Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Bruna Calsina - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Elena Piñeiro-Yáñez - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Ángel M Martínez-Montes - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Eduardo Caleiras - , Histopathology Core Unit (Author)
  • Ángel Fernández-Sanromán - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • María Monteagudo - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Rafael Torres-Pérez - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Coral Fustero-Torre - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Marta Pulgarín-Alfaro - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Eduardo Gil - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Rocío Letón - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Scherezade Jiménez - , Monoclonal Antibodies Core Unit (Author)
  • Santiago García-Martín - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Maria Carmen Martin - , Molecular Cytogenetics and Genome Engineering Group (Author)
  • Juan María Roldán-Romero - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Javier Lanillos - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Sara Mellid - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • María Santos - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Alberto Díaz-Talavera - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Ángeles Rubio - , Genomics Core Unit (Author)
  • Patricia González - , Histopathology Core Unit (Author)
  • Barbara Hernando - , Computational Oncology Group (Author)
  • Nicole Bechmann - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • Margo Dona - , Radboud University Medical Center (Author)
  • María Calatayud - , Endocrinology Department Hamburg (Author)
  • Sonsoles Guadalix - , Endocrinology Department Hamburg (Author)
  • Cristina Álvarez-Escolá - , La Paz University Hospital (Author)
  • Rita M Regojo - , La Paz University Hospital (Author)
  • Javier Aller - , Puerta de Hierro University Hospital in Majadahonda (Author)
  • Maria Isabel Del Olmo-Garcia - , Hospital de Basurto (Author)
  • Adrià López-Fernández - , Vall d'Hebron University Hospital (Author)
  • Stephanie M J Fliedner - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Elena Rapizzi - , University of Florence (Author)
  • Martin Fassnacht - , University Hospital of Würzburg (Author)
  • Felix Beuschlein - , Department of internal Medicine I (Author)
  • Marcus Quinkler - , Free University of Berlin (Author)
  • Rodrigo A Toledo - , Vall d'Hebron University Hospital (Author)
  • Massimo Mannelli - , University of Florence (Author)
  • Henri J Timmers - , Radboud University Medical Center (Author)
  • Graeme Eisenhofer - , Department of Internal Medicine III (Author)
  • Sandra Rodríguez-Perales - , Molecular Cytogenetics and Genome Engineering Group (Author)
  • Orlando Domínguez - , Genomics Core Unit (Author)
  • Geoffrey Macintyre - , Computational Oncology Group (Author)
  • Maria Currás-Freixes - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Cristina Rodríguez-Antona - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Alberto Cascón - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Juan Fernando García-García - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Cristina Montero-Conde - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)
  • Giovanna Roncador - , Monoclonal Antibodies Core Unit (Author)
  • Juan Fernando García-García - , University of Texas at Austin (Author)
  • Karel Pacak - , National Institutes of Health (NIH) (Author)
  • Fátima Al-Shahrour - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Mercedes Robledo - , Hereditary Endocrine Cancer Group. Spanish National Cancer Research Center (CNIO) (Author)

Abstract

The 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.

Details

Original languageEnglish
Article number1122
JournalNature communications
Volume14
Issue number1
Publication statusPublished - 28 Feb 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC9975198
Scopus 85149153457
ORCID /0000-0002-6932-333X/work/142239679

Keywords

Keywords

  • Humans, Adrenal Gland Neoplasms/genetics, Genomics, Neoplasms, Second Primary, Paraganglioma/genetics, Pheochromocytoma/genetics, Tumor Microenvironment/genetics