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Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

Author

Listed:
  • 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)
    Bioinformatics for Genomics and Proteomics, National Centre for Biotechnology (CNB-CSIC))

  • 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)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII))

  • 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
    University of Würzburg)

  • Felix Beuschlein

    (Klinikum der Universität München
    Universitätsspital Zürich (USZ) und Universität Zürich (UZH))

  • 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
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII))

  • Massimo Mannelli

    (University of Florence)

  • Henri J. Timmers

    (Radboud University Medical Centre)

  • Graeme Eisenhofer

    (University Hospital Carl Gustav Carus, Technische Universität Dresden
    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)
    Clínica Universidad de Navarra)

  • Cristina Rodríguez-Antona

    (Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII))

  • Alberto Cascón

    (Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII))

  • 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)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII))

  • 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)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII))

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.

Suggested Citation

  • 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 & Ed, 2023. "Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36769-6
    DOI: 10.1038/s41467-023-36769-6
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    References listed on IDEAS

    as
    1. Lauren Fishbein & Sanika Khare & Bradley Wubbenhorst & Daniel DeSloover & Kurt D’Andrea & Shana Merrill & Nam Woo Cho & Roger A. Greenberg & Tobias Else & Kathleen Montone & Virginia LiVolsi & Douglas, 2015. "Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas," Nature Communications, Nature, vol. 6(1), pages 1-6, May.
    2. Paul C. Tumeh & Christina L. Harview & Jennifer H. Yearley & I. Peter Shintaku & Emma J. M. Taylor & Lidia Robert & Bartosz Chmielowski & Marko Spasic & Gina Henry & Voicu Ciobanu & Alisha N. West & M, 2014. "PD-1 blockade induces responses by inhibiting adaptive immune resistance," Nature, Nature, vol. 515(7528), pages 568-571, November.
    3. Kosuke Yoshihara & Maria Shahmoradgoli & Emmanuel Martínez & Rahulsimham Vegesna & Hoon Kim & Wandaliz Torres-Garcia & Victor Treviño & Hui Shen & Peter W. Laird & Douglas A. Levine & Scott L. Carter , 2013. "Inferring tumour purity and stromal and immune cell admixture from expression data," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
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    5. Magnus Zethoven & Luciano Martelotto & Andrew Pattison & Blake Bowen & Shiva Balachander & Aidan Flynn & Fernando J. Rossello & Annette Hogg & Julie A. Miller & Zdenek Frysak & Sean Grimmond & Lauren , 2022. "Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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