Gene expression of MLH1 related to microsatellite instability, immuno-histochemistry, and promoter hypermethylation in colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3601-3601
Author(s):  
L. H. Jensen ◽  
A. Jakobsen ◽  
H. Kuramochi ◽  
B. Liu ◽  
C. L. Stephen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Quantitative Methods ◽  
Promoter Hypermethylation ◽  
Microsatellite Analysis ◽  
Wilcoxon Test ◽  
Specific Pcr ◽  
Immuno Histochemistry ◽  
Dna Microsatellite ◽  
Length Mutations

3601 Background: The subgroup of highly microsatellite instable (MSI-H) colorectal cancers (CRC), is well described with DNA microsatellite and immuno-histochemistry (IHC) analyses. MSI-H CRCs are most often caused by hypermethylation inactivation of MLH1 or to a lesser extent by hereditary mutations in this or other mismatch repair genes. Microsatellite analysis and IHC are qualitative rather than quantitative methods. Reports showing that MMR deficient CRC has a favorable prognosis and that these cancers may respond less to chemotherapy may be more informative if based on a quantitative method instead. The aim of the present study was to correlate the expression of MLH1 to microsatellite analysis, promoter hypermethylation, and IHC. Methods: Sections of paraffin-embedded tumors from 206 unselected consecutive patients with CRC were microdissected and RNA was isolated and reverse-transcribed to cDNA. The relative gene expression of MLH1 was measured with real-time PCR. DNA from tumor and blood was examined with five standard microsatellite markers to find length mutations indicating instability. Tumor DNA was further analyzed with a methylation specific PCR in the C region of the MLH1 promoter. Protein expression of MLH1 was analyzed with IHC. Results: For all quantifiable tumors the median (and lower and upper quartiles) of the relative MLH1 gene expression was 0.90 (0.68, 1.42). For MSI-H tumors, defined as presense of instability in at least two markers or lack of protein expression with IHC, the median was 0.36 (0.26, 0.56). For microsatellite stable cancers the median was 0.96 (0.73, 1.44), p<0.0001 (Wilcoxon test). Median and quartiles of MLH1 expression in hypermethylated and non-methylated tumors was 0.31 (0.26, 0.45) and 0.96 (0.73, 1.43) respectively (p<0.0001). Relative MLH1 expression in MSI-H tumors range up to 0.64. Fourteen % of MSS tumors are in this range, too. Conclusions: In this large unselcted group of CRC patients we found a significant relation between low gene expression, MSI-H, MLH1-hypermethylation and negative IHC. We further identify a subgroup of MSS patients with low gene expression of MLH1 and suggest this quantitative marker in studies of prognosis and treatment effect. [Table: see text]

scholarly journals Differential Hypermethylation of Death-Associated Protein Kinase Promoter in Central Neurocytoma and Oligodendroglioma

2014 ◽  
Vol 2014 ◽  
pp. 1-6
Author(s):  
Chia-Li Chung ◽  
Hung Pei Tsai ◽  
Cheng-Yu Tsai ◽  
Wan-Tzu Chen ◽  
Ann-Shung Lieu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Expression ◽  
Inverse Correlation ◽  
Promoter Hypermethylation ◽  
Central Neurocytoma ◽  
Specific Pcr ◽  
Significant Difference ◽  
Death Associated Protein Kinase ◽  
Formalin Fixed Paraffin Embedded ◽  
Apoptosis Pathways

