Mutation profiling in eight cases of vagal paragangliomas

Anna V Kudryavtseva,George S Razmakhaev,Tatiana B Demidova,Anastasiya V Snezhkina,Maria S Fedorova,Dmitry V Kalinin,Sergey A Simanovsky,Nataliya V Melnikova,Andrey А Poloznikov,Zulfiya G Guvatova,Alexey A Dmitriev,Elena N Slavnova,Anastasiya A Kobelyatskaya,Andrey P Polyakov,Vladislav S Pavlov,Elena A Pudova,Maria V Savvateeva,George S Krasnov,Alexander L Golovyuk

doi:10.1186/s12920-020-00763-4

Abstract

BackgroundVagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood.MethodsThe collection of VPGLs obtained from 8 patients of Russian population was used in the study. Exome library preparation and high-throughput sequencing of VPGLs were performed using an Illumina technology.ResultsBased on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas. SDHB variants were found in three patients, whereas SDHD was mutated in two cases. Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex. In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT). Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors.ConclusionsResults indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.

Highlights

Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors
Surgical resection is a primary treatment for VPGL, whereas radiation therapy is used in case of malignant and unresectable tumors [8, 9]
In VPGLs, we identified pathogenic/likely pathogenic variants of genes that were previously shown to be associated with PGLs/PCCs: VHL, SDHx, NF1, RET, HRAS, KRAS, EPAS1 (HIF2A), ATRX, CSDE1, BRAF, FGFR1, FGFR2, FGFR3, FGFR4, FGFRL1, SETD2, ARNT, TP53, TP53BP1, TP53BP2, TP53I13, KMT2D, BAP1, IDH1, IDH2, SDHAF1, SDHA P2, FH, EGLN1, MDH2, TMEM127, MAX, KIF1B, MEN1, GDNF, GNAS, CDKN2A, BRCA1, and BRCA2 [21] as well as in other groups of genes (Additional file 1)

Summary

Introduction

Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Vagal paraganglioma (VPGL) is a neuroendocrine tumor that arises from paraganglia along the course of the vagus nerve (cranial nerve X), the dominant nerve of the parasympathetic division of the autonomic nervous system [1]. The symptoms of VPGL depend on tumor location. They range from pulsatile tinnitus/ringing in the ear to deficits of cranial nerves (such as hoarseness and dysphagia) and intracranial extension associated with an increased risk of death [5]. VPGL has a lower risk for metastasis compared with carotid paraganglioma (CPGL) [10]

Methods

Results

Conclusion