{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T17:09:12Z","timestamp":1788800952448,"version":"build-2803163510"},"reference-count":118,"publisher":"Bioscientifica","issue":"9","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. Over the past two decades, the genomic characterization of PPGLs has profoundly transformed their diagnosis, classification, risk stratification, and therapeutic management. Up to 40% of PPGLs harbor germline pathogenic variants, the highest proportion among human neoplasms, and somatic driver events are identified in a substantial fraction of the remaining cases. Integrative multi-omic studies have established three main molecular clusters: a pseudohypoxic cluster driven by Krebs-cycle alterations (SDHx, FH, MDH2, DLST) and HIF-2\u03b1 pathway alterations (VHL, EPAS1, EGLN1\/2); a kinase-signaling cluster driven by activation of RAS\/MAPK and PI3K\/AKT pathways (RET, NF1, HRAS, TMEM127, MAX); and a Wnt-signaling cluster characterized primarily by MAML3 fusions. This review summarizes progress in PPGL genomics, highlighting geographic and sex-related particularities. Using EPAS1\/HIF-2\u03b1 and RET as paradigmatic examples, we illustrate how diverse germline, somatic, mosaic, and fusion events converge on common core signaling hubs that can be therapeutically exploited with FDA-approved selective inhibitors for relevant targets (e.g. belzutifan for HIF-2\u03b1; selpercatinib and pralsetinib for RET). We further review the genomic determinants of metastatic risk (SDHB, ATRX, TERT, and MAML3 fusions), the immune microenvironment of metastatic disease, and emerging radionuclide theranostics, liquid biopsy biomarkers, and integrative multi-omic approaches that are reshaping precision medicine for PPGLs.<\/jats:p>","DOI":"10.1530\/erc-26-0258","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T10:44:10Z","timestamp":1787309050000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Molecular clusters and precision medicine in pheochromocytomas and paragangliomas"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2957-6148","authenticated-orcid":true,"given":"Madson Q","family":"Almeida","sequence":"first","affiliation":[{"name":"Unidade de Adrenal, Laborat\u00f3rio de Endocrinologia Molecular e Celular LIM25, Divis\u00e3o de Endocrinologia e Metabologia, Hospital das Cl\u00ednicas, Faculdade de Medicina da Universidade de S\u00e3o Paulo 1 , ,","place":["S\u00e3o Paulo, Brazil"]},{"name":"Unidade de Oncologia End\u00f3crina, Instituto do C\u00e2ncer do Estado de S\u00e3o Paulo (ICESP), Faculdade de Medicina da Universidade de S\u00e3o Paulo 2 , ,","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-370X","authenticated-orcid":true,"given":"Patricia L M","family":"Dahia","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio (UTHSA) 3 , , ,","place":["San Antonio, Texas, USA"]},{"name":"Mays Cancer Center UTHSA 4 , , ,","place":["San Antonio, Texas, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6256-5902","authenticated-orcid":true,"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) 5 , ,","place":["Madrid, Spain"]},{"name":"Hereditary Endocrine Cancer Group, Cancer Genomics Program, Spanish National Cancer Research Centre (CNIO) 6 , ,","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026090712313516500_bib1","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1097\/HJH.0000000000002438","article-title":"Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension","volume":"38","author":"Lenders","year":"2020","journal-title":"J Hypertens"},{"key":"2026090712313516500_bib2","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":"2026090712313516500_bib3","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1097\/MPA.0000000000001792","article-title":"The North American Neuroendocrine Tumor Society Consensus Guidelines for surveillance and management of metastatic and\/or unresectable pheochromocytoma and paraganglioma","volume":"50","author":"Fishbein","year":"2021","journal-title":"Pancreas"},{"key":"2026090712313516500_bib4","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO classification of neuroendocrine neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026090712313516500_bib5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s12022-022-09704-6","article-title":"Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas","volume":"33","author":"Mete","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026090712313516500_bib6","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1210\/endrev\/bnab019","article-title":"Personalized management of pheochromocytoma and paraganglioma","volume":"43","author":"Nolting","year":"2022","journal-title":"Endocr Rev"},{"key":"2026090712313516500_bib7","doi-asserted-by":"crossref","first-page":"e1937","DOI":"10.1210\/clinem\/dgaa982","article-title":"Metastatic pheochromocytomas and abdominal paragangliomas","volume":"106","author":"Granberg","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib8","doi-asserted-by":"crossref","first-page":"6140","DOI":"10.1038\/ncomms7140","article-title":"Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas","volume":"6","author":"Fishbein","year":"2015","journal-title":"Nat