Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
Mol Genet Genomic Med. 2019 Sep;7(9):e880. doi: 10.1002/mgg3.880. Epub 2019 Jul 17.
von Hippel-Lindau (VHL) disease has a hereditary, autosomal dominant pattern, and multiple tumors can develop in multiple organs of a single patient. However, the exact mechanisms of tumorigenesis are unclear, and further studies are needed to clarify whether the same signaling pathways are involved in different VHL-related tumors.
Whole-exome sequencing (WES) of tumor and paired peripheral blood samples were performed for a VHL disease pedigree. A bioinformatics analysis was conducted to identify candidate somatic single-nucleotide variants (SNVs) present in all tumor tissues. Sanger sequencing was then used to validate the SNVs identified using WES. Immunohistochemistry was performed to analyze components of the mTOR pathway, which was abnormally activated in tumor tissues.
Two hemangioblastomas and two renal cell carcinomas were sequenced. The bioinformatics analysis revealed a VHL somatic variant in all tumors; no other SNV was detected. Immunohistochemistry showed the abnormal expression of the phospho-S6 ribosomal protein in the hemangioblastomas, but not in the renal clear cell carcinomas.
Except for a SNV in the VHL gene, no other somatic SNVs were detected using WES. The phospho-S6 ribosomal protein in the mTOR pathway is a potential target in VHL-related cerebellum hemangioblastomas.
von Hippel-Lindau（VHL）病呈常染色体显性遗传，同一患者的多个器官可发生多种肿瘤。然而，肿瘤发生的确切机制尚不清楚，需要进一步研究以阐明是否涉及相同的信号通路VHL 相关肿瘤。
对 VHL 病家系的肿瘤和配对外周血样本进行全外显子组测序（WES）。对所有肿瘤组织中存在的候选体细胞单核苷酸变异（SNV）进行生物信息学分析。然后使用 Sanger 测序验证 WES 鉴定的 SNVs。免疫组化分析分析了肿瘤组织中异常激活的 mTOR 通路的组成成分。
对两个血管母细胞瘤和两个肾细胞癌进行了测序。生物信息学分析显示所有肿瘤均存在 VHL 体细胞变异，未检测到其他 SNV。免疫组化显示血管母细胞瘤中磷酸化 S6 核糖体蛋白异常表达，但肾透明细胞癌中无表达。
除 VHL 基因中的 SNV 外，WES 未检测到其他体细胞 SNV。mTOR 通路中的磷酸化 S6 核糖体蛋白是 VHL 相关小脑血管母细胞瘤的潜在靶点。
