Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort

Bettina Winzeler, Nicola Tufton, Eugenie S Lim, Ben G Challis, Soo-Mi Park, Louise Izatt, Paul V Carroll, Anand Velusamy, Tony Hulse, Benjamin C Whitelaw, Ezequiel Martin, Fay Rodger, Melanie Maranian, Graeme R Clark, Scott A Akker, Eamonn R Maher, Ruth T Casey

Research output: Contribution to journalReview articlepeer-review


OBJECTIVES: Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom.

DESIGN AND PATIENTS: Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated.

MEASUREMENTS: Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed.

RESULTS: Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results.

CONCLUSIONS: Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

Original languageEnglish
Pages (from-to)448-459
Number of pages12
JournalClinical Endocrinology
Issue number4
Early online date6 Dec 2021
Publication statusPublished - Oct 2022


  • Adrenal Gland Neoplasms/pathology
  • Genetic Predisposition to Disease
  • Germ-Line Mutation/genetics
  • Humans
  • Paraganglioma/pathology
  • Pheochromocytoma/diagnosis
  • Retrospective Studies


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