Commun"},{"key":"2026090712313516500_bib9","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1210\/jc.2017-00992","article-title":"Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years","volume":"102","author":"Hamidi","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib10","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1186\/1471-2407-14-523","article-title":"The size of the primary tumor and age at initial diagnosis are independent predictors of the metastatic behavior and survival of patients with SDHB-related pheochromocytoma and paraganglioma: a retrospective cohort study","volume":"14","author":"Schovanek","year":"2014","journal-title":"BMC Cancer"},{"key":"2026090712313516500_bib11","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1210\/jc.2018-01968","article-title":"Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono Study): a European network for the study of adrenal tumors retrospective study","volume":"104","author":"Hescot","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib12","doi-asserted-by":"crossref","first-page":"e551","DOI":"10.1016\/S2589-7500(23)00094-8","article-title":"Prediction of metastatic pheochromocytoma and paraganglioma: a machine learning modelling study using data from a cross-sectional cohort","volume":"5","author":"Pamporaki","year":"2023","journal-title":"Lancet Digit Health"},{"key":"2026090712313516500_bib13","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1210\/jc.2010-1946","article-title":"Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators","volume":"96","author":"Ayala-Ramirez","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib14","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.amjoto.2013.03.010","article-title":"Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators","volume":"34","author":"Sethi","year":"2013","journal-title":"Am J Otolaryngol"},{"key":"2026090712313516500_bib15","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.surg.2018.05.001","article-title":"A clinical prediction model to estimate the metastatic potential of pheochromocytoma\/paraganglioma: ASES score","volume":"164","author":"Cho","year":"2018","journal-title":"Surgery"},{"key":"2026090712313516500_bib16","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1111\/j.1365-2362.2011.02518.x","article-title":"Metastatic pheochromocytoma: does the size and age matter?","volume":"41","author":"Zelinka","year":"2011","journal-title":"Eur J Clin Invest"},{"key":"2026090712313516500_bib17","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1177\/0004563217739931","article-title":"Clinical evaluation and treatment of phaeochromocytoma","volume":"55","author":"Davison","year":"2018","journal-title":"Ann Clin Biochem"},{"key":"2026090712313516500_bib18","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1016\/j.ejca.2011.07.016","article-title":"Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status","volume":"48","author":"Eisenhofer","year":"2012","journal-title":"Eur J Cancer"},{"key":"2026090712313516500_bib19","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvab163","article-title":"Dopamine-secreting pheochromocytoma and paraganglioma","volume":"5","author":"Miyamoto","year":"2021","journal-title":"J Endocr Soc"},{"key":"2026090712313516500_bib20","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0187398","article-title":"Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma","volume":"12","author":"Koh","year":"2017","journal-title":"PLoS One"},{"key":"2026090712313516500_bib21","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1210\/clinem\/dgaf259","article-title":"Approach to the patient with metastatic pheochromocytoma and paraganglioma","volume":"110","author":"Alkaissi","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib22","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ccell.2017.01.009","article-title":"Pheochromocytomas and paragangliomas, genetically diverse and minimalist, all at once!","volume":"31","author":"Dahia","year":"2017","journal-title":"Cancer Cell"},{"key":"2026090712313516500_bib23","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":"2026090712313516500_bib24","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nrendo.2016.185","article-title":"Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas","volume":"13","author":"Toledo","year":"2017","journal-title":"Nat Rev Endocrinol"},{"key":"2026090712313516500_bib25","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/er.2017-00062","article-title":"New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification","volume":"38","author":"Crona","year":"2017","journal-title":"Endocr Rev"},{"key":"2026090712313516500_bib26","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41574-021-00492-3","article-title":"International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers","volume":"17","author":"Amar","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"2026090712313516500_bib27","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1677\/erc.1.00838","article-title":"Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome","volume":"11","author":"Eisenhofer","year":"2004","journal-title":"Endocr