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Abbreviations HNPGL: Head and neck paraganglioma; CPGL: Carotid paraganglioma; VPGL: Vagal paraganglioma; CT: Computed tomography; US: Ultrasound study; CCA: Common carotid artery; ICA: Internal carotid artery; OCA: Outer carotid artery
Source publication
Background:
Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and g...
Citations
... The most frequent variant was a missense variant in the SDHD gene, NM_003002: c.A305G, p.H102R (chr11:111959726, rs104894302), which we detected in 14 tumor tissues obtained from 12 patients (1 patient had multifocal HNPGLs manifesting as two bilateral carotid PGLs and a vagal PGL (001tc1, 001tc2, and 001tv)) [12] (Table 2). We found this variant in 34% (12/35) of patients with SDHD mutations and 21% (12/57) of all SDHxmutated individuals in the studied case cohort. ...
... Three patients (all with multifocal tumors) harbored this mutation. In our cohort, we found SDHD:p.H102R in only one case of multifocal tumor that was previously described [12]. The prevalence of the variant in a previous study was approximately 3% and was equal to the frequency of synonymous substitution p.S68S, which was also determined in the SDHD gene and predicted as potentially influencing splicing. ...
Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in SDHx genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the SDHD gene. We determined this variant in 34% of the SDHD mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of SDHD:p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found SDHD:p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the SDHD:p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs.
... Up to 40% of these tumors are associated with germline mutations and might develop as part of the syndromes or be caused by de novo mutations in the following genes: RET (multiple endocrine neoplasia type (4,6). Somatic mutations have been detected in many genes, including SDHD, SDHA, EPAS1/ HIF2A, KIF1B, RET, NF1, HRAS, CSDE1, MAML3, TP53, IDH1/2, and others (6)(7)(8)(9)(10). The reported frequency of germline and somatic mutations in PPGLs vary in different cohorts. ...
Context
Head and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Nevertheless, paragangliomas present as polygenic diseases caused by combined alterations in multiple genes, however, many driver changes remain unknown.
Objective
The objective of the study was to analyze somatic mutation profiles in HNPGLs.
Design
Whole-exome sequencing of 42 tumors and matched normal tissues obtained from Russian patients with HNPGLs was carried out. Somatic mutation profiling included variant calling and utilizing of MutSig and SigProfiler packages.
Results
57% of patients harbored germline and somatic variants in the PGL susceptibility genes or potentially related genes. Somatic variants in novel genes were found in 17% of patients without mutations in any known PGL-related genes. The studied cohort was characterized by six significantly mutated genes: SDHD, BCAS4, SLC25A14, RBM3, TP53, and ASCC1, as well as four COSMIC SBS-96 mutational signatures (SBS5, SBS29, SBS1, and SBS7b). Tumors with germline variants specifically displayed SBS11 and SBS19, when SBS33 specific mutational signature was identified for cases without those. B allele frequency analysis of copy number variations revealed loss of heterozygosity of the wild-type allele in one patient with germline mutation c.287-2A>G in the SDHB gene. In patients with germline mutation c.A305G in the SDHD gene, frequent potential loss of chromosome 11 was observed.
Conclusion
These results give an understanding of somatic changes and the mutational landscape associated with HNPGLs and are important for the identification of molecular mechanisms involved in tumor development.
... Differential gene expression was also shown between SDHB-117 and VHL-mutated PHEOs, which confirmed different pseudohypoxic signatures [27]. 118 According to these results, the pseudohypoxia cluster was divided into two subgroups: 119 SDHx/SDHAF2-and VHL/EPAS1-related tumors (Clusters 1A and 1B, respectively). 120 SLC25A11-mutated tumors also demonstrate the pseudohypoxic phenotype and can be 121 assigned to this subtype [28]. ...
... How-366 ever, Petri et al. reported opposite results; it was shown that despite the loss of the p53 367 locus on 17p in many benign and malignant PHEOs, no mutations or rare positive nu-368 clear protein immunostaining were identified in association with metastatic disease[117].369 Several cases reported TP53 mutations occurring together with pathogenic variants in 370 other susceptibility genes in a multiple HNPGL (TP53 and SDHD)[119] and a malignant 371 PHEO (TP53 and SDHB)[120] ...
Paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors originating from paraganglionic tissue in many sites of the body. Most PPGLs are characterized by nonaggressive behavior but all of them have the potential to metastasize. PPGLs represent a great diagnostic dilemma as it is difficult to recognize tumors that are likely to be metastasizing; criteria of malignancy can be found both in benign and metastatic forms. This review aims to analyze the current knowledge of the nature of metastasizing PPGLs paying particular attention to head and neck paragangliomas (HNPGLs). Potential predictors of the malignancy risk for PPGLs were summarized and discussed. These data may also help in the development of diagnostic and prognostic strategies, as well as in the identification of novel potential therapeutic targets for patients with PPGLs.
... Mutations in any of the SDHx genes can cause a destabilization of the SDH complex, loss of its enzymatic activity, and a disruption in the electron transport function [47][48][49][50]. Numerous studies have reported a changed expression pattern of SDHB presented as negative or weak diffuse immunostaining in tumors with SDHA-, SDHB-, SDHC-, and SDHD mutations [24,[51][52][53]. It was shown that negative SDHB staining is more commonly associated with mutations in SDHB, whereas weak diffuse staining often occurs in SDHD-mutated tumors [52]. ...
Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in SDHx genes. The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of SDHx mutations in paragangliomas/pheochromocytomas. We compared the mutation status of SDHx genes with the immunohistochemical (IHC) staining of SDH subunits in CPGLs. To identify pathogenic/likely pathogenic variants in SDHx genes, exome sequencing data analysis among 42 CPGL patients was performed. IHC staining of SDH subunits was carried out for all CPGLs studied. We encountered SDHx variants in 38% (16/42) of the cases in SDHx genes. IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of SDHx (94%, 15/16). In SDHA-mutated CPGL, SDHA expression was completely absent and weak diffuse SDHB staining was detected. Positive immunoreactivity for all SDH subunits was found in one case with a variant in SDHD. Notably, CPGL samples without variants in SDHx also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26). Obtained results indicate that SDH immunohistochemistry does not fully reflect the presence of mutations in the genes; diagnostic effectiveness of this method was 71%. However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying SDHx mutations for recommendation of genetic testing.
... We conclude this special journal issue by the multiple paraganglioma cases report compiled by Vladislav Pavlov et al. [21] (this issue). The authors report a case of multiple paragangliomas, manifesting as bilateral carotid and vagal paragangliomas. ...
