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

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

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

Keywords

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

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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",

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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

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