Relat Cancer"},{"key":"2026090712313516500_bib28","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1371\/journal.pgen.0010008","article-title":"A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas","volume":"1","author":"Dahia","year":"2005","journal-title":"PLoS Genet"},{"key":"2026090712313516500_bib29","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbcan.2024.189141","article-title":"Clinical and molecular markers guide the genetics of pheochromocytoma and paraganglioma","volume":"1879","author":"Cascon","year":"2024","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"2026090712313516500_bib30","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrc3648","article-title":"Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity","volume":"14","author":"Dahia","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2026090712313516500_bib31","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":"2026090712313516500_bib32","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1210\/jc.2018-02411","article-title":"Positive impact of genetic test on the management and outcome of patients with paraganglioma and\/or pheochromocytoma","volume":"104","author":"Buffet","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib33","doi-asserted-by":"crossref","first-page":"e1907","DOI":"10.1210\/clinem\/dgac019","article-title":"Surveillance improves outcomes for carriers of SDHB pathogenic variants: a multicenter study","volume":"107","author":"Davidoff","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib34","doi-asserted-by":"crossref","DOI":"10.1016\/j.currproblcancer.2024.101116","article-title":"Management of metastatic pheochromocytomas and paragangliomas: when and what","volume":"51","author":"Sukrithan","year":"2024","journal-title":"Curr Probl Cancer"},{"key":"2026090712313516500_bib35","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/oncolo\/oyad285","article-title":"The landscape of US and global rare tumor research programs: a systematic review","volume":"29","author":"Vivelo","year":"2024","journal-title":"Oncologist"},{"key":"2026090712313516500_bib36","doi-asserted-by":"crossref","first-page":"e52","DOI":"10.1016\/S1470-2045(15)00386-1","article-title":"Rare cancers: a sea of opportunity","volume":"17","author":"Boyd","year":"2016","journal-title":"Lancet Oncol"},{"key":"2026090712313516500_bib37","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1210\/jcem.86.5.7496","article-title":"Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes","volume":"86","author":"Eisenhofer","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib38","doi-asserted-by":"crossref","first-page":"E1223","DOI":"10.1152\/ajpendo.90591.2008","article-title":"Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma","volume":"295","author":"Eisenhofer","year":"2008","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2026090712313516500_bib39","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1196\/annals.1353.023","article-title":"Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas","volume":"1073","author":"Dahia","year":"2006","journal-title":"Ann N Y Acad Sci"},{"key":"2026090712313516500_bib40","doi-asserted-by":"crossref","first-page":"9651","DOI":"10.1158\/0008-5472.CAN-05-1427","article-title":"Novel pheochromocytoma susceptibility loci identified by integrative genomics","volume":"65","author":"Dahia","year":"2005","journal-title":"Cancer Res"},{"key":"2026090712313516500_bib41","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/ng.533","article-title":"Germline mutations in TMEM127 confer susceptibility to pheochromocytoma","volume":"42","author":"Qin","year":"2010","journal-title":"Nat Genet"},{"key":"2026090712313516500_bib42","doi-asserted-by":"crossref","first-page":"6044","DOI":"10.1038\/ncomms7044","article-title":"Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas","volume":"6","author":"Castro-Vega","year":"2015","journal-title":"Nat Commun"},{"key":"2026090712313516500_bib43","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1210\/me.2010-0256","article-title":"Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas","volume":"24","author":"Lopez-Jimenez","year":"2010","journal-title":"Mol Endocrinol"},{"key":"2026090712313516500_bib44","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1210\/jc.2008-2504","article-title":"The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas","volume":"94","author":"Burnichon","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib45","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1093\/hmg\/ddr324","article-title":"Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma","volume":"20","author":"Burnichon","year":"2011","journal-title":"Hum Mol Genet"},{"key":"2026090712313516500_bib46","doi-asserted-by":"crossref","first-page":"6262","DOI":"10.1038\/s41467-022-34011-3","article-title":"Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment","volume":"13","author":"Zethoven","year":"2022","journal-title":"Nat