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 Martín, Juan María Roldán‐Romero, Javier Lanillos, Sara Mellid, María Santos, Alberto Díaz‐Talavera, Ángeles Rubio, Patricia González, Bárbara Hernando, Nicole Bechmann, Margo Dona, María Calatayud, Sonsoles Guadalix, Cristina Álvarez‐Escolá, Rita María Regojo, Javier Aller, María Isabel Del Olmo-García, Adrià López‐Fernández, Stephanie Fliedner, Elena Rapizzi, Martin Faßnacht, Felix Beuschlein, Marcus Quinkler, Rodrigo A. Toledo, Massimo Mannelli, Henri Timmers, Graeme Eisenhofer, Sandra Rodríguez, Orlando Domı́nguez, Geoffrey Macintyre, María Currás-Freixes, Cristina Rodríguez‐Antona, Alberto Cascón, Luis J. Leandro‐García, Cristina Montero‐Conde, Giovanna Roncador, Juan F. Garcı́a, Karel Pacák, Fátima Al‐Shahrour, Mercedes Robledo
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.