Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.
paraganglioma
phaeochromocytoma
somatic variant
Journal
Clinical endocrinology
ISSN: 1365-2265
Titre abrégé: Clin Endocrinol (Oxf)
Pays: England
ID NLM: 0346653
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
24
09
2021
received:
04
08
2021
accepted:
21
10
2021
pubmed:
7
12
2021
medline:
14
9
2022
entrez:
6
12
2021
Statut:
ppublish
Résumé
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. Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated. 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. 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. 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.
Identifiants
pubmed: 34870338
doi: 10.1111/cen.14639
pmc: PMC9543043
doi:
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
448-459Subventions
Organisme : Medical Research Council
ID : MR/W001101/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.
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