Calsina, BrunaPiñeiro-Yáñez, ElenaMartínez-Montes, Ángel MCaleiras, EduardoFernández-Sanromán, ÁngelMonteagudo, MaríaTorres-Pérez, RafaelFustero-Torre, CoralPulgarín-Alfaro, MartaGil, EduardoLetón, RocíoJiménez, ScherezadeGarcía-Martín, SantiagoMartin, Maria CarmenRoldán-Romero, Juan MaríaLanillos, JavierMellid, SaraSantos, MaríaDíaz-Talavera, AlbertoRubio, ÁngelesGonzález, PatriciaHernando, BarbaraBechmann, NicoleDona, MargoCalatayud, MaríaGuadalix, SonsolesÁlvarez-Escolá, CristinaRegojo, Rita MAller, JavierDel Olmo-Garcia, Maria IsabelLópez-Fernández, AdriàFliedner, Stephanie M JRapizzi, ElenaFassnacht, MartinBeuschlein, FelixQuinkler, MarcusToledo, Rodrigo AMannelli, MassimoTimmers, Henri JEisenhofer, GraemeRodriguez Perales, SandraDomínguez, OrlandoMacintyre, GeoffreyCurrás-Freixes, MariaRodríguez-Antona, CristinaCascón, AlbertoLeandro-García, Luis JRoncador, GiovannaGarcía-García, Juan FernandoPacak, KarelAl-Shahrour, FatimaRobledo Batanero, Mercedes2025-01-132025-01-132023-02-28Nat Commun . 2023 Feb 28;14(1):1122.https://hdl.handle.net/20.500.12105/26009The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.This work was supported by Project PI17/01796 and PI20/01169 to M.R. [Instituto de Salud Carlos III (ISCIII), Accion Estrategica en Salud, cofinanciado a traves del Fondo Europeo de Desarrollo Regional (FEDER)], Paradifference Foundation [no grant number applicable to M.R.], Pheipas Association [no grant number applicable to M.R.], the Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE to F.B., the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 (Project No. 314061271-TRR205 to to F.B., M.F., N.B., and G.E.) and the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation (Project No. PID2019-111356RA-I00 to G.M.). B.C. was supported by the Rafael del Pino Foundation (Becas de Excelencia Rafael del Pino 2017). A.M.M.-M. was supported by CAM (S2017/BMD-3724; TIRONET2-CM). A.F.-S. and J.L. received the support of a fellowship from La Caixa Foundation (ID 100010434; LCF/BQ/DR21/11880009 and LCF/BQ/DR19/11740015, respectively). M.M., S.M., and M.S. were supported by the Spanish Ministry of Science, Innovation and Universities "Formacion del Profesorado Universitario- FPU" fellowship with ID number FPU18/00064, FPU19/04940 and FPU16/05527. A.D.-T. is supported by the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER). L.J.L.-G. was supported both by the Banco Santander Foundation and La Caixa Postdoctoral Junior Leader Fellowship (LCF/BQ/PI20/11760011). C.M.-C. was supported by a grant from the AECC Foundation (AIO15152858 MONT). We thank the Spanish National Tumor Bank Network (RD09/0076/00047) for the support in obtaining tumorsamples and all patients, physicians and tumor biobanks involved in the study.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/SOMATIC MUTATIONSMICROSATELLITE INSTABILITYCOMPREHENSIVE ANALYSISRIBOSOME BIOGENESISTERT PROMOTERCELL CYCLECANCERTUMORSRNAACTIVATIONAttribution-NonCommercial-NoDerivatives 4.0 International368546741411122Nature Communicationsopen access