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.

Domain Landscapes of Somatic NF1 Mutations in Pheochromocytoma and Paraganglioma

“…Germline mutations in the NF1 gene are associated with neurofibromatosis type 1 and in these cases, the prevalence of pheochromocytomas is about 3%, up to about 12% are considered malignant (Nölting et al, 2022). Somatic mutations in NF1 in this study are identified in about 36%, which is slightly higher than the reported frequencies (20-25%)) (Winzeler et al, 2022;Zhikrivetskaya et al, 2017). Somatic mutations in NF1 are a commonly mutated gene in several different cancers e.g 34% of ovarian cancer, 27% breast cancer and 23% of glioblastoma (Philpott et al, 2017).…”

Editorial for Clinical Endocrinology special issue on “Genetics in Endocrinology”

“…5 Bettina Winzeler and colleagues provide original data and a review of the literature outlining the utility of somatic sequencing platforms in the clinical management of phaeochromocytoma and paraganglioma. 6 Juliane Lippert, Martin Fassnacht and Cristina Ronchi provide an overview on the utility of molecular testing in adrenocortical carcinoma. 7 Tansit Saengkaew and Sasha Howard describe recent advances in the understanding of biological mechanisms underpinning delayed puberty.…”

“…Kevin Colclough and colleagues outline a comprehensive approach to the diagnosis of Maturity Onset Diabetes of the Young 5 . Bettina Winzeler and colleagues provide original data and a review of the literature outlining the utility of somatic sequencing platforms in the clinical management of phaeochromocytoma and paraganglioma 6 . Juliane Lippert, Martin Fassnacht and Cristina Ronchi provide an overview on the utility of molecular testing in adrenocortical carcinoma 7 …”