Special Issue "Microsatellite Instability"

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics".

Deadline for manuscript submissions: closed (30 November 2014)

Special Issue Editor

Guest Editor
Dr. Maija Kohonen-Corish

Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia
Website | E-Mail

Special Issue Information

Dear Colleagues,

Microsatellites are short repetitive sequences of DNA, also known as simple sequence repeats, which have wide-ranging applications in the study of cancer, inflammation and aging as well as neurological and neuromuscular diseases.

This Special Issue is inviting reviews or original contributions relating to any type of microsatellite instability in humans or other model organisms as well as the genes and mechanisms that generate microsatellite instability and cause diseases.

Dr. Maija Kohonen-Corish
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • microsatellite instability (MSI)
  • cancer
  • neuromuscular diseases
  • neurological diseases
  • inflammation
  • aging
  • mononucleotide repeat
  • dinucleotide repeat
  • trinucleotide repeat
  • tetranucleotide repeat
  • DNA mismatch repair gene defects
  • DNA repair genes and mechanisms
  • diagnostic testing
  • genetic mapping

Published Papers (6 papers)

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Research

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Open AccessArticle Applicability of Next Generation Sequencing Technology in Microsatellite Instability Testing
Genes 2015, 6(1), 46-59; doi:10.3390/genes6010046
Received: 25 November 2014 / Accepted: 27 January 2015 / Published: 12 February 2015
Cited by 4 | PDF Full-text (7772 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Microsatellite instability (MSI) is a useful marker for risk assessment, prediction of chemotherapy responsiveness and prognosis in patients with colorectal cancer. Here, we describe a next generation sequencing approach for MSI testing using the MiSeq platform. Different from other MSI capturing strategies that
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Microsatellite instability (MSI) is a useful marker for risk assessment, prediction of chemotherapy responsiveness and prognosis in patients with colorectal cancer. Here, we describe a next generation sequencing approach for MSI testing using the MiSeq platform. Different from other MSI capturing strategies that are based on targeted gene capture, we utilize “deep resequencing”, where we focus the sequencing on only the microsatellite regions of interest. We sequenced a series of 44 colorectal tumours with normal controls for five MSI loci (BAT25, BAT26, BAT34c4, D18S55, D5S346) and a second series of six colorectal tumours (no control) with two mononucleotide loci (BAT25, BAT26). In the first series, we were able to determine 17 MSI-High, 1 MSI-Low and 26 microsatellite stable (MSS) tumours. In the second series, there were three MSI-High and three MSS tumours. Although there was some variation within individual markers, this NGS method produced the same overall MSI status for each tumour, as obtained with the traditional multiplex PCR-based method. Full article
(This article belongs to the Special Issue Microsatellite Instability)
Open AccessArticle Altered Ca2+ Homeostasis and Endoplasmic Reticulum Stress in Myotonic Dystrophy Type 1 Muscle Cells
Genes 2013, 4(2), 275-292; doi:10.3390/genes4020275
Received: 1 April 2013 / Revised: 3 May 2013 / Accepted: 16 May 2013 / Published: 4 June 2013
Cited by 8 | PDF Full-text (1030 KB) | HTML Full-text | XML Full-text
Abstract
The pathogenesis of Myotonic Dystrophy type 1 (DM1) is linked to unstable CTG repeats in the DMPK gene which induce the mis-splicing to fetal/neonatal isoforms of many transcripts, including those involved in cellular Ca2+ homeostasis. Here we monitored the splicing of three
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The pathogenesis of Myotonic Dystrophy type 1 (DM1) is linked to unstable CTG repeats in the DMPK gene which induce the mis-splicing to fetal/neonatal isoforms of many transcripts, including those involved in cellular Ca2+ homeostasis. Here we monitored the splicing of three genes encoding for Ca2+ transporters and channels (RyR1, SERCA1 and CACN1S) during maturation of primary DM1 muscle cells in parallel with the functionality of the Excitation-Contraction (EC) coupling machinery. At 15 days of differentiation, fetal isoforms of SERCA1 and CACN1S mRNA were significantly higher in DM1 myotubes compared to controls. Parallel functional studies showed that the cytosolic Ca2+ response to depolarization in DM1 myotubes did not increase during the progression of differentiation, in contrast to control myotubes. While we observed no differences in the size of intracellular Ca2+ stores, DM1 myotubes showed significantly reduced RyR1 protein levels, uncoupling between the segregated ER/SR Ca2+ store and the voltage-induced Ca2+ release machinery, parallel with induction of endoplasmic reticulum (ER) stress markers. In conclusion, our data suggest that perturbed Ca2+ homeostasis, via activation of ER stress, contributes to muscle degeneration in DM1 muscle cells likely representing a premature senescence phenotype. Full article
(This article belongs to the Special Issue Microsatellite Instability)

Review

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Open AccessReview EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression
Genes 2015, 6(2), 185-205; doi:10.3390/genes6020185
Received: 24 February 2015 / Revised: 19 March 2015 / Accepted: 23 March 2015 / Published: 31 March 2015
Cited by 11 | PDF Full-text (516 KB) | HTML Full-text | XML Full-text
Abstract
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high
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DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3. Full article
(This article belongs to the Special Issue Microsatellite Instability)
Open AccessReview Abnormal Base Excision Repair at Trinucleotide Repeats Associated with Diseases: A Tissue-Selective Mechanism
Genes 2013, 4(3), 375-387; doi:10.3390/genes4030375
Received: 2 May 2013 / Revised: 25 June 2013 / Accepted: 26 June 2013 / Published: 25 July 2013
Cited by 2 | PDF Full-text (324 KB) | HTML Full-text | XML Full-text
Abstract
More than fifteen genetic diseases, including Huntington’s disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can
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More than fifteen genetic diseases, including Huntington’s disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression. DNA damage and base excision repair (BER) are involved in repeat instability and might contribute to the tissue selectivity of the process. In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER. Full article
(This article belongs to the Special Issue Microsatellite Instability)

Other

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Open AccessDiscussion Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification
Genes 2015, 6(2), 150-162; doi:10.3390/genes6020150
Received: 30 November 2014 / Revised: 4 March 2015 / Accepted: 23 March 2015 / Published: 30 March 2015
Cited by 2 | PDF Full-text (2747 KB) | HTML Full-text | XML Full-text
Abstract
Inherited mutations in the DNA mismatch repair genes (MMR) can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI) is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a
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Inherited mutations in the DNA mismatch repair genes (MMR) can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI) is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants) are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review. Full article
(This article belongs to the Special Issue Microsatellite Instability)
Open AccessDiscussion Lynch Syndrome: An Updated Review
Genes 2014, 5(3), 497-507; doi:10.3390/genes5030497
Received: 3 December 2013 / Revised: 30 April 2014 / Accepted: 9 May 2014 / Published: 27 June 2014
Cited by 15 | PDF Full-text (100 KB) | HTML Full-text | XML Full-text
Abstract
Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the
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Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics. Full article
(This article belongs to the Special Issue Microsatellite Instability)

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