Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.

3rd Department of Internal Medicine Nephrology Rheumatology and Endocrinology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Centre for Cancer Research and Department of Clinical Pathology University of Melbourne Melbourne VIC Australia

Department of Medicine Division of Endocrinology Metabolism Diabetes University of Colorado Aurora CO USA

Department of Surgery Epworth Hospital Richmond VIC Australia

Department of Surgery Royal Melbourne Hospital Parkville VIC Australia

Div Hematology and Medical Oncology Department of Medicine Mays Cancer Center University of Texas Health Science Center at San Antonio San Antonio TX USA

Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda MD USA

Kolling Institute of Medical Research Royal North Shore Hospital Sydney NSW Australia

NSW Health Pathology Department of Anatomical Pathology Royal North Shore Hospital Sydney NSW Australia

Peter MacCallum Cancer Centre Melbourne VIC Australia

Sir Peter MacCallum Department of Oncology University of Melbourne Melbourne VIC Australia

Sydney Medical School University of Sydney Sydney NSW Australia

Tufts Medical Centre Boston MA USA

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Nat Commun. 2023 Jan 9;14(1):123. doi: 10.1038/s41467-022-35751-y. PubMed

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Role of B cells in intratumoral MBTA immunotherapy of murine pheochromocytoma model

Hand2 Immunohistochemistry in the Diagnosis of Paragangliomas and Other Neuroendocrine Neoplasms