through insertions or deletions, yielding non-functioning proteins.

The replication errors vary in length instead of sequence.

The rate and direction of the mutations yielding MSIs are the major components in determining genetic differences.

The mutation rates differ in loci position.

The greater the length of the MSI, the greater the mutation rate.

Most mutations of MSI are the result of frame-shift mutations.

Occasionally the mutation events leading to MSI are derived from the hypermethylation of the hMLH1 (MMR protein) promoter.

Oxidative damage yields mutations, thus yielding MSI

MSI targets include the transforming growth factor Beta receptor gene and the BAX gene.

May result in colon cancer, gastric cancer, endometrium cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, and skin cancers, but is most prevalent as the cause of colon cancers.

About 20-30% of patients with endometrial cancer have microsatellite instability high disease.

Based on findings from over 7,000 patients stratified for MSI-High (MSI-H), MSI-Low (MSI-L), or Microsatellite Stable (MSS) colon cancers, those with MSI-H had a more positive prognosis by 15% compared to MSI-L or MSS tumors.

It is estimated that 10-15% of all sporadic colorectal cancers are mismatch repair-deficient or microsatellite instability high.

Colorectal tumors with MSI are found in the right colon.

Postcolonoscopy colorectal cancers were more likely to arise in the proximal colon and to show microsatellite instability.

MSI colorectal tumors are associated with poor differentiated tissue, high mucinogens, tumor infiltrating lymphocytes, and a presence of a Crohn’s-like host response.

MSI-H tumors contributing to colorectal cancer exhibit less metastasis than other derived colorectal cancer, more representative in Stage II rather than Stage III cancers.

MSI-H status indicates the diagnosis of Lynch syndrome, non-metastatic prognosis, and less aggressive treatment regimens.

Lynch syndrome is caused by MSI and increases the risk for colon, endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin cancers.

In MSI-H CRC adjuvant 5-FU chemotherapy has no beneficial or even adverse effects, as it is assumed that there is a protective role of lymphocytes against the MSI-H CRC that prevents tumor metastasis.

MSI tumors in 15% of sporadic colorectal cancer result from the hypermethylation of the MLH 1 gene promoter, whereas MSI tumors in Lynch syndrome are caused by germline mutations in MLH 1, MSH 2, MSH 6, and PMS2.

MSI has been evident in the cause of sebaceous carcinomas.

Pembrolizumab (PD-1 inhibitor) was approved for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment.

This indication is independent of PD-L1 expression assessment, tissue type and tumor location.

MSI is a good marker for determining Lynch syndrome and determining a prognosis for cancer treatments.

There are five microsatellite markers necessary to determine MSI presence: two mononucelotides, BAT25 and BAT26, and three dinucelotide repeats, D2S123, D5S346, and D17S250.

MSI-H tumors result from MSI of greater than 30% of unstable MSI biomarkers.

MSI-L tumors result from less than 30% of unstable MSI biomarkers.

MSI-L tumors are classified as tumors of alternative etiologies.

MSI-H patients may respond best to surgery alone, rather than chemotherapy and surgery, thus preventing patients from needlessly experiencing chemotherapy.

Microsatellites are areas of the genome at which the DNA sequence is repetitive.

Genomic instability divided into microsatellite instability and chrmosomal intability.

A result of sliding in the DNA chain because of shortening or elongation repeat zones of DNA during replication.

Referred to as a change in the length of the DNA microsatellites due to the insertion and deletion of repeating units, usually 1-5 nucleotides long, caused by defects in this match repair genes such as MLH1, MSH2, or MSH6, and others, or methylation of the MLH1 promoter.

It is usually corrected by the enzymes coded by DNA mismatch repair genes.

Detection of microsatellite instability is a sign of the disorder in the MMR (mismatch repair) genes, particularly hMLH1 and hMSH2.

Defective DNA mismatch repair-associated with nonpolyposis colon cancer, 15-20% of sporadic colon carcinomas and has been described in endometrial, stomach, pancreas, prostate, lung, breast, and bladder cancer.

