{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T06:22:52Z","timestamp":1780986172846,"version":"3.54.1"},"reference-count":24,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Pheochromocytomas and paragangliomas (PPGLs) typically secrete catecholamines and their metabolites (metanephrines [MN] and normetanephrine [NMN]). Catecholamines are synthesized by several enzymes: phenylalanine hydroxylase (encoded by <jats:italic>PAH<\/jats:italic>), tyrosine hydroxylase (<jats:italic>TH<\/jats:italic>), aromatic L\u2010amino acid decarboxylase (<jats:italic>DDC<\/jats:italic>), dopamine \u03b2\u2010hydroxylase (<jats:italic>DBH<\/jats:italic>), and phenylethanolamine N\u2010methyltransferase (<jats:italic>PNMT<\/jats:italic>). MN\/NMN secretion varies between anatomical and molecular subgroups. The aim of this study was to assess the correlation between DNA methylation of catecholamine synthesis genes and MN\/NMN secretion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gene promoter methylation of <jats:italic>PAH, TH, AADC, DBH,<\/jats:italic> and <jats:italic>PNMT<\/jats:italic> were extracted and calculated based on publicly available data. Comparisons and correlation analysis were performed between MN\u00a0\u00b1\u00a0NMN (MN\/NMN), NMN only, and neither\/unknown secretion patterns. Methylation levels and MN\/NMN patterns were compared by three genetic alteration subgroups: pseudohypoxia (PH), kinase signaling (KS), and others.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 178 cases were included. Methylation of PAH CpGs negatively correlated with probability for MN\/NMN secretion (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.05 for all CpGs) and positively with NMN\u2010only secretion. NMN\u2010only secreting tumors had significantly higher promoter methylation of PAH, DBH, and PNMT compared with MN\/NMN\u2010secreting tumors. MN\/NMN\u2010secreting PPGLs had mainly KS alterations (52.1%), whereas NMN\u2010only PPGLs had PH alterations (41.9%). PPGLs in the PH versus KS group had gene promoter hypermethylation of <jats:italic>PAH<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.002), <jats:italic>DBH<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.02), and <jats:italic>PNMT<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.003).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Promoter methylation of genes encoding catecholamine synthesis enzymes is strongly and inversely correlated with MN\/NMN patterns in PPGLs. KS and PH\u2010related tumors have distinct methylation patterns. These results imply that methylation is a key regulatory mechanism of catecholamine synthesis in PPGLs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.35426","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T03:05:10Z","timestamp":1718334310000},"page":"3289-3296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma"],"prefix":"10.1002","volume":"130","author":[{"given":"Anna","family":"Kaplinsky","sequence":"first","affiliation":[{"name":"Cancer Center  Ramat Gan Israel"},{"name":"Tel Aviv University Faculty of Medicine  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-667X","authenticated-orcid":false,"given":"Reut","family":"Halperin","sequence":"additional","affiliation":[{"name":"Tel Aviv University Faculty of 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