Background. Central neurocytoma and oligodendroglioma are rare tumors of the central nervous system. However, diagnosis between these two types of tumors is challenging due to their many cytological and histological similarities. Death-associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine protein kinase involved in many apoptosis pathways, and repressed expression of DAPK by promoter hypermethylation has been found in a variety of human cancers. The purpose of this study was to assess DAPK protein expression and promoter hypermethylation in central neurocytoma and oligodendroglioma.Method. Central neurocytoma and oligodendroglioma samples were obtained from age- and sex-matched patients. DAPK protein expression was performed using immunohistochemical assays in formalin-fixed, paraffin-embedded sections. DAPK promoter hypermethylation was carried out using bisulfite-modified genomic DNA in methylation-specific PCR followed by separation in agarose gels.Findings. A statistically significant difference (P=0.021) in DAPK promoter hypermethylation between central neurocytoma (76.9%) and oligodendroglioma (20%) was observed. High levels of DAPK protein expression were generally found in oligodendroglioma (90%), compared with 38.5% in central neurocytoma (P=0.054; not statistically significant). There was an inverse correlation between DAPK protein expression and DAPK promoter hypermethylation in the cohort of 23 patients (P=0.002).Conclusions. The results show that DAPK promoter hypermethylation and repressed expression of DAPK protein were more common in central neurocytoma than in oligodendroglioma. Thus, DAPK promoter hypermethylation could be useful for differential diagnosis between these two types of tumors, whereas DAPK protein expression might be less predictive. The role of DAPK promoter hypermethylation in the pathogenesis of central neurocytoma warrants further study.

scholarly journals PAR2 Promoter Hypomethylation Regulates PAR2 Gene Expression and Promotes Lung Adenocarcinoma Cell Progression

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Kuan Wu ◽  
Lei Xu ◽  
Ling Cheng
Keyword(s):  
Gene Expression ◽  
Lung Adenocarcinoma ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Bioinformatics Analysis ◽  
Promoter Hypermethylation ◽  
Cellular Level ◽  
Specific Pcr ◽  
Cancer Occurrence ◽  
Cell Progression

Objective. Protease-activated receptor-2 (PAR2) also known as F2RL1 is a G protein-coupled receptor that intimately correlates with cancer occurrence. DNA methylation turns out a vital mechanism regulating gene expression, while PAR2 promoter methylation is proven to be involved in cancer development. Hence, this study attempted to clarify the molecular mechanism by which PAR2 mediates lung adenocarcinoma (LUAD) progression, via identifying the effect of PAR2 promoter methylation on LUAD cell progression. Methods. Associations of PAR2 promoter methylation with PAR2 gene expression and prognosis of LUAD patients were analyzed via bioinformatics analysis. PAR2 promoter methylation and gene expression at the cellular level were measured using methylation-specific PCR, qRT-PCR, and Western blot assays. DNA methyltransferase inhibitor 5-AzadC was used to treat cells to assess PAR2 gene expression alteration. Cell biological behaviors upon PAR2 overexpression were characterized via MTT, wound healing assay, and Transwell assay. Results. Bioinformatics analysis revealed that PAR2 promoter methylation was negatively related to PAR2 gene expression, while PAR2 promoter hypermethylation and low gene expression indicated favorable LUAD prognosis. Besides, it turned out that PAR2 presented upregulated expression and hypomethylated promoter in LUAD cells. Moreover, PAR2 gene expression was elevated in cells treated with 5-AzadC, and the proliferative, migratory, and invasive capabilities of cells with 5-AzadC or high PAR2 gene expression were all enhanced. Conclusion. In sum, PAR2 promoter hypomethylation potentiates LUAD cell progression, in turn affecting the prognosis of LUAD patients.

scholarly journals Protein citrullination as a source of cancer neoantigens

2021 ◽  
Vol 9 (6) ◽  
pp. e002549
Author(s):  
Hiroyuki Katayama ◽  
Makoto Kobayashi ◽  
Ehsan Irajizad ◽  
Alejandro Sevillarno ◽  
Nikul Patel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Immune Response ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Family Members ◽  
Immunohistochemical Analysis ◽  
Cancer Cell Lines ◽  
Mhc Ii

BackgroundCitrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.MethodsProtein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.ResultsProteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).ConclusionsAn immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.

scholarly journals Challenges with Methods for Detecting and Studying the Transcription Factor Nuclear Factor Kappa B (NF-κB) in the Central Nervous System

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1335
Author(s):  
Marina Mostafizar ◽  
Claudia Cortes-Pérez ◽  
Wanda Snow ◽  
Jelena Djordjevic ◽  
Aida Adlimoghaddam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Quantitative Methods ◽  
Nuclear Factor Kappa B ◽  
Inflammatory Responses ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Regulated Gene Expression ◽  
Transcription Factor Nuclear Factor

