Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/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 PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

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SUMMARY Reduced expression of the Indy (= I am Not Dead, Yet) gene in D. melanogaster and C. elegans prolongs life span, and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout-mouse model of the mammalian Indy (mIndy) homologue, SLC13A5. Deletion of mIndy in mice (mINDY−/− mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1α, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect mINDY−/− mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.

Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Patients present with signs of steroid hormone excess (e.g. Cushing's syndrome, virilization) or an abdominal mass. Tumour size at presentation (mean diameter at diagnosis > 10 cm) is the most important indicator of malignancy. In addition, computed tomography (CT) typically demonstrates an inhomogeneous adrenal lesion with irregular margins and variable enhancement of solid components after intravenous contrast media. Magnetic resonance imaging (MRI) is equally effective as CT and is particularly helpful to visualize invasion into large vessels. Complete tumour removal (R0 resection) offers by far the best chance for long-term survival and therefore surgery is the treatment of choice in stage I-III ACC. Despite tumour resection for cure most patients will eventually develop local recurrence or distant metastases. Thus adjuvant treatment options need to be evaluated in high-risk patients (e.g. radiation therapy of the tumour bed and/or chemotherapy). In tumour recurrence re-operation should always be considered. In metastatic disease (stage IV ACC) not amenable to surgery mitotane (o,p'DDD) remains the first-line therapy. Drug monitoring is needed for effective treatment aiming at concentrations between 14 and 20 mg/l. Patients not responding to mitotane may benefit from cytotoxic chemotherapy (23% partial remissions, 4% complete remissions). Only large prospective multicentre trials comparing different treatment options will allow to make systematic progress in the management of ACC.