Quasimonomorphic Mononucleotide Repeats for High-Level Microsatellite Instability Analysis

Microsatellite instability (MSI) analysis is becoming more and more important to detect sporadic primary tumors of the MSI phenotype as well as in helping to determine Hereditary Non-Polyposis Colorectal Cancer (HNPCC) cases. After some years of conflicting data due to the absence of consensus markers for the MSI phenotype, a meeting held in Bethesda to clarify the situation proposed a set of 5 microsatellites (2 mononucleotide repeats and 3 dinucleotide repeats) to determine MSI tumors. A second Bethesda consensus meeting was held at the end of 2002. It was discussed here that the 1998 microsatellite panel could underestimate high-level MSI tumors and overestimate low-level MSI tumors. Amongst the suggested changes was the exclusive use of mononucleotide repeats in place of dinucleotide repeats. We have already proposed a pentaplex MSI screening test comprising 5 quasimonomorphic mononucleotide repeats. This article compares the advantages of mono or dinucleotide repeats in determining microsatellite instability.

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Methylation in p14ARF is Frequently Observed in Colorectal Cancer with Low-level Microsatellite Instability

Journal of International Medical Research ◽

10.1177/147323000903700408 ◽

2009 ◽

Vol 37 (4) ◽

pp. 1038-1045 ◽

Cited By ~ 8

Author(s):

K Kominami ◽

T Nagasaka ◽

HM Cullings ◽

N Hoshizima ◽

H Sasamoto ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Gene Promoters ◽

Braf Mutations ◽

Low Level ◽

Methylguanine Dna Methyltransferase ◽

High Level

Colorectal cancer (CRC) can be classified as high-level microsatellite instability (MSI-H), low-level MSI (MSI-L) and microsatellite stable (MSS) depending on levels of MSI. MSI-H CRC relies on a distinct molecular pathway due to the mismatch repair (MMR) deficiency and shows methylation in multiple gene promoters. The genetic pathway leading to MSI-L is unknown, although higher levels of promoter methylation are observed in this group compared with MSS CRCs. This study explored how promoter methylation affects MSI phenotype, by analysing the methylation status of eight CRC-related promoters, MSI phenotype and KRAS/BRAF mutations in a series of 234 CRCs. Promoter methylation of p14ARF was significantly related to MSI-L CRC with KRAS mutation. The MSI-H phenotype was related to methylation of MLH1 as expected, while the MSS phenotype was related to methylation of p16INK4a and O6-methylguanine-DNA methyltransferase, although this was not statistically significant. Thus, promoter methylation of p14ARF could be a significant alteration leading to CRC with MSI-L.

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Immunohistochemical expression (IHC) and microsatellite instability (MSI) analysis in families with clustering of colorectal cancer

Gastroenterology ◽

10.1016/s0016-5085(03)80273-1 ◽

2003 ◽

Vol 124 (4) ◽

pp. A55

Author(s):

Andrea E. De Jong ◽

Marjo Van Puijenbroek ◽

Carli M.J. Tops ◽

Juul Wijnen ◽

Patrick F. Franken ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Immunohistochemical Expression ◽

Msi Analysis

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Correlations between microsatellite instability and the biological behaviour of tumours

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-019-03053-4 ◽

2019 ◽

Vol 145 (12) ◽

pp. 2891-2899 ◽

Cited By ~ 3

Author(s):

Guang Yang ◽

Ru-yi Zheng ◽

Zai-shun Jin

Keyword(s):

Microsatellite Instability ◽

Relevant Literature ◽

Treatment Strategies ◽

Repair System ◽

Biological Behaviour ◽

Low Level ◽

Coding Regions ◽

The Individual ◽

High Level ◽

Frameshift Peptides

Abstract Purpose Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. Methods The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. Results Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. Conclusion MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.

