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World Journal of Gastroenterology Jun 2012There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic... (Review)
Review
There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI- cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.
Topics: Animals; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; MicroRNAs; Microsatellite Instability; Mutation; Phenotype; Transcription, Genetic
PubMed: 22719182
DOI: 10.3748/wjg.v18.i22.2745 -
European Journal of Cancer (Oxford,... Sep 2022Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability (MSI)-high and microsatellite stable (MSS) gastric cancer (GC).
DESIGN
We analysed MSI status by polymerase chain reaction (PCR) and/or mismatch repair (MMR) status by immunohistochemistry in a pooled analysis of individual patient data from one retrospective cohort from Cologne, and the randomised phase III clinical trials D1/D2 and CRITICS. All patients had resectable adenocarcinoma of the stomach and/or gastro-oesophageal junction. Patients were treated with either surgery only or perioperative chemo(radio)therapy.
RESULTS
MSI and/or MMR analyses on 1307 tumours resulted in 1192 (91.2%) MSS and/or MMR proficient (MMRP) [median age, 65 years; 759 males (63.7%); 619 treated with surgery only (51.9%)], and 115 (8.8%) MSI-high [median age, 69 years; 67 males (58.3%); 76 treated with surgery only (66.1%)] GC cases. Males had shorter overall survival (OS) than female MSI-high GC (5-year OS 34.7% vs. 69.7%; hazard ratio (HR) 2.68, 95%CI 1.60 to 4.49; p < 0.001). Females with MSI-high had longer OS than those with MSS/MMRP GC (HR 0.61, 95%CI 0.41 to 0.92; p = 0.02). Males with MSI-high did not have longer OS than those with MSS/MMRP GC (HR 1.26, 95%CI 0.94 to 1.69; p = 0.12).
CONCLUSIONS
MSI-high GC males had a significantly worse prognosis compared to their female counterparts in three independent cohorts. In addition, the favourable prognostic value of MSI was only seen in females and not in males. These observations emphasise the need to consider sex differences in prognosis and treatment effects in oncology.
CLINICAL TRIAL REGISTRATION
The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.
Topics: Aged; DNA Mismatch Repair; Female; Humans; Male; Microsatellite Instability; Prognosis; Retrospective Studies; Sex Characteristics; Stomach Neoplasms
PubMed: 35863110
DOI: 10.1016/j.ejca.2022.06.025 -
Biomedica : Revista Del Instituto... May 2022Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability,...
Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Proto-Oncogene Proteins p21(ras); Retrospective Studies
PubMed: 35866738
DOI: 10.7705/biomedica.5957 -
Genes Jul 2023Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch... (Review)
Review
Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch repair (dMMR). MSI has been associated with distinct clinical, histological, and molecular features of tumors and has proven its prognostic and therapeutic value in different types of cancer. Recently, another type of microsatellite instability named elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported across many different tumors. EMAST tumors have been associated with chronic inflammation, higher tumor stage, and poor prognosis. Nevertheless, the clinical significance of EMAST and its relation to MSI remains unclear. It has been proposed that EMAST arises as a result of isolated MSH3 dysfunction or as a secondary event in MSI tumors. Even though previous studies have associated EMAST with MSI-low phenotype in tumors, recent studies show a certain degree of overlap between EMAST and MSI-high tumors. However, even in stable tumors, (MSS) frameshifts in microsatellites can be detected as a purely stochastic event, raising the question of whether EMAST truly represents a distinct type of microsatellite instability. Moreover, a significant fraction of patients with MSI tumors do not respond to immunotherapy and it can be speculated that in these tumors, EMAST might act as a modifying factor.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Microsatellite Repeats; Prognosis; DNA Mismatch Repair
PubMed: 37510378
DOI: 10.3390/genes14071474 -
Targeted Oncology Feb 2020Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch... (Review)
Review
Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore, mutational profile) are discussed.
Topics: Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Microsatellite Instability
PubMed: 31786718
DOI: 10.1007/s11523-019-00690-0 -
Genes Jan 2023Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by...
Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch Repair (MMR) machinery, including , , , , , , and . The unrepaired DNA replication errors turn into mutations at several thousand sites that contain repetitive sequences, mainly mono- or dinucleotides, and some of them are related to Lynch syndrome, a predisposition condition linked to a germline mutation in one of these genes. In addition, some mutations shortening the microsatellite (MS) stretch could occur in the 3'-intronic regions, i.e., in the (ATM serine/threonine kinase), (MRE11 homolog) or the (Heat shock protein family H) genes. In these three cases, aberrant pre-mRNA splicing was observed, and it was characterized by the occurrence of selective exon skipping in mature mRNAs. Because both the and genes, which as act as players in the MNR (/ (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences.
Topics: Humans; Microsatellite Instability; RNA Precursors; Mutation; DNA Repair; Colorectal Neoplasms, Hereditary Nonpolyposis
PubMed: 36833239
DOI: 10.3390/genes14020311 -
International Journal of Cancer Oct 2022Microsatellite instability (MSI) is an important biomarker for predicting the response to immunotherapy and prognosis that mainly results from a defective DNA mismatch...
Microsatellite instability (MSI) is an important biomarker for predicting the response to immunotherapy and prognosis that mainly results from a defective DNA mismatch repair (MMR) system and strongly correlates with high tumor mutation burden (TMB). Herein, we developed a novel method that integrates MSI score, MMR mutation status and TMB level to identify MSI status from next-generation sequencing (NGS) data. The novel method displays a sensitivity of 96.80%, a specificity of 99.96% and an overall accuracy of 99.89%, compared to current standards. Using our novel method, we analyzed 11 395 Chinese patients across 30 cancer types. High microsatellite instability (MSI-H) was detected in 210 (1.84%) samples in 18 of 30 cancer types assessed. Mutations in ACVR2A (73%), KMT2D (68%), KMT2B (66%) and MMR-related genes (MLH1, MSH2, MSH6 and PMS2) were enriched in MSI-H samples. Furthermore, MSI-H samples were more likely to have high TMB (P < .01), high PD-L1 expression (P < .05) and more tumor-infiltrating immune cells than microsatellite-stable (MSS) samples. Compared to the TCGA patients, the prevalence of MSI-H in the Chinese cohort was significantly lower in colorectal, gastric and pancreatic cancer, while significantly higher in urinary and prostate cancer. Mutations in ACVR2A (73% vs 28%, P < .01) and MMR-related genes (51.4% vs 21.3%, P < .01) were significantly higher in the Chinese population. Thus, our study suggests the fraction of MSI-H attributable to MMR inactivation mutations were lower in European than in Chinese patients, while the proportion of MSI-H due to other events may be higher.
Topics: China; Colorectal Neoplasms; DNA Mismatch Repair; Genomics; Humans; Microsatellite Instability; Microsatellite Repeats; Neoplasms
PubMed: 35567574
DOI: 10.1002/ijc.34119 -
Polish Journal of Pathology : Official... Sep 2015Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations... (Review)
Review
Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability
PubMed: 26619098
DOI: 10.5114/pjp.2015.54953 -
International Journal of Molecular... Nov 2023According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite... (Review)
Review
According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.
Topics: Humans; Stomach Neoplasms; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Chromosomal Instability; Microsatellite Instability
PubMed: 38069284
DOI: 10.3390/ijms242316961 -
Journal of Comparative Effectiveness... Nov 2021Compare overall survival (OS) between microsatellite instability (MSI) high and MSI-stable and analyze the effect of chemotherapy on OS. National cancer database was...
Compare overall survival (OS) between microsatellite instability (MSI) high and MSI-stable and analyze the effect of chemotherapy on OS. National cancer database was queried for patients diagnosed with colorectal adenocarcinoma between 2010 and 2016. We evaluated the OS and the chemotherapy effect using Kaplan-Meier estimates and multivariate Cox regression analyses. Total of 30,436 stage II patients and 30,302 stage III patients were included. In stage II with high-risk features and MSI-high, patients who received chemotherapy had better OS compared to patients who didn't receive chemotherapy. The same was found in stage II with no high-risk features and MSI-high group. Stage II colorectal cancer patients with high-risk features and MSI-high who received chemotherapy have better OS compared to patients who didn't receive chemotherapy.
Topics: Adenocarcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Humans; Kaplan-Meier Estimate; Microsatellite Instability; Neoplasm Staging; Prognosis
PubMed: 34608819
DOI: 10.2217/cer-2021-0013