IDH1基因突变胶质瘤的多模态MRI特征及其机制研究

The state of isocitrate dehydrogenase (IDH) gene in patients with glioma affects the prognosis and the therapy of patients. It has been proved that IDH mutated glioma cells lead to a decrease in a-ketoglutarate (a-KG) and gain novel catalytic activity leading to production of D-2-hydroxylglutarate (D-2-HG), which inhibits multiple a-ketoglutarate-dependent dioxygenase activities in glioma. MRI could response the cell density and angiogenesis of tumors. So we suggest that MRI could preoperatively forecast the state of IDH gene in patients with glioma through the internal structure and signal of tumors. We will prospectively collect 120 patients with suspicious glioma in Huashan hospital. Routine MRI, diffusion weighted imaging and dynamic contrast magnetic resonance imaging will be performed. Routine imaging features will be evaluated. Minimal apparent diffusion coefficient value and DCE-MRI parameters including ktrans, ve and kep will be measured. Pathologic specimens of patients will be collected and a series examinations will be undergone, including HE staining to understand the WHO grade of tumors, gene sequencing to know the state of IDH gene and immunohistochemical analysis to get the expressed level of hypoxia inducible factor-1alpha (HIF-1α), vascular endothelial growth factor (VEGF）and epidermal growth factor receptor (EGFR). In statistical analysis, the difference of imaging findings between IDH mutated glioma and IDH wild glioma in the same WHO grade will be observed. Then the difference of imaging features among IDH mutated gliomas with different WHO grades will be analyze. By these methods we will prespectively illuminate the imaging features of IDH gene mutant glioma. Relevance analysis between imaging features and immunohistochemistry will be performed to explore the molecular mechanism of imaging features.

异柠檬酸盐脱氢酶基因（IDH）状态影响胶质瘤患者预后及治疗方式选择。IDH突变胶质瘤细胞通过代谢产物（2-HG）影响多种下游物质表达已经得到证实，MRI可以反映胶质瘤的细胞密度和血管生成情况，因此我们假设MRI通过显示肿瘤内部结构反映胶质瘤的IDH基因状态。拟前瞻性收集临床怀疑胶质瘤患者120例，术前进行常规MRI、弥散加权成像、动态增强MRI检查，评价肿瘤一般影像学特征、测量表观弥散系数、ktrans值、ve值、kep值，术后进行HE染色（确定胶质瘤WHO分级）、基因测序（确定IDH基因状态）、免疫组化分析（确定HIF-1α、EGFR、VEGF表达水平）。分析同一WHO分级下的胶质瘤IDH基因野生型和突变型、不同分级下IDH基因突变型胶质瘤的影像学指标是否存在统计学差异，从而筛选IDH基因突变胶质瘤的影像特征，并将影像学指标与免疫组化结果进行相关性分析，从而探讨影像学表现的分子病理机制。

胶质瘤中存在异柠檬酸盐脱氢酶（isocitrate dehydrogenase, IDH）基因突变是神经肿瘤学近几年中的重大发现之一，IDH1/2突变胶质瘤有更好的预后及较长的生存期，术前无创性诊断胶质瘤IDH基因状态意义重大。本课题基于大数据分析的方法，将胶质瘤的常规影像表现与其IDH1基因类型相结合，同时联合应用了多种最新功能MRI技术（DTI、APT、ASL、DCE-MRI、DSC-MRI、IVIM），无创性诊断弥漫性胶质细胞瘤IDH1基因类型提供了新的定量的影像参数和影像学特征。经大数据分析常规影像学，得出低级别弥漫性胶质细胞瘤中：年龄、块状强化、发病位置（脑干、左侧额叶、岛叶）、T2WI信号等特征组成的集合有助于鉴别IDH1基因状态。高级别弥漫性胶质细胞瘤中：强化程度、水肿均匀性、坏死、强化均匀性、团块状强化、钙化等组成的特征集有助于判断IDH1基因状态。联合CBF值及APT值可以有效提高高级别胶质瘤IDH1基因正确预测率。 DCE-MRI成像和DSC-MRI成像为判断脑弥漫性胶质细胞瘤的IDH1基因状态提供了可靠的影像学手段，联合rCBV值、Kep值及Ktrans值可以提高IDH1基因整体预测正确率。低级别胶质瘤组鉴别IDH1基因的有效参数：Kep、Ktrans、TTP、Ve、rCBV、rCBF；高级别胶质瘤组鉴别IDH1基因的有效参数：Kep、Ktrans、Ve、MAXSlope、AUC、rCBV、rCBF。同时IVIM为无创性判断弥漫性胶质细胞瘤的IDH1基因状态提供了一种新的影像学方法。联合F值及nrADC值可以提高低级别胶质瘤组IDH1基因整体正确预测率。发生IDH1/2基因突变的少突胶质细胞源性肿瘤多表现为较高的最小ADC值 和较低的最大 FA 值。DTI 相关参数的定量分析显示 FA 值和 ADC 值与 Ki-67 增殖指数和 MVD 指 数存在密切相关性。发生 IDH1/2 突变的病例具有较低的 Ki-67 增殖指数和 MVD 指数也提示 IDH1/2 突变可能具有抑制肿瘤增殖和血管生成的作用。基于大数据分析及多发功能磁共振技术联合应用为鉴别胶质瘤IDH1基因状态提供了新的方法，为胶质瘤分子诊断时代提供无创、精准技术支持。