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Expression of HTRA Genes and Its Association with Microsatellite Instability and Survival of Patients with Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21113947 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3947

Author(s):

Dorota Zurawa-Janicka ◽

Jarek Kobiela ◽

Tomasz Slebioda ◽

Rafal Peksa ◽

Marcin Stanislawowski ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Survival Data ◽

Patient Survival ◽

Mrna Level ◽

Metastatic Potential ◽

Colorectal Carcinogenesis ◽

Cancer Tissue ◽

Protein Levels ◽

High Level

HtrA proteases regulate cellular homeostasis and cell death. Their dysfunctions have been correlated with oncogenesis and response to therapeutic treatment. We investigated the relation between HtrA1-3 expression and clinicopathological, and survival data, as well as the microsatellite status of tumors. Sixty-five colorectal cancer patients were included in the study. The expression of HTRA1-3 was estimated at the mRNA and protein levels by quantitative PCR and immunoblotting. Microsatellite status was determined by high-resolution-melting PCR. We found that the HTRA1 mRNA level was higher in colorectal cancer tissue as compared to the unchanged mucosa, specifically in primary lesions of metastasizing cancer. The levels of HtrA1 and HtrA2 proteins were reduced in tumor tissue when compared to unchanged mucosa, specifically in primary lesions of metastasizing disease. Moreover, a decrease in HTRA1 and HTRA2 transcripts’ levels in cancers with a high level of microsatellite instability compared to microsatellite stable ones has been observed. A low level of HtrA1 or/and HtrA2 in cancer tissue correlated with poorer patient survival. The expression of HTRA1 and HTRA2 changes during colorectal carcinogenesis and microsatellite instability may be, at least partially, associated with these changes. The alterations in the HTRA1/2 genes’ expression are connected with metastatic potential of colorectal cancer and may affect patient survival.

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Use of microsatellite instability in non-hereditary advanced colorectal cancer to predict response to chemotherapy and overall survival: A study of the Dutch Colorectal Cancer Group (DCCG)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4118 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4118-4118

Author(s):

M. Koopman ◽

G. A. Kortman ◽

L. Mekenkamp ◽

M. J. Ligtenberg ◽

N. Hoogerbrugge ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Microsatellite Instability ◽

Early Stage ◽

Tissue Microarrays ◽

Primary Tumors ◽

Mlh1 Promoter ◽

Cancer Group ◽

Response To Chemotherapy ◽

Embedded Blocks

4118 Background: Microsatellite instability (MSI) is present in 10–20% of patients (pts) with non-hereditary colorectal cancer (CRC) and is generally associated with improved overall survival. The effect of chemotherapy in such pts is uncertain, and most data are derived from early stage CRC. Therefore the outcome of treatment in relation to presence or absence of MSI was studied in pts with non- hereditary advanced CRC. Methods: Data were collected from previously untreated advanced CRC pts randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) vs 1st line CapIri and 2nd line CapOx. Formalin-fixed, paraffin embedded blocks of primary tumors and normal tissue were collected and tissue microarrays were made. Expression of the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was examined by immunohistochemistry. Additionally MSI analysis and hypermethylation of the MLH1-promoter were performed. Pts with a tumor showing MSI caused by hypermethylation of the MLH1-promoter were included to study the correlation between MSI status and response to 1st line treatment and overall survival. Results: MSI caused by hypermethylation of the MLH1-promoter was found in 14 (3%) of 512 eligible pts. In 461 evaluable pts, disease control (CR+PR+SD=4 months) in 12 pts with MSI was 58% [95% CI 28%- 85%] and in 449 without MSI 83% [95% CI 79%-86%, p= 0.03].The median OS in pts with MSI was 7 months [95% CI 4–17] and in pts without MSI 18 months [95% CI 16–19, log rank p=0.08]. Conclusions: MSI in advanced non-hereditary CRC is very rare, and predicts a significantly worse outcome in terms of response to chemotherapy with a trend towards a decreased OS. No significant financial relationships to disclose.

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Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?

Virchows Archiv ◽

10.1007/s00428-003-0922-z ◽

2004 ◽

Vol 444 (2) ◽

pp. 135-141 ◽

Cited By ~ 41

Author(s):

Kristina Lagerstedt ◽

Mef Nilbert ◽

Britta Halvarsson ◽

Annika Lindblom ◽

Eva Rambech

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Hereditary Nonpolyposis Colorectal Cancer ◽

Instability Analysis ◽

Hereditary Nonpolyposis ◽

Microsatellite Instability Analysis

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Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

Tumor Biology ◽

10.1177/1010428317692246 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769224 ◽

Cited By ~ 4

Author(s):

Britta Kleist ◽

Thuja Meurer ◽

Micaela Poetsch

Keyword(s):

