scholarly journals DNA Methylation and Genetic Aberrations in Gastric Cancer

Digestion ◽  
2020 ◽  
pp. 1-8
Author(s):  
Genki Usui ◽  
Keisuke Matsusaka ◽  
Yasunobu Mano ◽  
Masayuki Urabe ◽  
Sayaka Funata ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Tyrosine Kinases ◽  
Cpg Islands ◽  
Gene Mutations ◽  
Gastric Carcinogenesis ◽  
The Cancer Genome Atlas ◽  
Dna Hypermethylation ◽  
Genomic Amplification ◽  
Genetic Aberrations

<b><i>Background:</i></b> Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. <b><i>Summary:</i></b> Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows <i>CDKN2A</i> silencing, <i>PIK3CA</i> mutations, <i>PD-L1/2</i> overexpression, and lack of <i>TP53</i> mutations. MSI, exhibiting high DNA methylation, often has <i>MLH1</i> silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows <i>CDH1/RHOA</i> mutations or <i>CLDN18–ARHGAP</i> fusion. CIN is generally an intestinal-type GC and frequently has <i>TP53</i> mutations and genomic amplification of receptor tyrosine kinases. <b><i>Key Messages:</i></b> The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.

scholarly journals A Sparse and Low-Rank Regression Model for Identifying the Relationships Between DNA Methylation and Gene Expression Levels in Gastric Cancer and the Prediction of Prognosis

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 854
Author(s):  
Yishu Wang ◽  
Lingyun Xu ◽  
Dongmei Ai
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Dna Methylation ◽  
Regression Model ◽  
The Cancer Genome Atlas ◽  
Low Rank ◽  
Expression Levels ◽  
Rank Regression ◽  
Prediction Of Prognosis ◽  
Gene Expression Levels

DNA methylation is an important regulator of gene expression that can influence tumor heterogeneity and shows weak and varying expression levels among different genes. Gastric cancer (GC) is a highly heterogeneous cancer of the digestive system with a high mortality rate worldwide. The heterogeneous subtypes of GC lead to different prognoses. In this study, we explored the relationships between DNA methylation and gene expression levels by introducing a sparse low-rank regression model based on a GC dataset with 375 tumor samples and 32 normal samples from The Cancer Genome Atlas database. Differences in the DNA methylation levels and sites were found to be associated with differences in the expressed genes related to GC development. Overall, 29 methylation-driven genes were found to be related to the GC subtypes, and in the prognostic model, we explored five prognoses related to the methylation sites. Finally, based on a low-rank matrix, seven subgroups were identified with different methylation statuses. These specific classifications based on DNA methylation levels may help to account for heterogeneity and aid in personalized treatments.

scholarly journals A Prognostic Nomogram Model Based on mRNA Expression of DNA Methylation-Driven Genes for Gastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Zuhua Chen ◽  
Bo Liu ◽  
Minxiao Yi ◽  
Hong Qiu ◽  
Xianglin Yuan
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Mrna Expression ◽  
Risk Model ◽  
Cox Regression ◽  
Risk Group ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Clinicopathological Parameters ◽  
Dna Hypomethylation

PurposeThe exploration and interpretation of DNA methylation-driven genes might contribute to molecular classification, prognostic prediction and therapeutic choice. In this study, we built a prognostic risk model via integrating analysis of the transcriptome and methylation profile for patients with gastric cancer (GC).MethodsThe mRNA expression profiles, DNA methylation profiles and corresponding clinicopathological information of 415 GC patients were downloaded from The Cancer Genome Atlas (TCGA). Differential expression and correlation analysis were performed to identify DNA methylation-driven genes. The candidate genes were selected by univariate Cox regression analyses followed by the least absolute shrinkage and selection operator (LASSO) regression. A prognostic risk nomogram model was then built together with clinicopathological parameters.Results5 DNA methylation-driven genes (CXCL3, F5, GNAI1, GAMT and GHR) were identified by integrated analyses and selected to construct the prognostic risk model with clinicopathological parameters. High expression and low DNA hypermethylation of F5, GNAI1, GAMT and GHR, as well as low expression and high DNA hypomethylation of CXCL3 were significantly associated with poor prognosis rates, respectively. The high-risk group showed a significantly shorter prognosis than the low-risk group in the TCGA dataset (HR = 0.212, 95% CI = 0.139–0.322, P = 2e-15). The final nomogram model showed high predictive efficiency and consistency in the training and validation group.ConclusionWe construct and validate a prognostic nomogram model for GC based on five DNA methylation-driven genes with high performance and stability. This nomogram model might be a powerful tool for prognosis evaluation in the clinic and also provided novel insights into the epigenetics in GC.

scholarly journals Epigenetic Variation Analysis Leads to Biomarker Discovery in Gastric Adenocarcinoma

2020 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhang ◽  
Dianjing Guo
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Dna Methylation ◽  
Gastric Adenocarcinoma ◽  
Histone Modifications ◽  
Biomarker Discovery ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Integrated Analysis ◽  
Epigenetic Variation