Commun"},{"key":"2026090712313516500_bib47","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev-cancerbio-030617-050527","article-title":"The von Hippel\u2013Lindau tumor suppressor protein","volume":"2","author":"Kaelin","year":"2018","journal-title":"Ann Rev Cancer Biol"},{"key":"2026090712313516500_bib48","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1101\/sqb.2011.76.010975","article-title":"Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases","volume":"76","author":"Kaelin","year":"2011","journal-title":"Cold Spring Harb Symp Quant Biol"},{"key":"2026090712313516500_bib49","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"2026090712313516500_bib50","doi-asserted-by":"crossref","DOI":"10.1016\/j.beem.2024.101931","article-title":"MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma","volume":"38","author":"Monteagudo","year":"2024","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026090712313516500_bib51","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1158\/1541-7786.MCR-20-0992","article-title":"Mastermind like transcriptional coactivator 3 (MAML3) drives neuroendocrine tumor progression","volume":"19","author":"Alzofon","year":"2021","journal-title":"Mol Cancer Res"},{"key":"2026090712313516500_bib52","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":"Letouze","year":"2013","journal-title":"Cancer Cell"},{"key":"2026090712313516500_bib53","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1101\/gad.191056.112","article-title":"Inhibition of \u03b1-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors","volume":"26","author":"Xiao","year":"2012","journal-title":"Genes Dev"},{"key":"2026090712313516500_bib54","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/cge.13553","article-title":"Clinical implications of the oncometabolite succinate in SDHx-mutation carriers","volume":"97","author":"Eijkelenkamp","year":"2020","journal-title":"Clin Genet"},{"key":"2026090712313516500_bib55","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1210\/endrev\/bnag005","article-title":"Epigenetics and disease progression in neuroendocrine neoplasms","volume":"47","author":"Lobato","year":"2026","journal-title":"Endocr Rev"},{"key":"2026090712313516500_bib56","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1016\/j.celrep.2020.03.022","article-title":"TET-mediated hypermethylation primes SDH-deficient cells for HIF2\u03b1-driven mesenchymal transition","volume":"30","author":"Morin","year":"2020","journal-title":"Cell Rep"},{"key":"2026090712313516500_bib57","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1530\/ERC-21-0211","article-title":"Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma","volume":"28","author":"Eckardt","year":"2021","journal-title":"Endocr Relat Cancer"},{"key":"2026090712313516500_bib58","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1101\/gad.12.21.3320","article-title":"The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development","volume":"12","author":"Tian","year":"1998","journal-title":"Genes Dev"},{"key":"2026090712313516500_bib59","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1210\/endrev\/bnac025","article-title":"Hypoxia-inducible factor 2 alpha (HIF2alpha) inhibitors: targeting genetically driven tumor hypoxia","volume":"44","author":"Toledo","year":"2023","journal-title":"Endocr Rev"},{"key":"2026090712313516500_bib60","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1056\/NEJMoa2504964","article-title":"Belzutifan for advanced pheochromocytoma or paraganglioma","volume":"393","author":"Jimenez","year":"2025","journal-title":"N Engl J Med"},{"key":"2026090712313516500_bib61","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1056\/NEJMoa1205119","article-title":"Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia","volume":"367","author":"Zhuang","year":"2012","journal-title":"N Engl J Med"},{"key":"2026090712313516500_bib62","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1530\/ERC-13-0101","article-title":"In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas","volume":"20","author":"Toledo","year":"2013","journal-title":"Endocr Relat Cancer"},{"key":"2026090712313516500_bib63","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1200\/JCO.2012.47.1912","article-title":"New syndrome of paraganglioma and somatostatinoma associated with polycythemia","volume":"31","author":"Pacak","year":"2013","journal-title":"J Clin Oncol"},{"key":"2026090712313516500_bib64","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.144368","article-title":"Developmental vascular malformations in EPAS1 gain-of-function syndrome","volume":"6","author":"Rosenblum","year":"2021","journal-title":"JCI Insight"},{"key":"2026090712313516500_bib65","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa2110051","article-title":"Belzutifan, a potent HIF2alpha inhibitor, in the pacak-zhuang syndrome","volume":"385","author":"Kamihara","year":"2021","journal-title":"N Engl J Med"},{"key":"2026090712313516500_bib66","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1056\/NEJMc2518226","article-title":"Belzutifan for advanced pheochromocytoma or paraganglioma","volume":"394","author":"Alkaissi","year":"2026","journal-title":"N