Genetic and immune features of resectable malignant brainstem gliomas
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Yang Zhang1,*, Changcun Pan1,*, Junmei Wang2, Jingli Cao3, Yuhan Liu1, Yajie Wang3 and Liwei Zhang1
1Department of Neurosurgery/China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
2Department of Pathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China
3Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
*These authors have contributed equally to this work
Liwei Zhang, email: [email protected]
Keywords: brainstem gliomas, genetic features, programmed death ligand 1, CD8+ T cell infiltration, prognosis
Received: August 15, 2016 Accepted: April 29, 2017 Published: July 28, 2017
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 10cm3 (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.
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