The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammation and host defense. Thus, an understanding of the methodological issues around its detection for localization, quantification, and mechanistic insights should have a broad interest across the molecular neuroscience community. In this review, we summarize the available methods for the proper detection and analysis of NF-κB among various brain tissues, cell types, and subcellular compartments, using both qualitative and quantitative methods. We also summarize the flexibility and performance of these experimental methods for the detection of the protein, accurate quantification in different samples, and the experimental challenges in this regard, as well as suggestions to overcome common challenges.

scholarly journals Toll-like receptor 2 induced senescence in intervertebral disc cells of patients with back pain can be attenuated by o-vanillin

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Matthew Mannarino ◽  
Hosni Cherif ◽  
Li Li ◽  
Kai Sheng ◽  
Oded Rabau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Back Pain ◽  
Protein Expression ◽  
Disc Degeneration ◽  
Cell Senescence ◽  
Enzyme Linked Immunosorbent Assay ◽  
Matrix Synthesis ◽  
Gene And Protein Expression ◽  
Pain Patients ◽  
In Cells

Abstract Background There is an increased level of senescent cells and toll-like teceptor-1, -2, -4, and -6 (TLR) expression in degenerating intervertebral discs (IVDs) from back pain patients. However, it is currently not known if the increase in expression of TLRs is related to the senescent cells or if it is a more general increase on all cells. It is also not known if TLR activation in IVD cells will induce cell senescence. Methods Cells from non-degenerate human IVD were obtained from spine donors and cells from degenerate IVDs came from patients undergoing surgery for low back pain. Gene expression of TLR-1,2,4,6, senescence and senescence-associated secretory phenotype (SASP) markers was evaluated by RT-qPCR in isolated cells. Matrix synthesis was verified with safranin-O staining and Dimethyl-Methylene Blue Assay (DMMB) confirmed proteoglycan content. Protein expression of p16INK4a, SASP factors, and TLR-2 was evaluated by immunocytochemistry (ICC) and/or by enzyme-linked immunosorbent assay (ELISA). Results An increase in senescent cells was found following 48-h induction with a TLR-2/6 agonist in cells from both non-degenerate and degenerating human IVDs. Higher levels of SASP factors, TLR-2 gene expression, and protein expression were found following 48-h induction with TLR-2/6 agonist. Treatment with o-vanillin reduced the number of senescent cells, and increased matrix synthesis in IVD cells from back pain patients. Treatment with o-vanillin after induction with TLR-2/6 agonist reduced gene and protein expression of SASP factors and TLR-2. Co-localized staining of p16INK4a and TLR-2 demonstrated that senescent cells have a high TLR-2 expression. Conclusions Taken together our data demonstrate that activation of TLR-2/6 induce senescence and increase TLR-2 and SASP expression in cells from non-degenerate IVDs of organ donors without degeneration and back pain and in cells from degenerating human IVD of patients with disc degeneration and back pain. The senescent cells showed high TLR-2 expression suggesting a link between TLR activation and cell senescence in human IVD cells. The reduction in senescence, SASP, and TLR-2 expression suggest o-vanillin as a potential disease-modifying drug for patients with disc degeneration and back pain.

Hepatocellular expression of glucose-6-phosphatase is unaltered during hepatic regeneration

1998 ◽  
Vol 275 (4) ◽  
pp. G717-G722 ◽  
Author(s):  
Wisam F. Zakko ◽  
Carl L. Berg ◽  
John L. Gollan ◽  
Richard M. Green
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Protein Expression ◽  
Partial Hepatectomy ◽  
Initial Phase ◽  
Physiological Function ◽  
Liver Homogenate ◽  
Hepatic Regeneration ◽  
Mrna Levels ◽  
Microsomal Enzyme

