Comprehensive DNA Methylation Profiling Identifies Novel Diagnostic Biomarkers for Thyroid Cancer

Park, Jong‐Lyul; Jeon, Sora; Seo, Eun‐Hye; Bae, Dong Hyuck; Jeong, Young Mun; Kim, Yourha; Bae, Ja Seong; Kim, Seon‐Kyu; Jung, Chan Kwon; Kim, Yong‐Sung

doi:10.1089/thy.2019.0011

Cited by 29 publications

(17 citation statements)

References 34 publications

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“…Detailed demographic and baseline characteristics of patients are summarized in the Table 1. The present study was performed on the same cohort and tissue samples used in our previous study investigating DNA methylation biomarkers [50].…”

Section: Study Subjectsmentioning

confidence: 99%

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MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer

Park

Kim

Jeon

et al. 2021

Cancers

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The challenge in managing thyroid nodules is to accurately diagnose the minority of those with malignancy. We aimed to identify diagnostic and prognostic miRNA markers for thyroid nodules. In a discovery cohort, we identified 20 candidate miRNAs to differentiate between noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and papillary thyroid carcinomas (PTC) by using the high-throughput small RNA sequencing method. We then selected three miRNAs (miR-136, miR-21, and miR-127) that were differentially expressed between the PTC follicular variant and other variants in The Cancer Genome Atlas data. High expression of three miRNAs differentiated thyroid cancer from nonmalignant tumors, with an area under curve (AUC) of 0.76–0.81 in an independent cohort. In patients with differentiated thyroid cancer, the high-level expression of the three miRNAs was an independent indicator for both distant metastases and recurrent or persistent disease. In patients with PTC, a high expression of miRNAs was associated with an aggressive histologic variant, extrathyroidal extension, distant metastasis, or recurrent or persistent disease. Three miRNAs may be used as diagnostic markers for differentiating thyroid cancers from benign tumors and tumors with extremely low malignant potential (NIFTP), as well as prognostic markers for predicting the risk of recurrent/persistent disease for differentiated thyroid cancer.

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Section: Study Subjectsmentioning

confidence: 99%

“…Genomic DNA was isolated from 10-µm thick paraffin-embedded tissue sections using the RecoverAll™ Total Nucleic Acid Isolation Kit (Life Technologies). After PCR amplification of the extracted DNA, the sequences of BRAF exon 15 were analyzed by direct sequencing of amplicons, as described previously [50,56,57].…”

Section: Braf Mutational Analysismentioning

confidence: 99%

MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer

Park

Kim

Jeon

et al. 2021

Cancers

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“…The mapping of genome-wide DNA methylation is of great importance for understanding tumorigenesis [12]. This modi cation participates in many cancers, including thyroid cancer [13], non-small cell lung cancer [14], gastric cancer [15], etc. DNA methylation is involved in the development and progression of breast cancer [16].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Genome-Wide DNA Methylome and Whole-Transcriptome Landscapes of Spontaneous Intraductal Papilloma in Tree Shrews (Tupaia Belangeri)

Liu

Han

Tong

et al. 2020

Preprint

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BackgroundBreast intraductal papilloma (IP) is mainly caused by the abnormal proliferation of ductal epithelial cells. Tree shrews are a potential animal model for studying breast tumours. However, little is known about the transcriptome and DNA methylome landscapes of breast IP in tree shrews. In this work, we performed whole-genome DNA methylation and transcriptome analyses of breast IPs and normal mammary glands in tree shrews.ResultsDNA methylation profiles with a single-base resolution were generated via whole-genome bisulphate sequencing (WGBS) in both the IP and Control groups of tree shrews. This provided a genome-wide perspective regarding the epigenetic regulation of protein-coding genes in breast IP in tree shrews. The methylation levels at CG sites were considerably higher than those at CHG and CHH sites, and methylation levels were highest in gene body regions. We identified 3486, 82 and 361 differentially methylated regions (DMRs) in CG, CHG, and CHH contexts, respectively, and 701 differentially methylated genes (DMGs) were found. Furthermore, transcriptomic analysis identified 62 differentially expressed genes (DEGs), 50 long noncoding RNAs (lncRNAs), and 32 circular RNAs (circRNAs) in IPs compared with normal mammary glands. Correlation analysis between the DNA methylation and transcriptome data showed that 25 DMGs were also DEGs, among which the expression levels of 9 genes were negatively correlated with methylation levels in gene body regions. Importantly, integrated analysis identified three genes, PDZK1, ATP2B4 and LCP1, that could be used as candidates for further studying breast IP in tree shrews.ConclusionsOverall, this research provides the comprehensive landscape of the transcriptome and DNA methylome of spontaneous IP in tree shrews and highlights candidate genes for eliciting tumorigenesis. These results contribute to the application of tree shrews as an animal model of breast tumours.

