Journal article
Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment
M Zethoven, L Martelotto, A Pattison, B Bowen, S Balachander, A Flynn, FJ Rossello, A Hogg, JA Miller, Z Frysak, S Grimmond, L Fishbein, AS Tischler, AJ Gill, RJ Hicks, PLM Dahia, R Clifton-Bligh, K Pacak, RW Tothill
Nature Communications | Published : 2022
Abstract
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 ..
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Awarded by Llywodraeth Cymru
Funding Acknowledgements
We acknowledge the Victorian Cancer Biobank for provision of patient samples. Staff from the flow cytometry facility and Centre for Advanced Histology and Microscopy at the Peter MacCallum Cancer Centre and the Clinical Genomics Platform at University of Melbourne Centre for Cancer Research for their support in generating primary data. Brian Fritz and 10x Genomics for contribution of reagents to the study. We thank Alistair Forrest and Rui Hou at the Harry Perkins Institute of Cancer Research for assistance with NATMI analysis and Alicia Oschlack for her helpful advice on data analysis. This work was supported by funds from the PMF Foundation and a National Health and Medical Research Project Grant (APP1108032, RCB, RWT). RWT was supported by a Victorian Cancer Agency Mid-Career Fellowship (TP828750). A.Pa and A.F. were supported by the Joseph Herman Trust at the University of Melbourne. K.P. was supported by the Intramural Research Program of the NICHD, NIH. P.L.M.D. is a Robert Tucker Hayes Distinguished Chair in Oncology and was supported by funds the NIH/NIGMS (GM114102), NIH/NCI (CA264248), Neuroendocrine Tumor Research Foundation. L.F. was supported in part by ACS MRSG-15-063-01. A.S.T. was supported by the Neuroendocrine Tumor Research Foundation and Paradifference Foundation.