Engl J Med"},{"key":"2026090712313516500_bib67","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.eprac.2025.09.204","article-title":"Belzutifan for HIF2A-Related pheochromocytoma and paraganglioma: a retrospective study of real-world data","volume":"32","author":"Alkaissi","year":"2026","journal-title":"Endocr Pract"},{"key":"2026090712313516500_bib68","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1210\/jc.2014-3863","article-title":"Pheochromocytoma and paraganglioma in cyanotic congenital heart disease","volume":"100","author":"Opotowsky","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib69","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1056\/NEJMc1716652","article-title":"EPAS1 mutations and paragangliomas in cyanotic congenital heart disease","volume":"378","author":"Vaidya","year":"2018","journal-title":"N Engl J Med"},{"key":"2026090712313516500_bib70","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1210\/clinem\/dgac362","article-title":"Genetic analysis of pheochromocytoma and paraganglioma complicating cyanotic congenital heart disease","volume":"107","author":"Ogasawara","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib71","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1158\/2159-8290.CD-24-0943","article-title":"Convergent genetic adaptation in human tumors developed under systemic hypoxia and in populations living at high altitudes","volume":"15","author":"Arenillas","year":"2025","journal-title":"Cancer Discov"},{"key":"2026090712313516500_bib72","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nrc3680","article-title":"RET revisited: expanding the oncogenic portfolio","volume":"14","author":"Mulligan","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2026090712313516500_bib73","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1001\/jama.1996.03540190047028","article-title":"The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis","volume":"276","author":"Eng","year":"1996","journal-title":"JAMA"},{"key":"2026090712313516500_bib74","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/nrendo.2011.139","article-title":"Management of medullary thyroid carcinoma and MEN2 syndromes in childhood","volume":"7","author":"Waguespack","year":"2011","journal-title":"Nat Rev Endocrinol"},{"key":"2026090712313516500_bib75","article-title":"A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions","volume":"3","author":"Estrada-Zuniga","year":"2022","journal-title":"Cell Rep Med"},{"key":"2026090712313516500_bib76","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1200\/PO.21.00127","article-title":"Novel RET fusion RET-SEPTIN9 predicts response to selective RET inhibition with selpercatinib in malignant pheochromocytoma","volume":"5","author":"Mweempwa","year":"2021","journal-title":"JCO Precis Oncol"},{"key":"2026090712313516500_bib77","doi-asserted-by":"crossref","first-page":"424","DOI":"10.3390\/genes11040424","article-title":"RET gene fusions in malignancies of the thyroid and other tissues","volume":"11","author":"Santoro","year":"2020","journal-title":"Genes"},{"key":"2026090712313516500_bib78","doi-asserted-by":"crossref","first-page":"e600","DOI":"10.1210\/clinem\/dgae283","article-title":"Clinical activity of selpercatinib in RET-mutant pheochromocytoma","volume":"110","author":"Deschler-Baier","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib79","doi-asserted-by":"crossref","first-page":"e350","DOI":"10.1210\/clinem\/dgaa741","article-title":"Genotype-Phenotype features of germline variants of the TMEM127 pheochromocytoma susceptibility gene: a 10-Year update","volume":"106","author":"Armaiz-Pena","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib80","doi-asserted-by":"crossref","first-page":"e3142","DOI":"10.1210\/clinem\/dgaa396","article-title":"Functional characterization of TMEM127 variants reveals novel insights into its membrane topology and trafficking","volume":"105","author":"Flores","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib81","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2023.113070","article-title":"TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation","volume":"42","author":"Guo","year":"2023","journal-title":"Cell Rep"},{"key":"2026090712313516500_bib82","doi-asserted-by":"crossref","DOI":"10.1210\/clinem\/dgag288","article-title":"Identifying TMEM127-deficient pheochromocytomas\/paragangliomas via RET overexpression by immunohistochemistry","author":"Estrada-Zuniga","year":"2026","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib83","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1016\/j.cell.2023.07.016","article-title":"A membrane-associated MHC-I inhibitory axis for cancer immune evasion","volume":"186","author":"Chen","year":"2023","journal-title":"Cell"},{"key":"2026090712313516500_bib84","doi-asserted-by":"crossref","DOI":"10.1016\/j.tem.2026.06.007","article-title":"A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma","author":"Toledo","year":"2026","journal-title":"Trends Endocrinol Metab"},{"key":"2026090712313516500_bib85","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.ccell.2025.03.022","article-title":"Precision