Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma

• Published in: Scientific reports Vol. 13; no. 1; p. 11588
• Main Authors: Karakaya, Sinan, Gunnesson, Lisa, Elias, Erik, Martos-Salvo, Paula, Robledo, Mercedes, Nilsson, Ola, Wängberg, Bo, Abel, Frida, Påhlman, Sven, Muth, Andreas, Mohlin, Sofie
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.07.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adrenal Gland Neoplasms - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biomarkers; Cancer; Cancer and Oncology; Cancer och onkologi; Clinical Medicine; Cytoplasm; Cytoplasm - metabolism; Ethanol; Ethics; Genomics; Genotype & phenotype; Humans; Kinases; Kirurgi; Klinisk medicin; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Metastases; Metastasis; Mutation; Neuroendocrine tumors; Paraganglioma; Paraganglioma - diagnosis; Paraganglioma - genetics; Paraganglioma - pathology; Patients; Peripheral Nervous System Neoplasms; Phenotypes; Pheochromocytoma - genetics; Proteins; Surgery
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-38606-8

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.