Abstract
BackgroundCarotid paragangliomas (CPGLs) are rare neuroendocrine tumors that arise from the paraganglion at the bifurcation of the carotid artery and are responsible for approximately 65% of all head and neck paragangliomas. CPGLs can occur sporadically or along with different hereditary tumor syndromes. Approximately 30 genes are known to be associated with CPGLs. However, the genetic basis behind the development of these tumors is not fully elucidated, and the molecular mechanisms underlying CPGL pathogenesis remain unclear.MethodsWhole exome and transcriptome high-throughput sequencing of CPGLs was performed on an Illumina platform. Exome libraries were prepared using a Nextera Rapid Capture Exome Kit (Illumina) and were sequenced under 75 bp paired-end model. For cDNA library preparation, a TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Gold (Illumina) was used; transcriptome sequencing was carried out with 100 bp paired-end read length. Obtained data were analyzed using xseq which estimates the influence of mutations on gene expression profiles allowing to identify potential causative genes.ResultsWe identified a total of 16 candidate genes (MYH15, CSP1, MYH3, PTGES3L, CSGALNACT2, NMD3, IFI44, GMCL1, LSP1, PPFIBP2, RBL2, MAGED1, CNIH3, STRA6, SLC6A13, and ATM) whose variants potentially influence their expression (cis-effect). The strongest cis-effect of loss-of-function variants was found in MYH15, CSP1, and MYH3, and several likely pathogenic variants in these genes associated with CPGLs were predicted.ConclusionsUsing the xseq probabilistic model, three novel potential causative genes, namely MYH15, CSP1, and MYH3, were identified in carotid paragangliomas.
Highlights
Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors that arise from the paraganglion at the bifurcation of the carotid artery and are responsible for approximately 65% of all head and neck paragangliomas
Using exome and transcriptome data from the same carotid paragangliomas (25 samples), we evaluated the impact of somatic loss-of-function variants on gene expression profiles using xseq [54]
Using the xseq model, we estimated the probability that potential loss-of-function somatic variants impact gene expression in individual patients [P(F) value] and across the population of patients [P(D) value]
Summary
Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors that arise from the paraganglion at the bifurcation of the carotid artery and are responsible for approximately 65% of all head and neck paragangliomas. CPGLs can occur sporadically or along with different hereditary tumor syndromes. In the head and neck, paragangliomas most frequently arise from carotid glomus at the bifurcation of the carotid artery [1]. Carotid paragangliomas (CPGLs) are highly vascularized tumors and are anatomically classified on three groups based on the size and involvement of the carotid artery [2]. The majority of carotid paragangliomas belong to groups 2 and 3 (primarily large size CPGLs with moderate or high arterial attachment), which are surgically challenging. The new WHO classification describes paragangliomas as tumors with variable metastatic potential [5]
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