oncology and genetic ancestry: the science behind population-based cancer disparities","volume":"43","author":"Davis","year":"2025","journal-title":"Cancer Cell"},{"key":"2026090712313516500_bib86","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1210\/clinem\/dgaa502","article-title":"Sino-European differences in the genetic landscape and clinical presentation of pheochromocytoma and paraganglioma","volume":"105","author":"Jiang","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib87","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1210\/clinem\/dgad028","article-title":"Evidence for a founder effect of SDHB exon 1 deletion in Brazilian patients with paraganglioma","volume":"108","author":"Fagundes","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib88","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1136\/jmg.2007.054965","article-title":"Molecular characterisation of a common SDHB deletion in paraganglioma patients","volume":"45","author":"Cascon","year":"2008","journal-title":"J Med Genet"},{"key":"2026090712313516500_bib89","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2022.999329","article-title":"SDHB exon 1 deletion: a recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas","volume":"13","author":"Manotas","year":"2023","journal-title":"Front Genet"},{"key":"2026090712313516500_bib90","doi-asserted-by":"crossref","first-page":"4710","DOI":"10.1210\/jc.2016-1665","article-title":"A SDHC founder mutation causes paragangliomas (PGLs) in the French Canadians: new insights on the SDHC-related PGL","volume":"101","author":"Bourdeau","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib91","doi-asserted-by":"crossref","DOI":"10.1530\/EC-21-0560","article-title":"Dutch founder SDHB exon 3 deletion in patients with pheochromocytoma-paraganglioma in South Africa","volume":"11","author":"Gordon","year":"2022","journal-title":"Endocr Connect"},{"key":"2026090712313516500_bib92","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/j.1399-0004.2011.01653.x","article-title":"High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands","volume":"81","author":"Hensen","year":"2012","journal-title":"Clin Genet"},{"key":"2026090712313516500_bib93","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvag070","article-title":"SDHB-associated paraganglioma in Saudi Arabia: high metastatic risk linked to a likely founder mutation","volume":"10","author":"Alzahrani","year":"2026","journal-title":"J Endocr Soc"},{"key":"2026090712313516500_bib94","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1210\/clinem\/dgad515","article-title":"Asymmetric adrenals: sexual dimorphism of adrenal tumors","volume":"109","author":"Bechmann","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib95","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvae038","article-title":"Patient sex and origin influence distribution of driver genes and clinical presentation of paraganglioma","volume":"8","author":"Richter","year":"2024","journal-title":"J Endocr Soc"},{"key":"2026090712313516500_bib96","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1210\/endrev\/bnad011","article-title":"Biochemical assessment of pheochromocytoma and paraganglioma","volume":"44","author":"Eisenhofer","year":"2023","journal-title":"Endocr Rev"},{"key":"2026090712313516500_bib97","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1097\/JS9.0000000000001995","article-title":"Genetic background and intraoperative haemodynamic instability in patients with pheochromocytoma and paraganglioma: a multicentre retrospective study","volume":"111","author":"Li","year":"2025","journal-title":"Int J Surg"},{"key":"2026090712313516500_bib98","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1210\/jc.2014-2998","article-title":"Per-operative hemodynamic instability in normotensive patients with incidentally discovered pheochromocytomas","volume":"100","author":"Lafont","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib99","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1097\/01.hjh.0000185714.60788.52","article-title":"Increased blood pressure variability in pheochromocytoma compared to essential hypertension patients","volume":"23","author":"Zelinka","year":"2005","journal-title":"J Hypertens"},{"key":"2026090712313516500_bib100","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1210\/clinem\/dgz188","article-title":"Efficacy of alpha-blockers on hemodynamic control during pheochromocytoma resection: a randomized controlled trial","volume":"105","author":"Buitenwerf","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib101","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1210\/clinem\/dgaa441","article-title":"Approach to the patient: perioperative management of the patient with pheochromocytoma or sympathetic paraganglioma","volume":"105","author":"Berends","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib102","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvac004","article-title":"Perioperative management of pheochromocytomas and sympathetic paragangliomas","volume":"6","author":"Fagundes","year":"2022","journal-title":"J