Dataset Information

Specific Glioma Prognostic Subtype Distinctions Based on DNA Methylation Patterns.

ABSTRACT: DNA methylation is an important regulator of gene expression and may provide an important basis for effective glioma diagnosis and therapy. Here, we explored specific prognosis subtypes based on DNA methylation status using 653 gliomas from The Cancer Genome Atlas (TCGA) database. Five subgroups were distinguished by consensus clustering using 11,637 cytosines preceding a guanosine (CpGs) that significantly influenced survival. The specific DNA methylation patterns were correlated with age, tumor stage, and prognosis. Additionally, weighted gene co-expression network analysis (WGCNA) analysis of CpG sites revealed that 11 of them could distinguish the samples into high- and low-methylation groups and could classify the prognostic information of samples after cluster analysis of the training set samples using the hierarchical clustering algorithm. Similar results were obtained from the test set and 12 glioma patients. Moreover, in vitro experiments revealed an inverse relationship between methylation level and migration ability or insensitivity to temozolomide (or radiotherapy) of glioma cells based on the final prognostic predictor. Thus, these results suggested that the model constructed in this study could provide guidance for clinicians regarding the prognosis of various epigenetic subtypes.

SUBMITTER: Chen X

PROVIDER: S-EPMC6751377 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Specific Glioma Prognostic Subtype Distinctions Based on DNA Methylation Patterns.

Chen Xueran X Zhao Chenggang C Zhao Zhiyang Z Wang Hongzhi H Fang Zhiyou Z

Frontiers in genetics 20190912

DNA methylation is an important regulator of gene expression and may provide an important basis for effective glioma diagnosis and therapy. Here, we explored specific prognosis subtypes based on DNA methylation status using 653 gliomas from The Cancer Genome Atlas (TCGA) database. Five subgroups were distinguished by consensus clustering using 11,637 cytosines preceding a guanosine (CpGs) that significantly influenced survival. The specific DNA methylation patterns were correlated with age, tumo ...[more]

PMID: 31572431

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Project description:Tumor subtype and menopausal status are strong predictors of breast cancer (BC) prognosis. We aimed to find and validate subtype- or menopausal-status-specific changes in tumor DNA methylation (DNAm) associated with all-cause mortality or BC progression. Associations between site-specific tumor DNAm and BC prognosis were estimated among The Cancer Genome Atlas participants (n = 692) with Illumina Infinium HumanMethylation450 BeadChip array data. All-cause mortality and BC progression were modeled using Cox proportional hazards models stratified by tumor subtypes, adjusting for age, race, stage, menopausal status, tumor purity, and cell type proportion. Effect measure modification by subtype and menopausal status were evaluated by incorporating a product term with DNAm. Site-specific inference was used to identify subtype- or menopausal-status-specific differentially methylated regions (DMRs) and functional pathways. The validation of the results was carried out on an independent dataset (GSE72308; n = 180). We identified a total of fifteen unique CpG probes that were significantly associated ( P≤1×10-7 with survival outcomes in subtype- or menopausal-status-specific manner. Seven probes were associated with overall survival (OS) or progression-free interval (PFI) for women with luminal A subtype, and four probes were associated with PFI for women with luminal B subtype. Five probes were associated with PFI for post-menopausal women. A majority of significant probes showed a lower risk of OS or BC progression with higher DNAm. We identified subtype- or menopausal-status-specific DMRs and functional pathways of which top associated pathways differed across subtypes or menopausal status. None of significant probes from site-specific analyses met genome-wide significant level in validation analyses while directions and magnitudes of coefficients showed consistent pattern. We have identified subtype- or menopausal-status-specific DNAm biomarkers, DMRs and functional pathways associated with all-cause mortality or BC progression, albeit with limited validation. Future studies with larger independent cohort of non-post-menopausal women with non-luminal A subtypes are warranted for identifying subtype- and menopausal-status-specific DNAm biomarkers for BC prognosis.

Project description:Many studies have demonstrated that epigenetic mechanisms are important in the regulation of gene expression during embryogenesis, gametogenesis, and other forms of tissue-specific gene regulation. We sought to explore the possible role of epigenetics, specifically DNA methylation, in the establishment and maintenance of cell type-restricted gene expression in the retina. To assess the relationship between DNA methylation status and expression level of retinal genes, bisulfite sequence analysis of the 1000 bp region around the transcription start sites (TSS) of representative rod and cone photoreceptor-specific genes and gene expression analysis were performed in the WERI and Y79 human retinoblastoma cell lines. Next, the homologous genes in mouse were bisulfite sequenced in the retina and in non-expressing tissues. Finally, bisulfite sequencing was performed on isolated photoreceptor and non-photoreceptor retinal cells isolated by laser capture microdissection. Differential methylation of rhodopsin (RHO), retinal binding protein 3 (RBP3, IRBP) cone opsin, short-wave-sensitive (OPN1SW), cone opsin, middle-wave-sensitive (OPN1MW), and cone opsin, long-wave-sensitive (OPN1LW) was found in the retinoblastoma cell lines that inversely correlated with gene expression levels. Similarly, we found tissue-specific hypomethylation of the promoter region of Rho and Rbp3 in mouse retina as compared to non-expressing tissues, and also observed hypomethylation of retinal-expressed microRNAs. The Rho and Rbp3 promoter regions were unmethylated in expressing photoreceptor cells and methylated in non-expressing, non-photoreceptor cells from the inner nuclear layer. A third regional hypomethylation pattern of photoreceptor-specific genes was seen in a subpopulation of non-expressing photoreceptors (Rho in cones from the Nrl -/- mouse and Opn1sw in rods). These results demonstrate that a number of photoreceptor-specific genes have cell-specific differential DNA methylation that correlates inversely with their expression level. Furthermore, these cell-specific patterns suggest that DNA methylation may play an important role in modulating photoreceptor gene expression in the developing mammalian retina.

Dataset Information

Specific Glioma Prognostic Subtype Distinctions Based on DNA Methylation Patterns.

Publications

Specific Glioma Prognostic Subtype Distinctions Based on DNA Methylation Patterns.

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