Colorectal Cancer ◽

Lymph Node ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Lymph Node Metastases ◽

Primary Tumor ◽

Distant Metastases ◽

Primary Tumors ◽

Node Metastases ◽

Mitochondrial Microsatellite Instability

This study attempts to determine whether primary tumor tissue could reliably represent metastatic colorectal cancer in therapy-guiding analysis of mitochondrial microsatellite instability. Therefore, we investigated the concordance of microsatellite instability in D310, D514, and D16184 (mitochondrial DNA displacement loop), and its association with selected clinical categories and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status between primary and metastatic colorectal cancer tissue from 119 patients. Displacement loop microsatellite instability was significantly more frequently seen in lymph node metastases (53.1%) compared to primary tumors (37.5%) and distant metastases (21.4%) ( p = 0.0183 and p = 0.0005). The discordant rate was significantly higher in lymph node metastases/primary tumor pairs (74.6%) than in distant metastases/primary tumor pairs (52.4%) or lymph node metastases/distant metastases pairs (51.6%) ( p = 0.0113 and p = 0.0261) with more gain (86.7%) than loss (61.1%) of microsatellite instability in the discordant lymph node metastases ( p = 0.0024). Displacement loop instability occurred significantly more frequently in lymph node metastases and distant metastases of patients with early colorectal cancer onset age <60 years ( p = 0.0122 and p = 0.0129), was found with a significant high rate in a small cohort of TP53-mutated distant metastases ( p = 0.0418), and was associated with TP53 wild-type status of primary tumors ( p = 0.0009), but did not correlate with KRAS, NRAS, BRAF, or PIK3CA mutations. In conclusion, mitochondrial microsatellite instability and its association with selected clinical and molecular markers are discordant in primary and metastatic colorectal cancer, which could have importance for surveillance and therapeutic strategies.

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The “Fas counterattack” is not an active mode of tumor immune evasion in colorectal cancer with high-level microsatellite instability

Human Pathology ◽

10.1016/j.humpath.2007.06.010 ◽

2008 ◽

Vol 39 (2) ◽

pp. 243-250 ◽

Cited By ~ 18

Author(s):

Aileen M. Houston ◽

Julie M. Michael-Robinson ◽

Michael D. Walsh ◽

Margaret C. Cummings ◽

Aideen E. Ryan ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Immune Evasion ◽

Tumor Immune Evasion ◽

Active Mode ◽

High Level

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The Idylla MSI Test (CE-IVD) multi-center concordance study: Microsatellite instability detection in colorectal cancer samples.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15112 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15112-e15112

Author(s):

Patrick Pauwels ◽

Torben Steiniche ◽

Muriel Gazin ◽

Jan Van de Velde ◽

Ellen Bellon ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

High Performance ◽

University Hospital ◽

Clinical Routine ◽

Routine Diagnostics ◽

Ffpe Samples ◽

Analysis System ◽

Msi Analysis ◽

Formalin Fixed

e15112 Background: To validate the Idylla MSI Test to detect microsatellite instability (MSI) in colorectal cancer (CRC) samples in comparison with Promega MSI Analysis System v1.2 (Promega MSI) and in conditions similar to normal use. Methods: The study was performed on residual formalin-fixed and paraffin-embedded (FFPE) samples obtained from routine diagnostics by two centers, University Hospital Aarhus and University Hospital Antwerp. Samples originated from CRC patients (all stages). Both centers performed the Idylla MSI Test (with 7 novel homopolymer deletion markers) at their premises on 150 and 180 samples, respectively. The comparator method, Promega MSI, was performed for all 330 samples by University Hospital Antwerp. Results: Seven (n=7) of 330 samples were excluded from the concordance analysis due to invalid or error (failed) results for Idylla MSI Test and/or Promega MSI. For the 323 valid results, overall, positive and negative percentage agreement were 99.7% (98.3%-100%;), 98.7% (92.9%-99.8%) and 100% (98.5%-100%), respectively. A higher number of invalids was observed for Promega MSI (2.1%) compared to the Idylla MSI Test (0.6%) taking into account per protocol retesting (18 retests for Promega MSI (6%) and 3 for Idylla MSI Test (1%)). Conclusions: This study validated the Idylla MSI Test with high performance and low invalid rate to discriminate MSI-H from MSS status on a clinical routine set of CRC samples.

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