复发性室管膜瘤的演进过程及驱动基因ADGRLX的作用机制研究

肿瘤复发尤其是多次复发，是肿瘤难治的关键，其生物遗传学背景和演进模式（evolution）亟待阐明。中枢神经系统肿瘤是肿瘤研究的热点，仍缺乏肿瘤演进方面的报道。我们收治了一例多次多部位复发的室管膜瘤患者，9年间接受7次肿瘤切除手术及同步放化疗，最终死于颅内多部位复发。该罕见病例为肿瘤复发、演进提供了绝佳的研究模型。我们收集患者病理、影像、治疗资料和肿瘤组织标本，进行回顾性分析和全基因组测序。通过生物信息学方法分析发现ADGRLX在整个发病过程中发生了编码区同一位点的突变，室管膜瘤大样本检测发现其表达水平与肿瘤级别呈负相关，与肿瘤的预后不良潜在相关。本研究将着重从分子、细胞、动物水平深入开展功能研究，明确ADGRLX在室管膜瘤多次复发演进过程中的重要作用和调节机制，寻找有效的阻断方法。该研究成果有望破译肿瘤演化规律，明确其指导临床的重要意义，为肿瘤早期检测和干预提供生物学标记，指导精准医学。

Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors of the central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the tumor evolutionary process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. The girl was diagnosed as anaplastic ependymoma, who experienced 7 tumor removal surgeries but finally ceased with intracranial multiregional recurrences. The genetic profiles of seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. Strikingly, ADGRLX was found consistently mutated during the entire disease process at the same CDS region. Its mRNA level was lower in ependymoma as compared to normal brain tissues and potentially related with poor prognosis of ependymoma patients. Our findings demonstrate a rare evolutionary process of ependymoma and suggest that ADGRLX might play roles in the progression of the disease. In the current study, we will focus on deciphering the function and signaling regulation of ADGRLX in ependymoma, and searching the efficient candidates to target ADGRLX or its pathways through drug repurposing and small molecular bank.