As one of the most common malignant tumors worldwide, gastric adenocarcinoma (GC) and its prognosis are still poorly understood. Various genetic and epigenetic factors have been indicated in GC carcinogenesis. However, a comprehensive and in-depth investigation of epigenetic alteration in gastric cancer is still missing. In this study, we systematically investigated some key epigenetic features in GC, including DNA methylation and five core histone modifications. Data from The Cancer Genome Atlas Program and other studies (Gene Expression Omnibus) were collected, analyzed, and validated with multivariate statistical analysis methods. The landscape of epi-modifications in gastric cancer was described. Chromatin state transition analysis showed a histone marker shift in gastric cancer genome by employing a Hidden-Markov-Model based approach, indicated that histone marks tend to label different sets of genes in GC compared to control. An additive effect of these epigenetic marks was observed by integrated analysis with gene expression data, suggesting epigenetic modifications may cooperatively regulate gene expression. However, the effect of DNA methylation was found more significant without the presence of the five histone modifications in our study. By constructing a PPI network, key genes to distinguish GC from normal samples were identified, and distinct patterns of oncogenic pathways in GC were revealed. Some of these genes can also serve as potential biomarkers to classify various GC molecular subtypes. Our results provide important insights into the epigenetic regulation in gastric cancer and other cancers in general. This study describes the aberrant epigenetic variation pattern in GC and provides potential direction for epigenetic biomarker discovery.

High-Resolution Analyses of Epigenetic Aberrations in Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2425-2425
Author(s):  
Go Yamamoto ◽  
Fumihiko Nakamura ◽  
Mitsuru Iio ◽  
Motohiro Kato ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cpg Islands ◽  
Tiling Array ◽  
Gene Mutations ◽  
Gene Clusters ◽  
Neoplastic Processes ◽  
Human Genomes ◽  
Genome Wide ◽  
Hematopoietic Disorders ◽  
On Chip

Abstract Myelodysplastic syndromes are heterogeneous groups of clonal hematopoietic disorders characterized by ineffective blood cells production and predisposition to acute myeloid leukemia, and as such, it is well established that these syndromes actually represent neoplastic processes in which a series of gene mutations accumulate in blood cell precursors, leading to neoplastic expansion of dominant clones. During the past two decades, a number of genetic abnormalities have been described in MDS cases, including copy number alterations of particular chromosomal segments, mutations of Ras, p53, runx1, and Flt3 genes, and translocation involving Evi-1 family genes, TEL, MLL and Nup98 genes. On the other hand, epigenetic abnormalities are also thought to play an important role in the pathogenesis of MDS, because demethylating agents such as 5-azacydine and decitabine are often effective for high risk MDS. Unfortunately, however, only a few genes, such as INK4B gene, have been implicated in MDS pathogenesis. Especially, no genome-wide analysis of epigenetic changes in MDS has been reported. So, in the current study, we comprehensively investigated abnormalities of DNA methylation in 30 MDS specimens, using Affymetrix tiling array combined with methylated DNA immunoprecipitation (MeDIP). In this method, genomic DNA from MDS specimens was first fragmentized with ultrasonication and immuno-precipitated with anti-methylcytosine antibody (MeDIP). The immunoprecipitated DNA was then amplified by PCR and subjected to hybridization to the promorter tiling array. In this array, regulatory regions of more than 25,000 genes are tiled by 6.5 millions of oligonucleotide probes to enable sensitive detection of target sequences and approximately 59% of CpG islands in the human genomes are covered in a single array. The extent and distribution of methylation were highly variable between specimens, although some CpG islands, such as p15INK4B and HOX gene clusters, seemed to be commonly involved in different cases (Figure). In conclusion, MeDIP on chip analysis could be a powerful method for genome-wide detection of DNA methylation and facilitate our understanding of the pathogenesis of MDS. Figure Figure

scholarly journals Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad

2014 ◽  
Vol 21 (4) ◽  
pp. 567-577 ◽  
Author(s):  
Florian Haller ◽  
Evgeny A Moskalev ◽  
Fabio R Faucz ◽  
Sarah Barthelmeß ◽  
Stefan Wiemann ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Level ◽  
Gene Locus ◽  
Cpg Islands ◽  
Tumor Development ◽  
Rare Condition ◽  
Methylation Pattern ◽  
Dna Hypermethylation ◽  
Carney Triad ◽  
Alternate Mechanism

Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney–Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

scholarly journals PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands

2021 ◽  
Vol 5 (1) ◽  
pp. e202101228
Author(s):  
Xiaokang Wang ◽  
Wojciech Rosikiewicz ◽  
Yurii Sedkov ◽  
Tanner Martinez ◽  
Baranda S Hansen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Cpg Islands ◽  
Dna Demethylation ◽  
Dna Hypermethylation ◽  
Genome Wide ◽  
Associated Proteins ◽  
Tet Enzymes ◽  
Tet Protein ◽  
First Time

DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation.

scholarly journals The Biological Role of Sponge Circular RNAs in Gastric Cancer: Main Players or Coadjuvants?

