Mutation profiling in eight cases of vagal paragangliomas

Kudryavtseva et al. BMC Medical Genomics 2020, 13(Suppl 8):115 https://doi.org/10.1186/s12920-020-00763-4 RESEARCH Open Access Mutation profiling in eight cases of vagal paragangliomas Anna V. Kudryavtseva1*, Dmitry V. Kalinin2, Vladislav S. Pavlov1, Maria V. Savvateeva1, Maria S. Fedorova1, Elena A. Pudova1, Anastasiya A. Kobelyatskaya1, Alexander L. Golovyuk2, Zulfiya G. Guvatova1, George S. Razmakhaev3, Tatiana B. Demidova4, Sergey A. Simanovsky4, Elena N. Slavnova3, Andrey А. Poloznikov3, Andrey P. Polyakov3, Nataliya V. Melnikova1, Alexey A. Dmitriev1, George S. Krasnov1 and Anastasiya V. Snezhkina1 From 11th International Young Scientists School “Systems Biology and Bioinformatics” – SBB-2019 Novosibirsk, Russia. 24-28 June 2019 Abstract Background: 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. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood. Methods: The 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. Results: Based 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. Conclusions: Results 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. Keywords: Vagal paraganglioma, Pathogenic/likely pathogenic mutations, SDHx genes, SHD assembly factor-coding genes, Exome, High-throughput sequencing * Correspondence: 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kudryavtseva et al. BMC Medical Genomics 2020, 13(Suppl 8):115 Background 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 role of vagus paraganglia is not clear enough; they have been proposed to serve a chemoreceptive function and to participate in the immune response to infections [2, 3]. VPGL presents as a painless and slow-growing mass involving the parapharyngeal space [4]. 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 accounts for approximately 13% of all head and neck paragangliomas (HNPG Ls) and occurs more frequently in women [6, 7]. Surgical resection is a primary treatment for VPGL, whereas radiation therapy is used in case of malignant and unresectable tumors [8, 9]. VPGL has a lower risk for metastasis compared with carotid paraganglioma (CPGL) [10]. About 30% of HNPGLs develop as inherited tumors [11, 12]. A familial form of HNPGLs predominantly occurs as paraganglioma syndromes and results from mutations in SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes, encoding for succinate dehydrogenase (SDH; mitochondrial complex II) components [11]. Mutations in the SDHD gene are the most frequently found in HNPGLs, followed by SDHB and SDHC mutations [13, 14]. The inheritance pattern for SDHA, SDHB and SDHC is autosomal dominant, whereas for SDHD and SDHAF2 the transmission pattern is consistent with genomic imprinting (with a predominance of paternal transmission) [15]. SDHAF2 variants rarely present in paragangliomas/pheochromocytomas (PGLs/ PCCs) [16, 17]. Familial mutations in SDHA have been reported for Leigh syndrome [18] and, most recently, a few have been identified for HNPGLs [19–21]. Mutations in the VHL, TMEM127, RET, NF1, and MAX genes also harbor the risk for HNPGL development [22, 23]. Additionally, potentially driver somatic/germline variants were identified in several other genes, such as ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, JAG1, PRDM2, PRDM8, SETD2, ASPM, ZIC, and GRIK1 [21, 24, 25]. In this work, we performed whole-exome sequencing of VPGLs from 8 patients. Pathogenic/likely pathogenic mutations were identified and discussed for each individual case and in relation to overall VPGL pathogenesis. Methods Tumor samples Formalin-fixed paraffin-embedded (FFPE) VPGL tissues were collected at the Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation. VPGLs Page 2 of 11 were obtained from 8 patients who did not receive any radiotherapy or chemotherapy before surgery. All patients provided a written informed consent for their participation in the study. This study was approved by the ethics committee from the Vishnevsky Institute of Surgery and performed according to the Declaration of Helsinki (1964). DNA isolation, exome library preparation and sequencing Sections from FFPE tissues were prepared on glass slides (...truncated)