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

doi:10.1111/cen.14639

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

University Children’s Hospital Basel (UKBB),
St. Bartholomew's Hospital
Cambridge University Hospital Foundation Trust
University of Oxford
Department of Diabetes and Endocrinology
Department of Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UK.
King's College Hospital NHS Foundation Trust
University of Cambridge

Research output: Contribution to journal › Review article › peer-review

8 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	448-459
Number of pages	12
Journal	Clinical Endocrinology
Volume	97
Issue number	4
Early online date	6 Dec 2021
DOIs	https://doi.org/10.1111/cen.14639
Publication status	Published - Oct 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.1111/cen.14639Licence: CC BY 4.0

Cite this

Winzeler, B., Tufton, N., S Lim, E., Challis, B. G., Park, S.-M., Izatt, L., Carroll, P. V., Velusamy, A., Hulse, T., Whitelaw, B. C., Martin, E., Rodger, F., Maranian, M., Clark, G. R., A Akker, S., Maher, E. R., & Casey, R. T. (2022). Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort. Clinical Endocrinology, 97(4), 448-459. https://doi.org/10.1111/cen.14639

@article{f403bb3216dd409daea56a8fb1f18837,

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

abstract = "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.",

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

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

year = "2022",

month = oct,

doi = "10.1111/cen.14639",

language = "English",

volume = "97",

pages = "448--459",

journal = "Clinical Endocrinology",

issn = "0300-0664",

publisher = "Wiley-Blackwell",

number = "4",

}

Winzeler, B, Tufton, N, S Lim, E, Challis, BG, Park, S-M, Izatt, L, Carroll, PV, Velusamy, A, Hulse, T, Whitelaw, BC, Martin, E, Rodger, F, Maranian, M, Clark, GR, A Akker, S, Maher, ER & Casey, RT 2022, 'Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort', Clinical Endocrinology, vol. 97, no. 4, pp. 448-459. https://doi.org/10.1111/cen.14639

TY - JOUR

T1 - Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort

AU - Winzeler, Bettina

AU - Tufton, Nicola

AU - S Lim, Eugenie

AU - Challis, Ben G

AU - Park, Soo-Mi

AU - Izatt, Louise

AU - Carroll, Paul V

AU - Velusamy, Anand

AU - Hulse, Tony

AU - Whitelaw, Benjamin C

AU - Martin, Ezequiel

AU - Rodger, Fay

AU - Maranian, Melanie

AU - Clark, Graeme R

AU - A Akker, Scott

AU - Maher, Eamonn R

AU - Casey, Ruth T

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Adrenal Gland Neoplasms/pathology

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation/genetics

KW - Humans

KW - Paraganglioma/pathology

KW - Pheochromocytoma/diagnosis

KW - Retrospective Studies

UR - https://onlinelibrary.wiley.com/doi/10.1111/cen.14639

U2 - 10.1111/cen.14639

DO - 10.1111/cen.14639

M3 - Review article

C2 - 34870338

SN - 0300-0664

VL - 97

SP - 448

EP - 459

JO - Clinical Endocrinology

JF - Clinical Endocrinology

IS - 4

ER -

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

Abstract

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Keywords

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