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1982
Author(s):  
Adenilson Leão Pereira ◽  
Leandro Magalhães ◽  
Rafael Pompeu Pantoja ◽  
Gilderlanio Araújo ◽  
Ândrea Ribeiro-dos-Santos ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Interaction Network ◽  
Gastric Carcinogenesis ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Circular Rnas ◽  
Cancer Genome Atlas

Circular RNAs (circRNAs) are a new class of long noncoding RNAs able to perform multiple functions, including sponging microRNAs (miRNAs) and RNA-Binding Proteins (RBPs). They play an important role in gastric carcinogenesis, but its involvement during gastric cancer (GC) development and progression are not well understood. We gathered miRNA and/or RBPs sponge circRNAs present in GC, and accessed their biological roles through functional enrichment of their target genes or ligand RBPs. We identified 54 sponge circRNAs in GC that are able to sponge 51 miRNAs and 103 RBPs. Then, we evaluated their host gene expression using The Cancer Genome Atlas (TCGA) database and observed that COL1A2 is the most overexpressed gene, which may be due to circHIPK3/miR-29b-c/COL1A2 axis dysregulation. We identified 27 GC-related pathways that may be affected mainly by circPVT1, circHIPK3 and circNF1. Our results indicate that circHIPK3/miR-107/BDNF/LIN28 axis may mediate chemoresistance in GC, and that circPVT1, circHIPK3, circNF1, ciRS-7 and circ_0000096 appear to be involved in gastrointestinal cancer development. Lastly, circHIPK3, circNRIP1 and circSMARCA5 were identified in different ethnic populations and may be ubiquitous modulators of gastric carcinogenesis. Overall, the studied sponge circRNAs are part of a complex RBP-circRNA-miRNA-mRNA interaction network, and are involved in the establishment, chemoresistance and progression of GC.

Charting DNA methylation of long non-coding RNA in clear-cell renal cell carcinoma.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 432-432
Author(s):  
Gabriel Malouf ◽  
Jianping Zhang ◽  
Nizar M. Tannir ◽  
Erika Thompson ◽  
Jean-Philippe Spano ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Renal Cell ◽  
Clear Cell ◽  
Cpg Islands ◽  
Genomic Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Physiology ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Cancer Subtypes

432 Background: Long non-coding RNAs (lncRNA) play a key role in regulating cell physiology through different mechanisms including the recruitment of histone-modifying enzymes. Recently, lncRNA classification of clear-cell renal cell carcinomas (cc-RCC) established four subtypes with different clinico-pathological features. However, the interplay between those lncRNA and DNA methylation patterns remains unknown. Methods: We performed a genomic analysis of GENCODE lncRNAs in cc-RCC using The Cancer Genome Atlas (TCGA) molecular RNAseq profiles of 471 primary tumors. Furthermore, we reannotated data of DNA methylation combining 27K (n=173) and 450K (n=298) Infinium arrays. We described global correlations between lncRNA expression and DNA methylation and established lncRNA methylation subtypes based on distinct signatures. In addition, we identified lncRNA regulated by DNA methylation and associated with poor outcome. Results: We identified 2,138 lncRNAs which contain promoters located in CpG islands (CGI). Out of those, 59 (2.8%) lncRNAs showed DNA methylation in both normal and cancer as compared to 1,487 (69.5%) lncRNA which were unmethylated in both of them. Importantly, 592 (27.7%) lncRNAs gained DNA methylation in ccRCC and this was associated with the repression of the expression of 70 of them. Unsupervised clustering of lncRNA using the most variable DNA methylation probes revealed three robust subtypes associated with distinct outcome. Finally, by integrating cancer subtypes data with clinical information, we identified several lncRNAs which promoter methylation was associated with patient outcome. Conclusions: Our study represents the first integrative analysis of lncRNA and DNA methylation in ccRCC and provides new insights in the role of epigenetic alterations in kidney cancer. Furthermore, we identified a subset of lncRNA regulated epigenetically which may represent potential therapeutic targets.

Genetic and epigenetic modifications of HPDL and SOX17 associated with breast cancer prognosis: a study based on The Cancer Genome Atlas

2020 ◽  
Author(s):  
Chundi Gao ◽  
Huayao Li ◽  
Cun Liu ◽  
Jibiao Wu ◽  
Chao Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Cpg Islands ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Expression Of Genes ◽  
Number Variation ◽  
Patient Prognosis

Abstract Background：The high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis. Areas with high DNA methylation (such as CpG islands) were accompanied by copy number variation (CNV), and these genomic variations affected the level of DNA methylation. Methods: In this study, we characterized inter-tumor heterogeneity and analyzed the effects of CNV on DNA methylation and gene expression. In addition, we performed a Genetic Set Enrichment Analysis (GSEA) to identify key pathways for changes between patients with low and high expression of genes. Results: Our analysis found that the CNV of HPDL and SOX17 is not only related to the patient's prognosis, but also related to gene methylation and expression levels affecting the patient's survival time. Conclusion: This study provided an effective bioinformatics basis for further exploration of molecular mechanisms related to BRCA and assessment of patient prognosis, but the development of biomarkers for diagnosis and treatment still requires further clinical data validation.

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