Zhang Yang, Pan Changcun, Wang Junmei, Cao Jingli, Liu Yuhan, Wang Yajie, Zhang Liwei
Department of Neurosurgery/China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
Department of Pathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
Oncotarget. 2017 Jul 28;8(47):82571-82582. doi: 10.18632/oncotarget.19653. eCollection 2017 Oct 10.
We surveyed common genetic mutations (IDH1, H3F3A, PPM1D, and TP53) and immune features (PD-L1 expression and CD8 T cell tumor infiltration) in a series of 62 malignant brainstem gliomas that were resected via microsurgery. IDH1 mutations were mutually exclusive with H3F3A mutations. IDH1 mutations appeared only in adults and occurred more frequently in tumors larger than 10cm (8/29 vs 1/32, Fisher's exact test, p=0.010). H3F3A mutations occurred more frequently in children and adolescent patients (19/24 vs 18/38, chi-square test, p=0.013), low preoperative Karnofsky Performance Scale (KPS) patients (10/11 vs 20/43, chi-square test, p=0.021), and higher grade brainstem gliomas (8/21 in grade II vs 16/24 in grade III vs 13/17 in grade IV; chi-square test, p=0.038). PPM1D mutations clustered in H3F3A-mutated tumors (12/37), whereas were rare in H3F3A wildtype tumors (1/25). MGMT promoter methylations clustered in IDH1-mutated tumors (4/9), but were rare in H3F3A-mutated tumors (1/37). PD-L1 staining was detected in 59.7% of brainstem glioma specimens (37/62). High intra-tumoral CD8 T cell density was less frequent in the H3F3A-mutated than H3F3A-wild-type tumors (4/37 vs. 11/25, p=0.005). Patients with H3F3A-mutated tumors (13.8 months overall survival) had much worse prognoses than those with IDH1-mutated (54.9 months, p=0.001) or H3F3A-IDH1 co-wildtype tumors (38.4 months, p=0.001). H3F3A mutations independently increased the relative risk of death as much as 4.19-fold according to a multivariate Cox regression model. Taken together, resectable malignant brainstem gliomas can be classified into three subtypes: H3F3A-mutated, IDH1 mutated and H3F3A-IDH1 co-wildtype tumors, which have distinct clinical characteristics, prognoses, genetic and immune features.
我们对通过显微手术切除的62例恶性脑干胶质瘤中的常见基因突变（异柠檬酸脱氢酶1（IDH1）、组蛋白H3第3位点赖氨酸（H3F3A）、蛋白磷酸酶镁离子依赖性1D（PPM1D）和肿瘤蛋白p53（TP53））及免疫特征（程序性死亡受体配体1（PD-L1）表达和CD8 T细胞肿瘤浸润）进行了研究。IDH1突变与H3F3A突变相互排斥。IDH1突变仅出现在成人中，且在直径大于10cm的肿瘤中更常见（29例中有8例，32例中有1例，Fisher精确检验，p = 0.010）。H3F3A突变在儿童和青少年患者中更常见（24例中有19例，38例中有18例，卡方检验，p = 0.013）、术前卡氏评分（KPS）低的患者中更常见（11例中有10例，43例中有20例，卡方检验，p = 0.021）以及高级别脑干胶质瘤中更常见（II级21例中有8例，III级24例中有16例，IV级17例中有13例；卡方检验，p = 0.038）。PPM1D突变聚集在H3F3A突变的肿瘤中（37例中有12例），而在H3F3A野生型肿瘤中罕见（25例中有1例）。O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化聚集在IDH1突变的肿瘤中（9例中有4例），但在H3F3A突变的肿瘤中罕见（37例中有1例）。59.7%的脑干胶质瘤标本（62例中有37例）检测到PD-L1染色。H3F3A突变的肿瘤中瘤内CD8 T细胞高密度的频率低于H3F3A野生型肿瘤（37例中有4例对25例中有11例，p = 0.005）。H3F3A突变的肿瘤患者（总生存期13.8个月）的预后比IDH1突变的患者（54.9个月，p = 0.001）或H3F3A-IDH1双野生型肿瘤患者（38.4个月，p = 0.001）差得多。根据多变量Cox回归模型，H3F3A突变独立地使死亡相对风险增加多达4.19倍。综上所述，可切除的恶性脑干胶质瘤可分为三种亚型：H3F3A突变型、IDH1突变型和H3F3A-IDH1双野生型肿瘤，它们具有不同的临床特征、预后、遗传和免疫特征。
