The Section is conducting patient-oriented research about the etiology, epidemiology, pathophysiology, genetics, diagnosis, and treatment of pheochromocytoma (PHEO) and paraganglioma (PGL). Projects include not only translational research-applying basic science knowledge to clinical diagnosis, pathophysiology, and treatment-but also reverse translation research where appreciation of clinical findings leads to new concepts that basic researchers can pursue in the laboratory. In order to achieve our goals, the strategy of the Section is based on the multidisciplinary collaborations among NIH investigators and outside medical centers/institutions. Our Section links together a patient-oriented component with two bench-level components. The patient-oriented component (Medical Neuroendocrinology) is currently the main driving force for our hypotheses and discoveries. The two bench-level components (Tumor Pathogenesis & Genetics and Chemistry & Biomarkers) emphasize first, technologies of basic research tailored for pathway and target discovery and second, the development of the discoveries into clinical applications. In the TCGA study representing national and international collaborative effort, we reported a comprehensive molecular characterization of PHEO/PGL. Multi-platform integration revealed that PHEOs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PHEOs/PGLs susceptibility genes. CSDE1 was identified as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). This study also discovered fusion genes in PHEO/PGL pathogenesis, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PHEOs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PHEOs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PHEO/PGL precision medicine Clinical and genetic aspects of PHEO/PGL We conducted a retrospective analysis of 132 patients (27 children, 105 adults) diagnosed and treated for metastatic PHEO/PGL between 2000 and 2014. Seventy-three (55%) patients had SDHB mutations, while the remaining 59 (45%) had apparently sporadic tumors (AST). The average metastatic interval (MI) declined significantly with increasing age in both SDHB and AST patients. Only 16% of all primary tumors were smaller than 4.5 cm. Overall survival was significantly longer in children than in adults, especially in SDHB patients. We concluded that in children, metastatic PHEO/PGLs are mainly the result of SDHB mutations. For adults, they are equally distributed between SDHB mutations and AST. Pharmacological treatment is mandatory in patients with hormonally functional PHEO/PGL. A total of 381 patients were included in the study. Adequate pharmacological treatment was prescribed to 69.3%, of which 93.1% received alpha-adrenoceptor blockers. Regarding patients who were inappropriately treated, 53% did not receive any medication. We aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudo-hypoxic PGLs. RNA expression patterns of six HIF2A PGLs from two patients were compared with eight normal adrenal medullas and other hereditary pseudo-hypoxic PGLs (13 VHL, 15 SDHB, and 14 SDHD). Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudo-hypoxic PGLs after normalization of the adrenal medulla. Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes (TRHDE, LRRC63, IGSF10). Imaging aspects of PHEO/PGL The syndrome of PGL, somatostatinoma (SOM), and early childhood polycythemia in patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A) gene has been described in only a few patients worldwide. In our series of 7 patients, CT and MRI revealed cystic lesions at multiple sites and hemangiomas in four patients (57%), which were previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical for detecting these PGLs appeared to be 18F-FDOPA. Therefore, 18F-FDOPA PET/CT, and not 68Ga-DOTATATE PET/CT, is recommended for tumor localization and disease progression monitoring in this syndrome. Metabolic aspects of PHEO/PGL In one study, we used a head-to-head comparison between invivo and exvivo NMR spectroscopy for the detection of catecholamine-secreting tumors. This suggested that invivo assessment of tumoral catecholamines might play a unique role in the differential diagnosis of adrenal tumors to confirm or rule out the presence of PHEO/PGL, especially in unusual situations. We also predicted that this new approach would play an important role in the assessment of therapeutic responses of PHEO/PGLs by monitoring catecholamine content in these tumors. Based on several experiments, we have concluded that respiratory-triggered proton 1H-MRS could represent a functional, noninvasive, and nonionizing technique in the diagnosisof PHEO/PGL. However, the clinical utility of respiratory triggered single voxel 1H-MRS needs to be further evaluated in a larger series ofpatients with adrenal incidentalomas, which also includes more challenging situations such as cystic, hemorrhagic, and nonsecreting PHEOs, which are characterized by slightly high or a completely absence of catecholamine secretion. Moreover, a comparison between respiratory-triggered single voxel 1H-MRS and radionuclide imaging techniques (i.e., 123I-MIBG scintigraphy and 18F-FDOPA PET/CT) would be of particular interest for a definitive validation. Therapeutic aspects of PHEO/PGL We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.