Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

Bruna Calsina (), Elena Piñeiro-Yáñez, Ángel M. Martínez-Montes, Eduardo Caleiras, Ángel Fernández-Sanromán, María Monteagudo, Rafael Torres-Pérez, Coral Fustero-Torre, Marta Pulgarín-Alfaro, Eduardo Gil, Rocío Letón, Scherezade Jiménez, Santiago García-Martín, Maria Carmen Martin, Juan María Roldán-Romero, Javier Lanillos, Sara Mellid, María Santos, Alberto Díaz-Talavera, Ángeles Rubio, Patricia González, Barbara Hernando, Nicole Bechmann, Margo Dona, María Calatayud, Sonsoles Guadalix, Cristina Álvarez-Escolá, Rita M. Regojo, Javier Aller, Maria Isabel Del Olmo-Garcia, Adrià López-Fernández, Stephanie M. J. Fliedner, Elena Rapizzi, Martin Fassnacht, Felix Beuschlein, Marcus Quinkler, Rodrigo A. Toledo, Massimo Mannelli, Henri J. Timmers, Graeme Eisenhofer, Sandra Rodríguez-Perales, Orlando Domínguez, Geoffrey Macintyre, Maria Currás-Freixes, Cristina Rodríguez-Antona, Alberto Cascón, Luis J. Leandro-García, Cristina Montero-Conde, Giovanna Roncador, Juan Fernando García-García, Karel Pacak, Fátima Al-Shahrour and Mercedes Robledo ()
Additional contact information
Bruna Calsina: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Elena Piñeiro-Yáñez: Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Centre (CNIO)
Ángel M. Martínez-Montes: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Eduardo Caleiras: Histopathology Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO)
Ángel Fernández-Sanromán: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
María Monteagudo: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Rafael Torres-Pérez: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Coral Fustero-Torre: Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Centre (CNIO)
Marta Pulgarín-Alfaro: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Eduardo Gil: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Rocío Letón: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Scherezade Jiménez: Monoclonal Antibodies Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO)
Santiago García-Martín: Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Centre (CNIO)
Maria Carmen Martin: Molecular Cytogenetics and Genome Engineering Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Juan María Roldán-Romero: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Javier Lanillos: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Sara Mellid: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
María Santos: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Alberto Díaz-Talavera: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Ángeles Rubio: Genomics Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO)
Patricia González: Histopathology Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO)
Barbara Hernando: Computational Oncology Group, Structural Biology Program, Spanish National Cancer Research Centre (CNIO)
Nicole Bechmann: University Hospital Carl Gustav Carus, Technische Universität Dresden
Margo Dona: Radboud University Medical Centre
María Calatayud: 12 de Octubre University Hospital
Sonsoles Guadalix: 12 de Octubre University Hospital
Cristina Álvarez-Escolá: La Paz University Hospital
Rita M. Regojo: La Paz University Hospital
Javier Aller: Puerta de Hierro University Hospital
Maria Isabel Del Olmo-Garcia: University Hospital La Fe
Adrià López-Fernández: Vall d’Hebrón Hospital
Stephanie M. J. Fliedner: University Medical Center Schleswig-Holstein Lübeck
Elena Rapizzi: University of Florence
Martin Fassnacht: University Hospital Würzburg, University of Würzburg
Felix Beuschlein: Klinikum der Universität München
Marcus Quinkler: Endocrinology in Charlottenburg Stuttgarter Platz 1
Rodrigo A. Toledo: Gastrointestinal and Endocrine Tumors, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Massimo Mannelli: University of Florence
Henri J. Timmers: Radboud University Medical Centre
Graeme Eisenhofer: University Hospital Carl Gustav Carus, Technische Universität Dresden
Sandra Rodríguez-Perales: Molecular Cytogenetics and Genome Engineering Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Orlando Domínguez: Genomics Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO)
Geoffrey Macintyre: Computational Oncology Group, Structural Biology Program, Spanish National Cancer Research Centre (CNIO)
Maria Currás-Freixes: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Cristina Rodríguez-Antona: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Alberto Cascón: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Luis J. Leandro-García: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Cristina Montero-Conde: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Giovanna Roncador: Monoclonal Antibodies Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO)
Juan Fernando García-García: MD Anderson Cancer Center
Karel Pacak: Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Fátima Al-Shahrour: Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Centre (CNIO)
Mercedes Robledo: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36769-6

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