Non-Susceptibility Gene Variants in Head and Neck Paragangliomas

Abstract

Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale studies and individual cases have reported mutations in additional genes that may be involved in tumorigenesis. Consequently, numerous disease-causing mutations and genes responsible for the pathogenesis of HNPGLs remain poorly investigated. The aim of this study was to gain a deeper understanding of the genetic basis of HNPGLs by focusing on variants in genes that were not previously identified as well-known drivers. A whole-exome data analysis was conducted on a representative set of 152 HNPGLs. In 30% of the tumors examined, 53 potentially deleterious variants were identified in 36 different genes. The analysis identified pathogenic or likely pathogenic variants in the ARNT, IDH2, L2HGDH, MYH3, PIK3CA, and TERT genes. A functional network analysis of the mutated genes revealed numerous associations and a list of metabolic pathways (e.g., the TCA cycle, carbon metabolism, pyruvate metabolism, etc.) and signaling pathways (e.g., HIF1, PI3K-Akt, FoxO, AMPK, MAPK, etc.) that may play an important role in the development of HNPGLs. The identified range of genetic alterations affecting multiple genes and, potentially, influencing diverse cellular pathways provides an enhanced molecular genetic characterization of HNPGLs.

Keywords: gene network; genetic screening; head and neck paragangliomas; mutations.

Figure 1

A spectrum of genetic variants identified in non-susceptibility genes across a cohort of patients with head and neck paragangliomas. The bottom of the oncoprint includes the identification number of patients with head and neck paragangliomas of different localizations (carotid, vagal, and middle ear), as well as the age and sex of patients. The top of the oncoprint plot displays the following clinical and pathological characteristics: SDHx mutations, SDHB immunohistochemical pattern, tumor localization, features of the clinical course, and blood pressure. The right-hand side of the plot provides a list of the mutated genes. The center section of the oncoprint illustrates the types of each variant (missense, stop-gain, splicing, and frameshift) represented by different colors. Germline or somatic status, where available, is indicated by black figures. PGL, paraganglioma. SDHx, genes encoding subunits of the succinate dehydrogenase complex.

Figure 2

A functional enrichment analysis of mutated genes in head and neck paragangliomas based on the Kyoto Encyclopedia of Genes and Genomes (KEGG). (A) The number of genes categorized according to their involvement in the KEGG signaling and metabolic pathways. The blue columns indicate the number of identified mutated genes involved in signaling pathways. The orange columns indicate the number of genes involved in metabolic pathways. (B) The functional network showing multiple associations between mutated genes. Signaling and metabolic pathways are indicated by pink and yellow, respectively. The mutated genes are indicated by green coloring.