Cancers displaying MSI have a proximally 47 mutations per million bases and are considered hyper mutated.

Micro satellite stable malignant disease is characterized by an average of 2.8 mutations per million bases.

MSI present in 15-20% of colorectal tumors, and in 4-6% of metastatic colorectal tumors.

All patients with colon cancer should be tested for microsatellite status.

Present in most cases of Lynch syndrome colorectal cancers.

About 4% of patients with metastatic colorectal cancer have tumors with a high-degree of microsatellite instability (MSI-H due to deficiency in the DNA mismatch repair system (MMR)and these patients may be less responsive to conventional chemotherapy than are patients whose tumors are MMR proficient.

Status frequently determined by five genetic markers.

Found in half to two-thirds of sporadic colorectal cancers.

Caused by mutations in mismatch repair genes hMSH2, hMLH1 and hMSH6, which result in failure to correct errors that occur during replication.

Association between MSI-H phenotype and improved survival in stage II and stage III colorectal cancer patients.

Presence of mutation in transforming growth factor beta-RII with high microsatellite instability have an improved survival, and increased benefit with adjuvant chemotherapy.

Patients with colorectal cancers with microsatellite instability have a better recurrence free survival compared with those with microsatellite stable tumors.

In metastatic colon rectal cancer only 4-5% of tumors are classified as MSI-H and/or MMR-D and the rest are microsatellite stable (MSS) or mismatch repair proficient.

When MSI is high and mismatch repair is deficient the expected 5-year survival in colorectal cancer is 90% vs less than 75% for a microsatellite stable profile.

Tumors should be tested for microsatellite instability when colorectal cancer is diagnosed before the age of 50 years, the presence of colorectal cancers that are synchronous, or metachronous, or other tumors associated with hereditary nonpolyposis colorectal cancer regardless of age.

Tumors deficient in mismatch repair proteins are unable to repair mismatches that occur during DNA repair.

As a result of this deficiency to repair mutations accumulate and the more mutations the higher the probability that a tumor will create neoantigens that the immune system can target.

The deficiency of the mismatch repair system conceivably leads to an accumulation of DNA variations in the tumor genome, which increases the likelihood for the expression of the immunogenic neoantigens on the surface of the tumor cells that in turn can be the targets of immune response.

Molecular alterations are associated with a high tumor mutation burden and induced susceptibility to immunotherapeutic approaches.

MSI associated colon cancers do not show significant karyotypic abnormalities and are often diploid or nearly so.

Chromosomal instability associated cancers, in contrast to MSI associated cancers, are aneuploid and do not show instability at the nucleotide level.

MMR-deficient/MSI-H tumors are hypermutated and associated with elevated levels of tumor neoantigens and tumor-infiltrating lymphocytes and upregulated expression of checkpoint regulators in immune cells, including PD-! and PD-L1.

Checkpoint inhibitors are approved for immune therapy in the treatment of chemotherapy refractory microsatellite instable-high cancers regardless of the primary tumor site.

The levels of baseline T-cell lymphocyte infiltrates in tumors with a high degree of micsrosatellite instability (MSI-H tumors) have prognostic implications.

Most colorectal cancers have chromosomal instability rather than MSI.

Testing for MSI currently recommended for most patients after a diagnosis of colorectal cancer, both for hereditary syndrome screening and for the prognosis and treatment implications.

Patients with microsatellite instability-high and/or mismatch repair deficient metastatic colon rectal cancer benefit less from conventional chemotherapy than those with microsatellite stable/mismatch repair proficient metastatic colon rectal cancer.

Microsatellite instability-high/mismatch repair deficiency is a predictive marker of response to treatment with anti-program death checkpoint inhibitor therapy.

Pembrolizumab has led to significantly longer progression free survival than chemotherapy when received as  first line therapy for MSI-high or mismatch repair deficient metastatic Colorectal cancer.
In patients  with MSI-H cancers, treatment with immune checkpoint inhibitors is associated with a high activity and MSI status has a high predictive value for the benefit of immunotherapy.

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