Optimizing Genetic Workup in Pheochromocytoma and Paraganglioma by Integrating Diagnostic and Research Approaches.

Laura Gieldon,Barbara Klink,Winnie Jahn,Andreas Rump,Felix Beuschlein,Evelin Schröck,Nicole Bechmann,Thomas Knösel,Georgiana Constantinescu,Arne Jahn,Svenja Nölting,Doreen William,Mercedes Robledo,Karl Hackmann,Volker Gudziol,Letizia Canu,Graeme Eisenhofer,Susan Richter,Jimmy Masjkur,Daniela E Aust ,Henri J L M Timmers ,Karel Pacák ,Johannes Maximilian Wagner

doi:10.3390/cancers11060809

Abstract

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with a strong hereditary background and a large genetic heterogeneity. Identification of the underlying genetic cause is crucial for the management of patients and their families as it aids differentiation between hereditary and sporadic cases. To improve diagnostics and clinical management we tailored an enrichment based comprehensive multi-gene next generation sequencing panel applicable to both analyses of tumor tissue and blood samples. We applied this panel to tumor samples and compared its performance to our current routine diagnostic approach. Routine diagnostic sequencing of 11 PPGL susceptibility genes was applied to blood samples of 65 unselected PPGL patients at a single center in Dresden, Germany. Predisposing germline mutations were identified in 19 (29.2%) patients. Analyses of 28 PPGL tumor tissues using the dedicated PPGL panel revealed pathogenic or likely pathogenic variants in known PPGL susceptibility genes in 21 (75%) cases, including mutations in IDH2, ATRX and HRAS. These mutations suggest sporadic tumor development. Our results imply a diagnostic benefit from extended molecular tumor testing of PPGLs and consequent improvement of patient management. The approach is promising for determination of prognostic biomarkers that support therapeutic decision-making.

Highlights

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that originate from neural crest-derived chromaffin cells and develop either in the adrenal medulla or in extra-adrenal sympathetic and parasympathetic ganglia
In 19 of 65 cases (29.2%) we identified pathogenic or likely pathogenic germline mutations in a PPGL susceptibility gene, confirming a PPGL related hereditary tumor predisposition syndrome in these cases (Table 1)
Some of these genes have been found to be mutated both in the germline and somatically, while others only occur as somatic mutations [7,8,13,16,17,18,19,22,31,32]. Analyses of both tumor and blood-derived DNA aid in discrimination of sporadic from hereditary tumor forms [31]. This information is crucial for stratifying the risk of synchronous or metachronous tumor development in PPGL patients both regarding additional PPGLs and regarding other tumor types that, respectively, are associated with some of the PPGL susceptibility genes such as gastrointestinal stromal tumors (GIST ) with SDHx mutations [33]

Summary

Introduction

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that originate from neural crest-derived chromaffin cells and develop either in the adrenal medulla or in extra-adrenal sympathetic and parasympathetic ganglia. Identification of a predisposing germline variant enables predictive testing in PPGL families, clinical surveillance of healthy mutation carriers and risk stratification for malignant disease and for development of synchronous and metachronous tumors. Several additional susceptibility and candidate genes accounting for a small proportion of cases have been identified. These are, not yet commonly included in routine diagnostic analyses of affected patients. These include germline mutations in genes encoding components of metabolic pathways, e.g. MDH2, GOT2 and DLST [12,13,14]

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Conclusion