Abstract：
UNASSIGNED: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.
摘要：
■肾血管母细胞瘤（HB）是在中枢神经系统（CNS）之外出现的罕见HBs子集，其分子驱动因素仍然完全未知。在以前的研究中没有检测到显著的改变，包括vonHippel-Lindau基因改变,通常与CNS-HB相关。本研究旨在确定肾脏HB的真实分子身份，并更好地了解其与CNS-HB的关系。一组10肾HBs提交下一代测序技术。作为一种控制，类似地分析5种经典CNS-HBs。根据分子结果,在肾HB和CNS-HB病例中进一步进行了糖蛋白非转移性B（GPNMB）免疫组织化学。突变分析表明，所有10肾HBs在结节性硬化症1（TSC1，5例），TSC2（3例），和哺乳动物雷帕霉素靶蛋白（2例），大多数被归类为致病性或可能致病性。CNS-HB队列一致证明了vonHippel-Lindau基因的体细胞突变。GPNMB是强和弥漫性的在所有10肾HBs和完全阴性的CNS-HBs，加强分子研究结果。我们的研究揭示了肾HB中的特定分子标志，以复发性TSC/哺乳动物雷帕霉素靶突变为特征，将其定义为不同于CNS-HB的独特实体。这一分子发现潜在地扩展了肾性HB患者的治疗选择。可以考虑将GPNMB纳入免疫组织化学面板中以改善肾HB鉴定。
