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. 2018 Feb 13;11(Suppl 1):17.
doi: 10.1186/s12920-018-0327-0.

Exome analysis of carotid body tumor

Anastasiya V Snezhkina  1 , Elena N Lukyanova  1 , Dmitry V Kalinin  2 , Anatoly V Pokrovsky  2 , Alexey A Dmitriev  1 , Nadezhda V Koroban  3 , Elena A Pudova  1 , Maria S Fedorova  1 , Nadezhda N Volchenko  3 , Oleg A Stepanov  1   3 , Ekaterina A Zhevelyuk  1 , Sergey L Kharitonov  1 , Anastasiya V Lipatova  1 , Ivan S Abramov  1 , Alexander V Golovyuk  2 , Yegor E Yegorov  1 , Khava S Vishnyakova  1 , Alexey A Moskalev  1 , George S Krasnov  1 , Nataliya V Melnikova  1 , Dmitry S Shcherbo  4 , Marina V Kiseleva  3 , Andrey D Kaprin  3 , Boris Y Alekseev  3 , Andrew R Zaretsky  4 , Anna V Kudryavtseva  5   6
Affiliations

Exome analysis of carotid body tumor

Anastasiya V Snezhkina et al. BMC Med Genomics. .

Abstract

Background: Carotid body tumor (CBT) is a form of head and neck paragangliomas (HNPGLs) arising at the bifurcation of carotid arteries. Paragangliomas are commonly associated with germline and somatic mutations involving at least one of more than thirty causative genes. However, the specific functionality of a number of these genes involved in the formation of paragangliomas has not yet been fully investigated.

Methods: Exome library preparation was carried out using Nextera® Rapid Capture Exome Kit (Illumina, USA). Sequencing was performed on NextSeq 500 System (Illumina).

Results: Exome analysis of 52 CBTs revealed potential driver mutations (PDMs) in 21 genes: ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, SDHA, SDHB, SDHC, SDHD, SETD2, TP53BP1, TP53BP2, and TP53I13. In many samples, more than one PDM was identified. There are also 41% of samples in which we did not identify any PDM; in these cases, the formation of CBT was probably caused by the cumulative effect of several not highly pathogenic mutations. Estimation of average mutation load demonstrated 6-8 mutations per megabase (Mb). Genes with the highest mutation rate were identified.

Conclusions: Exome analysis of 52 CBTs for the first time revealed the average mutation load for these tumors and also identified potential driver mutations as well as their frequencies and co-occurrence with the other PDMs.

Keywords: Carotid body tumor; Exome; Head and neck paragangliomas; High-throughput sequencing; Mutations; Paragangliomas.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved by The Ethics committee of A.V. Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation. The study was done in accordance with the principles outlined in the Declaration of Helsinki (1964).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Conditions associated with the selected genes
Fig. 2
Fig. 2
Pathways associated with the selected genes
Fig. 3
Fig. 3
Distribution of high impact mutations in the genes of interest across the CBT samples. The list of mutation types, which belong to high impact category, is represented in Additional file 2. Colored scale indicates the number of mutations in one gene
Fig. 4
Fig. 4
Distribution of potential driver mutations in the genes of interest across the CBT samples. For PDM determination, we apply three additional filters for the previous list. We included mutations occurring only in healthy human population with less than 2% frequency according to the ExAC database and 1000 Genomes project. Only mutations reported as benign according to ClinVar were removed. We suggested that PDMs are only those mutations which are located in conservative DNA fragments. Fragments with conservative score higher than 0.6 (scale: from 0 - highly variable fragment, to 1 - highly conservative fragment) according to phastCons for three groups (46 placentals, 46 primates, and 100 vertebrates) were included. Colored scale indicates the number of mutations in one gene
Fig. 5
Fig. 5
Analysis of mutation load in carotid body tumor (CBT) samples. Distribution of potentially somatic deleterious mutations among the CBT samples was evaluated to estimate their number per megabase of coding regions
Fig. 6
Fig. 6
List of top 50 most frequently mutated genes in CBTs. Number of potentially somatic deleterious mutations normalized by gene length for 52 samples in total is indicated by Y-axis
Fig. 7
Fig. 7
Heatmap of potentially somatic deleterious mutations in CBTs normalized by gene length across all genes for all patients. Red color indicates highly mutated genes and blue color flags genes with low level of potentially somatic deleterious mutations
See this image and copyright information in PMC

References

    1. Amato B, Bianco T, Compagna R, Siano M, Esposito G, Buffone G, Serra R, de Franciscis S. Surgical resection of carotid body paragangliomas: 10 years of experience. Am J Surg. 2014;207(2):293–298. doi: 10.1016/j.amjsurg.2013.06.002. - DOI - PubMed
    1. Zhikrivetskaya SO, Snezhkina AV, Zaretsky AR, Alekseev BY, Pokrovsky AV, Golovyuk AL, Melnikova NV, Stepanov OA, Kalinin DV, Moskalev AA, et al. Molecular markers of paragangliomas/pheochromocytomas. Oncotarget. 2017;8(15):25756–25782. doi: 10.18632/oncotarget.15201. - DOI - PMC - PubMed
    1. Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012;44(5):328–333. doi: 10.1055/s-0031-1301302. - DOI - PubMed
    1. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459–1466. doi: 10.1056/NEJMoa020152. - DOI - PubMed
    1. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287(5454):848–851. doi: 10.1126/science.287.5454.848. - DOI - PubMed

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