{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T18:22:54Z","timestamp":1769538174481,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003945","name":"Link\u00f6ping University","doi-asserted-by":"crossref","award":["LiU-2022"],"award-info":[{"award-number":["LiU-2022"]}],"id":[{"id":"10.13039\/501100003945","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors primarily involving the adrenal medulla and its associated paraganglia, with heterogeneous clinical behavior and complex molecular drivers. This study aimed to characterize DNA methylation and gene expression patterns in PPGLs to understand the molecular differences between tumor subtypes and malignancy. We performed an integrative analysis of DNA methylation (Illumina EPIC 850K) and gene expression profiles (Affymetrix microarrays) in 24 PPGLs, comparing these with The Cancer Genome Atlas (TCGA) data, to delineate cluster- and malignancy-specific epigenetic patterns. Comparison between pseudohypoxic Cluster I and kinase-signaling Cluster II tumors revealed 13 differentially methylated CpG sites, with a specific CpG within DSCAML1 showing hypermethylation in Cluster II accompanied by increased expression, suggesting context-dependent gene body methylation effects. Benign versus malignant comparisons identified 101 differentially methylated CpGs, including hypermethylated CpG in BAIAP2L1 and hypomethylated CpG in SHANK1 in malignant tumors. Pathway enrichment of differentially methylated genes revealed alterations in Notch signaling, adherens junctions, cytoskeletal regulation, and intracellular transport. Gene expression analysis demonstrated partial overlap between clusters, with malignant tumors exhibiting distinct transcriptional profiles involving RNA processing, metabolism, and adhesion pathways. Correlation between methylation and expression was generally limited, emphasizing that methylation-dependent gene regulation is a locus-specific and context-dependent regulation. These findings illustrate a complex interplay between epigenetic modifications and transcriptional programs in PPGLs, enhancing our understanding of molecular heterogeneity and tumor classification, and identifying candidate biomarkers and therapeutic targets for malignant progression.<\/jats:p>","DOI":"10.3390\/cells15020198","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T17:20:42Z","timestamp":1768929642000},"page":"198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Epigenomic and Transcriptomic Profiling Define Malignancy- and Cluster-Specific Signatures in Pheochromocytomas and Paragangliomas"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2873-161X","authenticated-orcid":false,"given":"Mouna","family":"Tabebi","sequence":"first","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (BKV), Link\u00f6ping University, 58183 Link\u00f6ping, Sweden"},{"name":"Clinical Genomics Link\u00f6ping, Science for Life Laboratory, Link\u00f6ping University, 58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0244-759X","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"\u0141ysiak","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (BKV), Link\u00f6ping University, 58183 Link\u00f6ping, Sweden"},{"name":"Clinical Genomics Link\u00f6ping, Science for Life Laboratory, Link\u00f6ping University, 58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0054-664X","authenticated-orcid":false,"given":"Oliver","family":"Gimm","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (BKV), Link\u00f6ping University, 58183 Link\u00f6ping, Sweden"},{"name":"Clinical Department of Surgery Link\u00f6ping, Region \u00d6sterg\u00f6tland, 58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"S\u00f6derkvist","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences (BKV), Link\u00f6ping University, 58183 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1210\/jc.2014-1498","article-title":"Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline","volume":"99","author":"Lenders","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ccell.2017.01.001","article-title":"Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma","volume":"31","author":"Fishbein","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ccr.2013.04.018","article-title":"SDH mutations establish a hypermethylator phenotype in paraganglioma","volume":"23","author":"Martinelli","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1097\/CCO.0000000000000249","article-title":"Pheochromocytoma and paraganglioma: Molecular testing and personalized medicine","volume":"28","author":"Burnichon","year":"2016","journal-title":"Curr. Opin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1158\/1078-0432.CCR-16-0606","article-title":"Pheochromocytoma: The First Metabolic Endocrine Cancer","volume":"22","author":"Jochmanova","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1530\/ERC-19-0024","article-title":"Genotype\u2013phenotype correlations in pheochromocytoma and paraganglioma: A systematic review and individual patient meta-analysis","volume":"26","author":"Crona","year":"2019","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Saavedra T, J.S., Nati-Castillo, H.A., Valderrama Cometa, L.A., Rivera-Mart\u00ednez, W.A., Asprilla, J., Casta\u00f1o-Giraldo, C.M., S\u00e1nchez S, L., Heredia-Esp\u00edn, M., Arias-Intriago, M., and Izquierdo-Condoy, J.S. (2024). Pheochromocytoma: An updated scoping review from clinical presentation to management and treatment. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1433582"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1210\/endrev\/bnab019","article-title":"Personalized Management of Pheochromocytoma and Paraganglioma","volume":"43","author":"Bechmann","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s12022-024-09830-3","article-title":"The Molecular Classification of Pheochromocytomas and Paragangliomas: Discovering the Genomic and Immune Landscape of Metastatic Disease","volume":"35","year":"2024","journal-title":"Endocr. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e28981","DOI":"10.1002\/pbc.28981","article-title":"Pseudohypoxic pheochromocytomas and paragangliomas dominate in children","volume":"68","author":"Redlich","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"349","DOI":"10.37349\/etat.2024.00222","article-title":"Tumor metabolism in pheochromocytomas: Clinical and therapeutic implications","volume":"5","author":"Jeeyavudeen","year":"2024","journal-title":"Explor. Target. Anti-Tumor Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100527","DOI":"10.1016\/j.coemr.2024.100527","article-title":"Molecular genetics of pheochromocytoma\/paraganglioma","volume":"36","author":"Wachtel","year":"2024","journal-title":"Curr. Opin. Endocr. Metab. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1186\/s13148-023-01598-3","article-title":"A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide","volume":"15","author":"Chatzikyriakou","year":"2023","journal-title":"Clin. Epigenetics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3982","DOI":"10.1093\/bioinformatics\/btx513","article-title":"ChAMP: Updated methylation analysis pipeline for Illumina BeadChips","volume":"33","author":"Tian","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1186\/gb-2013-14-10-r115","article-title":"DNA methylation age of human tissues and cell types","volume":"14","author":"Horvath","year":"2013","journal-title":"Genome Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1158\/1078-0432.CCR-14-2804","article-title":"DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers","volume":"21","author":"Korpershoek","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pfeifer, G.P. (2018). Defining Driver DNA Methylation Changes in Human Cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041166"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12692","DOI":"10.1093\/nar\/gkab1167","article-title":"DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events","volume":"49","author":"Heery","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrendo.2014.188","article-title":"Paraganglioma and phaeochromocytoma: From genetics to personalized medicine","volume":"11","author":"Favier","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"44943","DOI":"10.1038\/srep44943","article-title":"Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations","volume":"7","author":"Backman","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.mce.2017.06.016","article-title":"Epigenetics of pheochromocytoma and paraganglioma","volume":"469","author":"Backman","year":"2018","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chao, A., Tsai, C.-L., Jung, S.-M., Chuang, W.-C., Kao, C., Hsu, A., Chen, S.-H., Lin, C.-Y., Lee, Y.-C., and Lee, Y.-S. (2015). BAI1-Associated Protein 2-Like 1 (BAIAP2L1) Is a Potential Biomarker in Ovarian Cancer. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0133081"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4987","DOI":"10.18632\/oncotarget.27080","article-title":"Methylation alteration of SHANK1 as a predictive, diagnostic and prognostic biomarker for chronic lymphocytic leukemia","volume":"10","author":"Loi","year":"2019","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.284.5415.770","article-title":"Notch signaling: Cell fate control and signal integration in development","volume":"284","author":"Rand","year":"1999","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrm3802","article-title":"Dynamic contacts: Rearranging adherens junctions to drive epithelial remodelling","volume":"15","author":"Takeichi","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00401-013-1165-y","article-title":"Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling","volume":"126","author":"Cama","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nrm.2016.94","article-title":"Notch signalling in context","volume":"17","author":"Bray","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nrm2774","article-title":"Kinesin superfamily motor proteins and intracellular transport","volume":"10","author":"Hirokawa","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/nrc3310","article-title":"Kinesins and cancer","volume":"12","author":"Rath","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1056\/NEJMra072067","article-title":"Epigenetics in cancer","volume":"358","author":"Esteller","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1002\/cncr.35426","article-title":"Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma","volume":"130","author":"Kaplinsky","year":"2024","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrc1279","article-title":"The history of cancer epigenetics","volume":"4","author":"Feinberg","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Kundaje","year":"2015","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13072-022-00443-w","article-title":"Pan-cancer predictions of transcription factors mediating aberrant DNA methylation","volume":"15","author":"Detilleux","year":"2022","journal-title":"Epigenetics Chromatin"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:11:00Z","timestamp":1769490660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020198"],"URL":"https:\/\/doi.org\/10.3390\/cells15020198","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}