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Pheochromocytoma and paraganglioma (PPGL) tumors show similar genomic profiles, but distinct gene expression patterns in primary tumors can predict future metastasis. This may aid early patient risk stratification.

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Area of Science:

  • Endocrinology
  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Pheochromocytoma and sympathetic paraganglioma (PPGL) affect 10-20% of patients, often presenting as metachronous lesions.
  • Accurate biomarkers for predicting PPGL biologic behavior at initial diagnosis are lacking.
  • Understanding molecular differences between localized and metastatic PPGL is crucial for improved patient management.

Purpose of the Study:

  • To investigate the molecular differences between localized and metastatic PPGL.
  • To identify potential biomarkers for predicting metastatic potential in PPGL.
  • To explore the role of chromosomal instability and gene expression in PPGL progression.

Main Methods:

  • Comprehensive molecular analysis of PPGL tumor samples from patients with localized or metastatic disease.
  • Application of single-cell whole-genome sequencing to assess karyotype complexity and variability.
  • Bulk transcriptome analysis, including RNA sequence variant detection, to identify differential gene expression.

Main Results:

  • PPGL tumors exhibit complex karyotypes with recurrent aneuploidies and significant cell-to-cell karyotype variability, indicating chromosomal instability (CIN) in both localized and metastatic types.
  • Transcriptome analysis revealed distinct differences between localized and metastatic PPGL, notably in TNFα and TGFβ signaling pathways.
  • These transcriptional differences were detectable in primary tumor samples even before the development of overt metastases.

Conclusions:

  • While genomic landscapes of localized and metastatic PPGL are largely comparable, significant transcriptional differences exist.
  • Transcriptional signatures, particularly involving TNFα and TGFβ signaling, in primary tumors may predict future metastatic potential.
  • These findings offer a potential tool for improved patient stratification and risk assessment at the initial diagnosis of PPGL.