PDF(Pubmed)
Abstract：
Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.
摘要：
迷走神经旁神经节瘤（VPGL）是一种罕见的神经内分泌肿瘤，起源于与迷走神经相关的神经节旁。VPGL在诊断和治疗方面提出了挑战。VPGL可以作为遗传性肿瘤发生，像其他头颈部副神经节瘤一样，最常见的是与SDHx基因的突变有关。然而,有关VPGL遗传学的数据有限。在这里，我们报道了一例41岁女性患者携带FH基因种系变异体的罕见病例.使用全外显子组测序，一个变体，FHp.S249R,已鉴定；在其他PPGL易感性和候选基因中未发现变异。杂合性缺失分析显示肿瘤中FH基因的野生型等位基因缺失。通过S-(2-琥珀酰)半胱氨酸(2SC)的免疫组织化学证实了p.S249R变体对FH活性的致病作用。在三个基因中发现了潜在的有害体细胞变异，SLC7A7、ZNF225和MED23。后两者编码可影响基因表达失调并参与肿瘤发展和进展的转录调节因子。此外，FH突变的VPGL的特征在于与SDHx突变的PPGL不同的分子表型。总之,证明了FH基因的遗传变化与VPGL的发展有关。种系变体FH:p.S249R和第二等位基因的体细胞缺失可导致促进肿瘤起始的双等位基因损伤。这些结果扩展了FH相关疾病的临床和突变谱，并提高了我们对VPGL发病机理的分子遗传机制的理解。
