The instability of microsatelite ( MSI ) is a genetic hyperbutability (predisposing to mutation) condition resulting from a DNA mismatch repair (MMR) disorder. The presence of MSI is a phenotypic proof that MMR is not functioning normally.
MMR corrects errors that occur spontaneously during DNA replication, such as single base mismatch or insertion and short deletion. The proteins involved in the MMR fix the polymerase faults by forming a complex that binds to an unsuitable piece of DNA, issuing an error, and entering the correct sequence in place. Cells with MMRs that are not functioning normally can not correct errors that occur during DNA replication and consequently accumulate errors. This led to the creation of new microsatellite fragments. Polymerase chain reaction based tests may reveal this new microsatellite and provide evidence of MSI's presence.
Microsatellite is a sequence of repetitive DNA. This sequence can be made from repeating units from one to six long base pairs. Although the length of these microsatellites varies greatly from person to person and contributes to individual DNA "fingerprints" of DNA, each individual has a microsatellite of defined length. The most common microsatellites in humans are dinucleotide repeats of nucleotides C and A, which occur tens of thousands of times throughout the genome. Microsatellites are also known as simple sequence repetition (SSRs).
Video Microsatellite instability
Structure
The structure of microsatellite instability consists of recurrent nucleotides, most often seen as GT/CA repeats.
Researchers have not confirmed the exact definition of the MSI structure. While all researchers agree that microsatellite is a recurring sequence, the length of the barrage remains questionable. Several studies have shown that MSI is a sequence of short tandem DNA replication from one to six base pairs across the genome, while other studies suggest that the range may be two to five.
Although researchers do not agree on a certain threshold for the number of tandem repetitions that are microsatellite, there is a consensus around their relative size. Longer sequences are called minisatellite, and even longer sequences are called satellite DNA sites. Some scientists distinguish between three categories with the minimum number of base pairs, and others use the minimum number of repeating units. The majority of repetitions occur in untranslated areas, especially introns. However, microsatellites occurring in the coding region often hamper the expansion of most downstream events. Microsatellite forms about three percent of the human genome, or more than one million DNA fragments. The microsatellite density increases with the size of the genome and is seen twice as much at the end of the chromosomal arm than in the chromosomal body.
Maps Microsatellite instability
Forms and functions
MSI was discovered in the 1970s and 1980s. The first human disease associated with MSI was xeroderma pigmentosum. The disease is produced from two alleles that activate mutations in the repair of nucleotide excision.
In a broad sense, MSI results from the inability of a mismatch repair protein (MMR) to correct DNA replication errors. DNA replication occurs in the "S" phase of the cell cycle; the wrong event creates the MSI region occurs during the second replication event. The original strand was unharmed, but the strands of her daughter had a frame-shift mutation due to skid DNA polymerase. Specifically, the slip DNA polymerase, creates a transient insertion-elimination loop, which is usually recognized by the MMR protein. However, when the MMR protein is not functioning normally, as in the case of MSI, the results of this loop in the frame-shift mutation, either through insertion or deletion, produce a malfunctioning protein.
MSI is unique to DNA polymorphism because replication errors vary in length rather than sequence. The rate and direction of mutations that produce MSI are the major components in determining genetic differences. To date, scientists agree that mutation rates differ in loci positions. The larger the length of the MSI, the greater the rate of mutation.
Although most of the MSI mutations are the result of frame-shift mutations, occasionally mutation events leading to MSI are derived from hypermethylation promoters of hMLH1 (MMR proteins). Hypermethylation occurs when a methyl group is added to a DNA nucleotide, producing a silencing gene, resulting in an MSI.
Researchers have shown that oxidative damage produces frame-shift mutations, resulting in MSI, but they have not yet agreed on the exact mechanism. It has been shown that the more oxidative stress is placed on the system, the more likely the mutation will occur. In addition, catalase reduces mutations, while copper and nickel improve mutations by increasing the reduction of peroxides. Some researchers believe that oxidative stress at specific loci produces DNA polymerase stops in these places, creating an environment for the occurrence of DNA slippage.
The first researchers believe that MSI is random, but there is evidence to suggest that the MSI target includes a growing list of genes. Examples include transformation of growth factor of Beta receptor gene and BAX gene. Each target leads to a different phenotype and pathology.
Clinical interests
Microsatellite instability can cause colon cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancers, urinary tract cancer, brain cancer, and skin cancer. MSI is most common cause of colon cancer. Every year, there are more than 500,000 cases of colon cancer worldwide. Based on findings from more than 7,000 stratified patients for MSI-High (MSI-H), MSI-Low (MSI-L), or Stable microsatellite (MSS) colon, those with MSI-H had a more positive prognosis of 15% to MSI-L or MSS tumors.
