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BP6. Metastatic progression of pheochromocytoma and paraganglioma occurs via parallel evolution

Friday, March 6, 2026
8:37 AM - 8:44 AM MST
Location: 301A

    Co-Author(s)

  • BW

    Bradley Wubbenhorst, MS

    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • KD

    Kurt D'Andrea, BS

    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • JP

    John Pluta, BS

    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • WA

    Wajid Amjad, BS

    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • JS

    Jake Shilan, MD

    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • DC

    Debbie L. Cohen, MD

    Professor of Medicine, Division of Renal-Electrolyte and Hypertension
    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • BW

    Bonita Weathers, MPH

    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • BB

    Bonita Bennett, RN

    Neuroendocrine Tumor Program
    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • MB

    Maria Bonanni, NP

    Nurse Practitioner Medical Genetics
    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • Kathleen Montone, MD

    Executive Vice Chair of Pathology and Laboratory Medicine
    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • KN

    Katharine Nathanson, MD

    Professor of Medicine, in the Division of Translational Medicine and Human Genetics
    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

  • Heather Wachtel, MD, MTR (she/her/hers)

    Associate Professor of Surgery
    University of Pennsylvania Health System
    Philadelphia, Pennsylvania, United States

    • Primary Presenter(s)

  • Andrew Pregnall, MSc, MPhil (he/him/his)

    Medical Student
    University of Pennsylvania
    Philadelphia, Pennsylvania, United States

    Slides
Introduction: Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and ganglia of the autonomic nervous system. Metastatic disease develops in up to 25% of patients with PCC/PGL; however, tumor evolution in metastatic PCC/PGL has not been well delineated.


Methods: We performed whole-exome sequencing of paired specimens from 27 patients with metastatic PCC/PGL to better understand cancer progression. In total, we sequenced 48 tumors from 27 patients, including 20 PCC (3 primary tumors; 17 metastases) and 28 PGL (8 primary tumors; 20 metastases). We applied MutationTimeR to estimate the relative timing and clonality of the somatic and copy number variants in our samples. We subsequently inferred the seeding pattern of individual metastases by calculating the Jaccard similarity index for primary-metastatic tumor pairs, and we estimated the time from the emergence of the metastatic founder population to the diagnosis of the primary tumor using a Gompertzian growth model that accounts for the number of shared and private mutations in the primary and metastatic tumors.


Results:

We observed a low fraction of recurrent somatic variants in primary-metastasis pairs (median 5.1%). Metastases demonstrated a higher proportion of clonal pathogenic variants than primary tumors (71.5% versus 28.5%, p < 0.001, two-proportions z-test). Across all pathogenic variants, 43.0% were classified as subclonal (n = 462), and only 6.0% were classified as early, clonal variants (n = 54). Copy number changes were estimated to occur early in molecular time in almost all samples. In all patients, the Jaccard similarity index was < 0.30, suggesting a monoclonal seeding pattern of metastases. Using published patient-level data on the doubling time and size at diagnosis of PCC/PGL, metastatic lineages of PCC/PGL were estimated to originate at a median of 15.9 years prior to the diagnosis of the primary tumor (IQR: 8.7 – 21.1), and metastases were estimated to seed approximately 10.2 years before the diagnosis of the primary tumor (IQR: 4.8 – 14.5).  


Conclusions:

Molecular clock analysis suggests that PCC/PGL metastases develop via monoclonal seeding with metastatic founder populations developing early in tumor progression. Parallel progression of metastases and primary tumors leads to significant inter-tumoral genomic heterogeneity with few shared driver alterations. These data suggest that targeted therapies may need to address multiple genomic drivers to simultaneously treat oligometastatic disease.

Learning Objectives:

  • Describe the genomic evolution and clonal architecture of metastatic pheochromocytoma and paraganglioma based on whole-exome sequencing data.
  • Explain how molecular clock analyses (e.g., MutationTimeR and Gompertzian growth modeling) can be used to infer the chronology of metastatic seeding and tumor progression
  • Discuss the clinical and therapeutic implications of early, monoclonal metastatic seeding and inter-tumoral heterogeneity for the development of targeted treatments