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“…However, the biological signi cance of DNA methylation in this region is poorly clari ed. Gene body methylation does not necessarily block the transcription as observed in promoter regions, but might increase the transcriptional activity, stimulate the transcription elongation, and impact in the splicing [19][20][21]. Accordingly, 80% of the probes presenting positive correlation between methylation/expression were annotated in gene body or 3'UTR.…”

Section: Discussionmentioning

confidence: 99%

Identification of aberrantly methylated differentially expressed genes in papillary thyroid carcinoma using integrated bioinformatic analysis

Cai

Chen³

et al. 2021

Preprint

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Background: DNA methylation has been reported as one of the most critical epigenetic aberrations during the tumorigenesis and development of papillary thyroid carcinoma (PTC). Although PTC has been explored by gene expression and DNA methylation studies, the regulatory mechanisms of the methylation on the gene expression was poorly clarified.Results: In this study, the comparisons between PTC and NT revealed 4995 methylated probes and 1446 differentially expressed transcripts cross-validated by The Cancer Genome Atlas (TCGA) database. The integrative analysis between DNA methylation and gene expression revealed 123 and 29 genes with hypomethylation/overexpression and hypermethylation/downexpression correlation, respectively. The DNA methylation pattern of seven selected CpGs (A: UNC80-cg04507925; B: TPO-cg09757588; C: LHX8-cg11842415; D: DLG2-cg16986720; E: FOXJ1-cg20373432; F: PALM2-cg21204870; G: IPCEF1-cg24635109, of which the candidate promoter CpG sites were preliminarily identified with the least absolute shrinkage and selection operator (LASSO) regression analysis. Then, the risk prognosis model was constructed by stepwise regression analysis. Furthermore, the receiver operating characteristic (ROC) and nomogram based on the verified independent prognostic factors was established for the prognostic prediction showed that it was able to predict 3-, 5-, and 7-year survival accurately. Kaplan-Meier survival estimate demonstrated that low DLG2 expression and DLG2-cg16986720 hypermethylation were independent biomarkers for OS. From the comprehensive meta-analysis, the combined Standardised Mean Difference (SMD) of DLG2 was 0.94 with 95% CI of (0.46,1.43), indicating that less DLG2 was expressed in the PTC tissue than in the normal tissue (P<0.05). Bisulfite sequencing PCR also showed that DLG2 methylation was higher in tumor group than in normal group. Components of immune microenvironment were analyzed using TIMER, and the correlation between immune cells and DLG2 was found to be distinct across cancer types. Based on Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, DLG2 was implicated in pathways involved in immunity, metabolism, cancer, and infectious diseases. PCT patients with DLG2-cg16986720 hypermethylation showed significantly short survival rates in progression- free survival concomitant with reduced infiltration of myeloid dendritic cells.Conclusions: The current study validated that DLG2 was lowly expressed in PTC. More importantly, DLG2 hypermethylation might function as a latent tumor biomarker in the prognosis prediction for PTC. The results of bioinformatics analyses may present a new method for investigating the pathogenesis of PTC. DNA methylation loss in non-promoter, poor CGI and enhancer-enriched regions was a significant event in PTC. In addition to the promoter region, gene body and 3’UTR methylation have also the potential to influence the gene expression levels (both, repressing and inducing). The integrative analysis revealed genes potentially regulated by DNA methylation pointing out potential drivers and biomarkers related to PTC development.

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Comprehensive DNA Methylation Profiling Identifies Novel Diagnostic Biomarkers for Thyroid Cancer

Cited by 29 publications

References 34 publications

MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer

MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer

WITHDRAWN: Genome-Wide DNA Methylome and Whole-Transcriptome Landscapes of Spontaneous Intraductal Papilloma in Tree Shrews (Tupaia Belangeri)

Identification of aberrantly methylated differentially expressed genes in papillary thyroid carcinoma using integrated bioinformatic analysis

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