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dc.contributor.authorWinzeler, Bettina
dc.contributor.authorTufton, Nicola
dc.contributor.authorS Lim, Eugenie
dc.contributor.authorChallis, Ben G
dc.contributor.authorPark, Soo-Mi
dc.contributor.authorIzatt, Louise
dc.contributor.authorCarroll, Paul V
dc.contributor.authorVelusamy, Anand
dc.contributor.authorHulse, Tony
dc.contributor.authorWhitelaw, Benjamin C
dc.contributor.authorMartin, Ezequiel
dc.contributor.authorRodger, Fay
dc.contributor.authorMaranian, Melanie
dc.contributor.authorClark, Graeme R
dc.contributor.authorA Akker, Scott
dc.contributor.authorMaher, Eamonn
dc.contributor.authorCasey, Ruth T
dc.description.abstractOBJECTIVES: 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.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.subjectsomatic variant
dc.titleInvestigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.
dc.publisher.departmentDepartment of Medical Genetics
prism.publicationNameClin Endocrinol (Oxf)
dc.contributor.orcidWinzeler, Bettina [0000-0001-8305-2700]
dc.contributor.orcidTufton, Nicola [0000-0003-2382-9711]
dc.contributor.orcidChallis, Ben G [0000-0002-1130-2851]
dc.contributor.orcidIzatt, Louise [0000-0003-1258-4843]
dc.contributor.orcidA Akker, Scott [0000-0003-3893-3116]
dc.contributor.orcidMaher, Eamonn [0000-0002-6226-6918]
dc.contributor.orcidCasey, Ruth T [0000-0003-4058-3135]
rioxxterms.typeJournal Article/Review
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International