Gluconeogenesis and glycogenolysis are essential hepatic functions required for glucose homeostasis. During the initial phase of hepatic regeneration, the immediate-early genes (IEG) are rapidly expressed, and the IEG RL-1 encodes for glucose-6-phosphatase (G-6- Pase). G-6- Pase is a microsomal enzyme essential for gluconeogenesis and glycogenolysis. This study employs a partial-hepatectomy model to examine the expression and activity of G-6- Pase. After partial hepatectomy, rat hepatic G-6- Pase gene expression is transcriptionally regulated, and mRNA levels are increased ≈30-fold. However, in contrast to this rapid gene induction, microsomal enzyme activity is unchanged after partial hepatectomy. Western blotting demonstrates that microsomal G-6- Pase protein expression is also unchanged after partial hepatectomy, and similar results are also noted in whole liver homogenate. Thus, despite marked induction in gene expression of the IEG G-6- Pase after partial hepatectomy, protein expression and enzyme activity remain unchanged. These data indicate that, although this hepatocyte IEG is transcriptionally regulated, the physiologically important level of regulation is posttranscriptional. This highlights the importance of correlating gene expression of IEG with protein expression and physiological function.

scholarly journals Elevation of gene expression of Btg2, Gadd 153, and antioxidant markers in RONS-induced PC12 cells

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Aravind P ◽  
Sarojini R. Bulbule ◽  
Hemalatha N ◽  
Anushree G ◽  
Babu R.L ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Pc12 Cells ◽  
Expression Pattern ◽  
High Glucose ◽  
Nitrosative Stress ◽  
Gene Expression Pattern ◽  
Marker Genes ◽  
Differential Stress

Abstract Background Free radicals generated in the biological system bring about modifications in biological molecules causing damage to their structure and function. Identifying the damage caused by ROS and RNS is important to predict the pathway of apoptosis due to stress in PC12 cells. The first defense mechanisms against them are antioxidants which act in various pathways through important cellular organelles like the mitochondria and endoplasmic reticulum. Specific biomarkers like Gadd153 which is a marker for endoplasmic reticulum stress, Nrf2 which responds to the redox changes and translocates the antioxidant response elements, and Btg2 which is an antioxidant regulator have not been addressed in different stress conditions previously in PC12 cells. Therefore, the study was conducted to analyze the gene expression pattern (SOD, Catalase, Btg2, Gadd153, and Nrf2) and the protein expression pattern (iNOS and MnSOD) of the antioxidant stress markers in differential stress-induced PC12 cells. Peroxynitrite (1 μM), rotenone (1 μM), H2O2(100 mM), and high glucose (33 mM) were used to induce oxidative and nitrosative stress in PC12 cells. Results The results obtained suggested that rotenone-induced PC12 cells showed a significant increase in the expression of catalase, Btg2, and Gadd153 compared to the control. Peroxynitrite-induced PC12 cells showed higher expression of Btg2 compared to the control. H2O2 and high glucose showed lesser expression compared to the control in all stress marker genes. In contrast, the Nrf2 gene expression is downregulated in all the stress-induced PC12 cells compared to the control. Further, MnSOD and iNOS protein expression studies suggest that PC12 cells exhibit a selective downregulation. Lower protein expression of MnSOD and iNOS may be resulted due to the mitochondrial dysfunction in peroxynitrite-, high glucose-, and H2O2-treated cells, whereas rotenone-induced cells showed lower expression, which could be the result of a dysfunction of the endoplasmic reticulum. Conclusion Different stress inducers like rotenone, peroxynitrite, H2O2, and high glucose increase the NO and ROS. Btg2 and Gadd153 genes were upregulated in the stress-induced cells, whereas the Nrf2 was significantly downregulated in differential stress-induced PC12 cells. Further, antioxidant marker genes were differentially expressed with different stress inducers.

scholarly journals Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression

2010 ◽  
Vol 28 (13) ◽  
pp. 2174-2180 ◽  
Author(s):  
Rafal Dziadziuszko ◽  
Daniel T. Merrick ◽  
Samir E. Witta ◽  
Adelita D. Mendoza ◽  
Barbara Szostakiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Expression ◽  
Squamous Cell ◽  
Copy Number ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Gene Copy ◽  
Cell Versus

