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, Mercedes Robledo

Journal: Nature communications 2023;14(1):1122

PMID: 36854674

Free Full Text on Nature Publishing Group View on PubMed

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.

Address: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [email protected].; Bioinformatics Unit, Structural Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Histopathology Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Bioinformatics for Genomics and Proteomics, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain.; Monoclonal Antibodies Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Molecular Cytogenetics and Genome Engineering Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain.; Genomics Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Computational Oncology Group, Structural Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.; Department of Endocrinology, 12 de Octubre University Hospital, Madrid, Spain.; Department of Endocrinology, La Paz University Hospital, Madrid, Spain.; Department of Pathology, La Paz University Hospital, Madrid, Spain.; Department of Endocrinology, Puerta de Hierro University Hospital, Madrid, Spain.; Department of Endocrinology and Nutrition, University Hospital La Fe, Valencia, Spain.; Department of Medical Oncology, Vall d'Hebrón Hospital, Barcelona, Spain.; Neuroendocrine Oncology and Metabolism, Medical Department I, Center of Brain, Behavior, and Metabolism, University Medical Center Schleswig-Holstein Lübeck, Lübeck, Germany.; Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.; Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.; Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.; Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.; Klinik für Endokrinologie Diabetologie und Klinische Ernährung, Universitätsspital Zürich (USZ) und Universität Zürich (UZH), Zürich, Switzerland.; Endocrinology in Charlottenburg Stuttgarter Platz 1, Berlin, Germany.; Gastrointestinal and Endocrine Tumors, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), Madrid, Spain.; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Department of Endocrinology, Clínica Universidad de Navarra, Madrid, Spain.; Department of Pathology, MD Anderson Cancer Center, Madrid, Spain.; Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [email protected].; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain. [email protected].

DOI: 10.1038/s41467-023-36769-6

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/adrenalglandcancer.html

Miscellaneous:

https://assays.cancer.gov/CPTAC-797

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-CD274-1

MeSH Terms: Humans, Adrenal Gland Neoplasms, Genomics, Neoplasms, Second Primary, Paraganglioma, Pheochromocytoma, Tumor Microenvironment