Work

Transcriptional subtypes on immune microenvironment and predicting postoperative recurrence and metastasis in human pheochromocytoma and paraganglioma

Year: 2025

Type: preprint

Abstract: Human pheochromocytomas and paragangliomas (PPGLs) exhibit substantial molecular and immune heterogeneity, complicating risk assessment and treatment. Here, we define three distinct tumor transcriptional subtypes (C1, C2, and C3) in a clinically annotated cohort of PPGL patients through integrative transcriptomic and immunogenomic profiling. C1 is characterized by hypoxia-driven pathways and an immunosuppressive microenvironment, correlating with poor prognosis. C2 exhibits a highly inflamed immune landscape with robust CD8 + T cell infiltration, suggesting potential sensitivity to immunotherapy. C3 is enriched in metabolic reprogramming pathways and displays intermediate clinical outcomes. Genetic analysis reveals subtype-specific mutational patterns, with pseudohypoxic driver mutations ( SDHB , VHL , SDHA , and SDHD ) predominant in C1 and C3, while kinase pathway alterations ( NF1 and RET ) define C2. Single-nucleus RNA sequencing of human PPGL tumors further delineates immune ecosystem diversity. Notably, we identify ANGPT2 , PCSK1N , and GPX3 as key subtype-specific biomarkers, with ANGPT2 driving tumor progression in C1 and emerging as a potential therapeutic target. Our findings provide a refined molecular classification integrating immune and genomic features in human PPGLs, offering a framework for improved prognostication and precision therapies in this rare neuroendocrine tumor type.

Source: eLife

DOI: 10.7554/elife.107108