PurposeThe purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis.Patients and MethodsOne hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181).ResultsIGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis.ConclusionIGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

scholarly journals Receptor-driven invasion profiles in diffuse intrinsic pontine glioma (DIPG)

2021 ◽  
Author(s):  
Anju Karki ◽  
Noah E Berlow ◽  
Jin-Ah Kim ◽  
Esther Hulleman ◽  
Qianqian Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Expression ◽  
Cell Viability ◽  
Rna Sequencing ◽  
Cell Invasion ◽  
Growth Factor Receptor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Sequencing Data ◽  
Pontine Glioma

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric cancer with unmet clinical need. DIPG is invasive in nature, where tumor cells interweave into the fiber nerve tracts of the pons making the tumor unresectable. Accordingly, novel approaches in combating the disease is of utmost importance and receptor-driven cell invasion in the context of DIPG is under-researched area. Here we investigated the impact on cell invasion mediated by PLEXINB1, PLEXINB2, platelet growth factor receptor (PDGFR)α, PDGFRβ, epithelial growth factor receptor (EGFR), activin receptor 1 (ACVR1), chemokine receptor 4 (CXCR4) and NOTCH1. Methods We used previously published RNA-sequencing data to measure gene expression of selected receptors in DIPG tumor tissue versus matched normal tissue controls (n=18). We assessed protein expression of the corresponding genes using DIPG cell culture models. Then, we performed cell viability and cell invasion assays of DIPG cells stimulated with chemoattractants/ligands. Results RNA-sequencing data showed increased gene expression of receptor genes such as PLEXINB2, PDGFRα, EGFR, ACVR1, CXCR4 and NOTCH1 in DIPG tumors compared to the control tissues. Representative DIPG cell lines demonstrated correspondingly increased protein expression levels of these genes. Cell viability assays showed minimal effects of growth factors/chemokines on tumor cell growth in most instances. Recombinant SEMA4C, SEM4D, PDGF-AA, PDGF-BB, ACVA, CXCL12 and DLL4 ligand stimulation altered invasion in DIPG cells. Conclusions We show that no single growth factor-ligand pair universally induces DIPG cell invasion. However, our results reveal a potential to create a composite of cytokines or anti-cytokines to modulate DIPG cell invasion.

scholarly journals Epigenetic events in medulloblastoma development

2005 ◽  
Vol 19 (5) ◽  
pp. 1-13 ◽  
Author(s):  
Janet C. Lindsey ◽  
Jennifer A. Anderton ◽  
Meryl E. Lusher ◽  
Steven C. Clifford
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor Genes ◽  
Molecular Basis ◽  
Gene Disruption ◽  
Functional Role ◽  
Promoter Hypermethylation ◽  
Therapeutic Approaches ◽  
Primary Tumors ◽  
Molecular Events ◽  
Epigenetic Events

Over the last decade, the analysis of genetic defects in primary tumors has been central to the identification of molecular events and biological pathways involved in the pathogenesis of medulloblastoma, the most common malignant brain tumor of childhood. Despite this, understanding of the molecular basis of the majority of cases remains poor. In recent years, the emerging field of epigenetics, which describes heritable alterations in gene expression that occur in the absence of DNA sequence changes, has forced a revision of the understanding of the mechanisms of gene disruption in cancer. Accumulating evidence indicates a significant involvement for epigenetic events in medulloblastoma development. Recent studies have identified a series of candidate tumor suppressor genes (for example, RASSF1A, CASP8, and HIC1) that are each specifically epigenetically inactivated in a large proportion (> 30%) of medulloblastomas by promoter hypermethylation, leading to the silencing of their gene expression. These findings shed new light on medulloblastoma and offer great potential for an improved understanding of its molecular pathology. The authors review the current understanding of epigenetic events in cancer and their contribution to medulloblastoma development. Their nature, origins, and functional role(s) in tumorigenesis are considered, and the authors assess the potential utility of these events as a basis for novel diagnostic and therapeutic approaches.

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