Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

被引：46

作者：

Calsina, Bruna ^{[1
]}

Pineiro-Yanez, Elena ^{[2
]}

Martinez-Montes, Angel M. ^{[1
]}

Caleiras, Eduardo ^{[3
]}

Fernandez-Sanroman, Angel ^{[1
]}

Monteagudo, Maria ^{[1
]}

Torres-Perez, Rafael ^{[1
,4
]}

Fustero-Torre, Coral ^{[2
]}

Pulgarin-Alfaro, Marta ^{[1
]}

Gil, Eduardo ^{[1
]}

Leton, Rocio ^{[1
]}

Jimenez, Scherezade ^{[5
]}

Garcia-Martin, Santiago ^{[2
]}

Martin, Maria Carmen ^{[6
]}

Roldan-Romero, Juan Maria ^{[1
]}

Lanillos, Javier ^{[1
]}

Mellid, Sara ^{[1
]}

Santos, Maria ^{[1
]}

Diaz-Talavera, Alberto ^{[1
,7
]}

Rubio, Angeles ^{[8
]}

Gonzalez, Patricia ^{[3
]}

Hernando, Barbara ^{[9
]}

Bechmann, Nicole ^{[10
]}

Dona, Margo ^{[11
]}

Calatayud, Maria ^{[12
]}

Guadalix, Sonsoles ^{[12
]}

Alvarez-Escola, Cristina ^{[13
]}

Regojo, Rita M. ^{[14
]}

Aller, Javier ^{[15
]}

Del Olmo-Garcia, Maria Isabel ^{[16
]}

Lopez-Fernandez, Adria ^{[17
]}

Fliedner, Stephanie M. J. ^{[18
]}

Rapizzi, Elena ^{[19
]}

Fassnacht, Martin ^{[20
,21
]}

Beuschlein, Felix ^{[22
,23
,24
]}

Quinkler, Marcus ^{[25
]}

Toledo, Rodrigo A. ^{[26
,27
]}

Mannelli, Massimo ^{[19
]}

Timmers, Henri J. ^{[11
]}

Eisenhofer, Graeme ^{[10
,28
]}

Rodriguez-Perales, Sandra ^{[6
]}

Dominguez, Orlando ^{[8
]}

Macintyre, Geoffrey ^{[9
]}

Curras-Freixes, Maria ^{[1
,29
]}

Rodriguez-Antona, Cristina ^{[1
,7
]}

Cascon, Alberto ^{[1
,7
]}

Leandro-Garcia, Luis J. ^{[1
]}

Montero-Conde, Cristina ^{[1
,7
]}

Roncador, Giovanna ^{[5
]}

Garcia-Garcia, Juan Fernando ^{[30
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Hereditary Endocrine Canc Grp, Madrid, Spain

[2] Spanish Natl Canc Res Ctr CNIO, Struct Biol Program, Bioinformat Unit, Madrid, Spain

[3] Spanish Natl Canc Res Ctr CNIO, Biotechnol Program, Histopathol Core Unit, Madrid, Spain

[4] CSIC, Bioinformat Genom & Prote, Natl Ctr Biotechnol CNB, Madrid, Spain

[5] Spanish Natl Canc Res Ctr CNIO, Biotechnol Program, Monoclonal Antibodies Core Unit, Madrid, Spain

[6] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Mol Cytogenet & Genome Engn Grp, Madrid, Spain

[7] Inst Hlth Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain

[8] Spanish Natl Canc Res Ctr CNIO, Biotechnol Program, Genom Core Unit, Madrid, Spain

[9] Spanish Natl Canc Res Ctr CNIO, Struct Biol Program, Comp Oncol Grp, Madrid, Spain

[10] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany

[11] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, Nijmegen, Netherlands

[12] 12 Octubre Univ Hosp, Dept Endocrinol, Madrid, Spain

[13] La Paz Univ Hosp, Dept Endocrinol, Madrid, Spain

[14] La Paz Univ Hosp, Dept Pathol, Madrid, Spain

[15] Puerta Hierro Univ Hosp, Dept Endocrinol, Madrid, Spain

[16] Univ Hosp La Fe, Dept Endocrinol & Nutr, Valencia, Spain

[17] Vall dHebron Hosp, Dept Med Oncol, Barcelona, Spain

[18] Univ Med Ctr Schleswig Holstein Lubeck, Ctr Brain Behav & Metab, Med Dept 1, Neuroendocrine Oncol & Metab, Lubeck, Germany

[19] Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy

[20] Univ Wurzburg, Univ Hosp Wurzburg, Dept Internal Med 1, Div Endocrinol & Diabet, Wurzburg, Germany

[21] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Wurzburg, Germany

[22] Klinikum Univ Munchen, Med Klin & Poliklin 4, Munich, Germany

[23] Univ Spital Zurich, Klin Endokrinol Diabet & Klin Ernahrung, Zurich, Switzerland

[24] USZ Univ Zurich UZH, Zurich, Switzerland

[25] Endocrinol, Charlottenburg Stuttgarter Pl 1, Berlin, Germany

[26] Vall dHebron Inst Oncol VHIO, Gastrointestinal & Endocrine Tumors, Barcelona, Spain

[27] Inst Hlth Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[28] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, Dresden, Germany

[29] Clin Univ Navarra, Dept Endocrinol, Madrid, Spain

[30] MD Anderson Canc Ctr, Dept Pathol, Madrid, Spain

[31] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Med Neuroendocrinol, Bethesda, MD USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

SOMATIC MUTATIONS; MICROSATELLITE INSTABILITY; COMPREHENSIVE ANALYSIS; RIBOSOME BIOGENESIS; TERT PROMOTER; CELL-CYCLE; CANCER; TUMORS; RNA; ACTIVATION;

D O I：

10.1038/s41467-023-36769-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.

引用

页数：20

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