Colorectal tumors with MSI are found in the right colon, associated with poor tissue differentiation, high mucinogens, lymphocyte infiltration tumors, and presence of host responses such as Crohn. MSI-H tumors contribute to colorectal cancer show less metastasis than other colorectal cancers. This is demonstrated by previous studies showing that MSI-H tumor is more representative in stage II than stage III cancer.
Scientists have explored the connection of vacuolar protein-breaking protein (VPS) to MSI. Like MSI, VPS is linked to stomach and colon cancers. One study reported that the VPS protein was associated with MSI-H cancer, but not MSI-L cancer, thus limiting VPS to MSI-H-specific cancers.
Furthermore, investigators agree that MSI-H status indicates a diagnosis of Lynch syndrome, a non-metastatic prognosis, and a less aggressive treatment regimen. Lynch syndrome is caused by MSI and increases the risk of colon, endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin cancer.
One study was conducted on 120 Lynch syndrome patients that linked reactions such as MSI-related Crohn (CLR) with "specific neopeptide tumors produced during MSI-H carcinogenesis." The study further reinforces that "the presence of antimetastatic immune protection in MSI-H CRC patients can explain recent findings that 5-FU adjuvant chemotherapy has no beneficial or even adverse effects in this collective." The researchers assume that there is a protective role of lymphocytes to MSI-H CRC that prevents tumor metastasis.
MSI tumors in 15% of sporadic colorectal cancers originate from MLH 1 gene promoter hypermethylation, whereas MSI tumors in Lynch syndrome are caused by germline mutations in MLH 1, MSH 2, MSH 6, and PMS2.
MSI has been proven in the cause of sebaceous carcinoma. Sebaceous carcinoma is part of a larger pathology, Muir-Torre syndrome. MSI is varied widely expressed in Muir-Torre syndrome, most often expressed by joint pathology in patients with colon cancer. Furthermore, MMR proteins MSH1, MSH2, MSH6, and PMS2 play a role in periocular sebaceous carcinoma, which is seen in the eyelids in 40% of sebaceous carcinoma.
In May 2017 the FDA made a historic announcement of immunotherapy produced by Merck under a brand name called Keytruda® (pembrolizumab) (a PD-1 inhibitor) approved for patients with inoperable or metastatic microsatellite instability (MSI-H) or mismatches to improve deficiency solid tumor (dMMR) that has evolved following previous treatments. This indication is not dependent on the assessment of PD-L1 expression, the type of tissue and the location of the tumor.
Diagnostic microsatellite instability
MSI is a good marker for determining Lynch's syndrome and determining the prognosis for cancer treatment. In 1996, the National Cancer Institute (NCI) organized an international workshop on Lynch Syndrome, which led to the development of the "Bethesda Guidelines" and loci for MSI testing. During this first workshop NCI has approved the five microsatellite markers needed to determine the existence of MSI: two mononucleotides, BAT25 and BAT26, and three repeats of dinucleotides, D2S123, D5S346, and D17S250. MSI-H tumor from MSI results in more than 30% of unstable MSI loci (& gt; 2 or more than 5 loci). MSI-L tumors produce less than 30% of unstable MSI biomarkers. MSI-L tumors are classified as alternate etiologic tumors. Several studies have shown that MSI-H patients respond best to surgery, rather than chemotherapy and surgery, thus preventing patients from unnecessary chemotherapy.
Six years later, during a second workshop organized by NCI to review Lynch Syndrome in 2002, the Revised Bethesda Guidelines (later published in 2004) recommended new criteria for MSI testing. Specifically, they identified five mononucleotide loci as superior, more than a mixture of mono locus and dinucleotide because the dinucleotide locus could appear to shift, when in fact it did not, thereby increasing the probability of a false positive MSI-H outcome. The first commercially available kit provided by Promega Corporation, Madison, Wisconsin is called the Microsatellite Instability 1.2 Analysis System (RUO). Since then, the MSI Promega Bill has been widely adopted since 2004, with more than 120 peer-reviewed publications mentioning that global standing as a gold standard in determining MSI status of cancer tissue.
Direct and indirect mechanisms contribute to chemotherapy resistance. Direct mechanisms include a pathway that metabolizes the drug, while indirect mechanisms include the pathway that responds to chemotherapy treatment. The NER DNA repair path plays an important role in reversing cellular damage caused by chemotherapy agents such as 5-FU.
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Researchers have found another MSI, called high microsatellite changes in certain tetranucleotide repetitions (EMAST). However, EMAST is unique in that it is not derived from MMR, and is generally associated with TP53 mutations.
EMAST is seen in a variety of cancers including lung, head and neck, colorectal, skin, urinary tract, and reproductive organs. The external organ sites have more potential for EMAST. Some researchers believe that EMAST may be a consequence of mutagenesis. Positive EMAST margins in negative cancer margins show recurrence disease for patients.
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