Endocr Soc"},{"key":"2026090712313516500_bib103","doi-asserted-by":"crossref","DOI":"10.1530\/ERC-22-0373","article-title":"Update on the genetics of paragangliomas","volume":"30","author":"Gimenez-Roqueplo","year":"2023","journal-title":"Endocr Relat Cancer"},{"key":"2026090712313516500_bib104","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1210\/jc.2007-0709","article-title":"Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas","volume":"92","author":"Amar","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib105","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1210\/jc.2005-1862","article-title":"Clinical presentation and penetrance of pheochromocytoma\/paraganglioma syndromes","volume":"91","author":"Benn","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2026090712313516500_bib106","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1158\/1078-0432.CCR-18-0139","article-title":"Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma","volume":"25","author":"Job","year":"2019","journal-title":"Clin Cancer Res"},{"key":"2026090712313516500_bib107","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1038\/s41467-025-57595-y","article-title":"Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles","volume":"16","author":"Flynn","year":"2025","journal-title":"Nat Commun"},{"key":"2026090712313516500_bib108","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/s41467-023-36769-6","article-title":"Genomic and immune landscape of metastatic pheochromocytoma and paraganglioma","volume":"14","author":"Calsina","year":"2023","journal-title":"Nat Commun"},{"key":"2026090712313516500_bib109","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41698-026-01291-7","article-title":"Metastatic progression of pheochromocytoma and paraganglioma occurs via parallel evolution","volume":"10","author":"Pregnall","year":"2026","journal-title":"NPJ Precis Oncol"},{"key":"2026090712313516500_bib110","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1093\/hmg\/ddi227","article-title":"Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations","volume":"14","author":"Pollard","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2026090712313516500_bib111","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S2213-8587(23)00038-4","article-title":"Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants","volume":"11","author":"Taieb","year":"2023","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026090712313516500_bib112","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2017.1358332","article-title":"Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: relationship with the hypoxic response, immune evasion and malignant behavior","volume":"6","author":"Pinato","year":"2017","journal-title":"Oncoimmunology"},{"key":"2026090712313516500_bib113","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.cell.2018.08.039","article-title":"A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging","volume":"174","author":"Keren","year":"2018","journal-title":"Cell"},{"key":"2026090712313516500_bib114","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/s41568-020-0273-y","article-title":"Metabolism of immune cells in cancer","volume":"20","author":"Leone","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"2026090712313516500_bib115","doi-asserted-by":"crossref","DOI":"10.1186\/s43556-026-00440-5","article-title":"Functional profiling of somatostatin receptors identifies somatostatin receptor subtype 2 as a vulnerability in succinate dehydrogenase SDHB-deficient pheochromocytomas and paragangliomas","volume":"7","author":"Garcia-Vioque","year":"2026","journal-title":"Mol Biomed"},{"key":"2026090712313516500_bib116","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13244-025-02195-z","article-title":"Precision imaging and evolving therapies in paragangliomas and pheochromocytomas: from molecular diagnostics to imaging-guided management","volume":"17","author":"Choucair","year":"2026","journal-title":"Insights Imaging"},{"key":"2026090712313516500_bib117","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2022.1070074","article-title":"Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma","volume":"13","author":"Mellid","year":"2023","journal-title":"Front Endocrinol"},{"key":"2026090712313516500_bib118","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1210\/clinem\/dgae797","article-title":"Biomarkers improving genetic and metastatic disease prediction in paraganglioma: insights from a prospective study","volume":"110","author":"Drossart","year":"2025","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-26-0258\/524079\/erc-26-0258.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-26-0258\/524079\/erc-26-0258.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T16:32:37Z","timestamp":1788798757000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/33\/9\/e260258\/78063\/Molecular-clusters-and-precision-medicine-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":118,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-26-0258","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]},"article-number":"e260258"}}