Original ArticlesHistone H3.3 G34-mutant Diffuse Gliomas in AdultsWang, Leiming MD, PhD*; Shao, Liwei MD†; Li, Hainan MD‡; Yao, Kun PhD§; Duan, Zejun MD, PhD§; Zhi, Cheng MD∥; Song, Shuangshuang MD¶; Cheng, Ye MD, PhD#; Wang, Fuyu MD**; Wang, Wei MD*; Piao, Yueshan MD, PhD*; Gui, Qiuping MD†; Lu, Dehong MD*; Qi, Xueling MD§; Teng, Lianghong MD, PhD* Author Information Departments of *Pathology ¶Radiology #Neurosurgery, Xuanwu Hospital, Capital Medical University Departments of †Pathology **Neurosurgery, The First Medical Center of Chinese PLA General Hospital §Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing ‡Department of Pathology, Guangdong Sanjiu Brain Hospital ∥Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China X.Q. and L.T. are co-corresponding authors. L.W., L.S., and H.L. contributed equally. L.W., L.S., and H.L.: analyzed the data and performed the experiments. S.S., Y.C., and F.W.: analyzed the imaging features and clinical data. X.Q., K.Y., Z.D., C.Z., and W.W.: provided essential material. Y.P., Q.G., and D.L.: reviewed the pathologic diagnosis. L.W. and L.T.: wrote the draft of the manuscript. X.Q. and L.T.: supervised the study and critically reviewed the manuscript. Conflicts of Interest and Source of Funding: Supported by the Beijing Nova program (Z201100006820149), Beijing Higher Education Young Elite Teacher Project (CIT&TCD201904091) to L.W., and Beijing, Tianjin and Hebei Basic Research Cooperation Project (19JCZDJC64900(Z)) to L.T. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Lianghong Teng, MD, PhD, Department of Pathology, Xuanwu Hospital Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing 100053, China (e-mail: [email protected]). The American Journal of Surgical Pathology: February 2022 - Volume 46 - Issue 2 - p 249-257 doi: 10.1097/PAS.0000000000001781 Buy SDC Metrics Abstract The characteristics of H3.3 G34-mutant gliomas in adults have yet to be specifically described. Thirty adults with H3.3 G34-mutant diffuse gliomas were retrospectively reviewed for clinical and pathologic information. Molecular profiling using next-generation sequencing was performed in 29 of the 30 H3.3 G34-mutant patients with 1 patient lacking available tumor samples, as well as 82 IDH/H3 wild-type adult diffuse glioma patients. The age at diagnosis of H3.3 G34-mutant diffuse gliomas was significantly younger than IDH/H3 wild-type gliomas (24 vs. 57 y, P<0.001). Overall, 19 of the 30 patients were diagnosed of glioblastoma with the primitive neuronal component, and 8 were glioblastoma. The molecular profiling analysis revealed higher frequencies of Olig-2 loss of expression, TP53 mutation, ATRX mutation, PDGFRA mutation, and MGMT promoter methylation (P<0.05) in H3.3 G34-mutant gliomas than IDH/H3 wild-type gliomas. No TERT promoter mutation and only 1 case of EGFR amplification were detected in the H3.3 G34-mutant cohort, the frequencies of which were significantly higher in the IDH/H3 wild-type cohort. A dismal prognosis was observed in H3.3 G34-mutant patients comparing to IDH/H3 wild-type cohort (overall survival: 14 vs. 22 mo; P=0.026). Univariate and multivariate analyses showed that the extent of resection and TP53 mutation were independently affecting prognosis. The distinct pathologic and molecular features of H3.3 G34-mutant diffuse gliomas in adult patients demonstrated the clinical importance of detecting H3.3 G34R/V mutations. The dismal prognosis of this rare high-grade glioma disease we reported here would further promote the investigation of dedicated therapeutic strategies. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.