title: TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas.
abstract: IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Zhen-Yu
authors: ZY
authors: Zhang
authors: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors: Aden Ka-Yin
authors: AK
authors: Chan
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Xiao-Jie
authors: XJ
authors: Ding
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Zhi-Yong
authors: ZY
authors: Qin
authors: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors: Christopher S
authors: CS
authors: Hong
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Ling-Chao
authors: LC
authors: Chen
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Xin
authors: X
authors: Zhang
authors: Genetron Health, Inc., Chaoyang District, Beijing, China.
authors: Fang-Ping
authors: FP
authors: Zhao
authors: Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Yin
authors: Y
authors: Wang
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Yang
authors: Y
authors: Wang
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Liang-Fu
authors: LF
authors: Zhou
authors: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors: Zhengping
authors: Z
authors: Zhuang
authors: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors: Ho-Keung
authors: HK
authors: Ng
authors: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors: Hai
authors: H
authors: Yan
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Yu
authors: Y
authors: Yao
authors: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Ying
authors: Y
authors: Mao
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D059186:Chemoradiotherapy, Adjuvant; D015331:Cohort Studies; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D060787:Neoplasm Grading; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C509186:TERT protein, human; D019098:Telomerase
keywords: IDH; TERT promoter; chemotherapy; gliomas; radiation therapy