Oncotarget

Research Papers:

TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas

Zhen-Yu Zhang, Aden Ka-Yin Chan, Xiao-Jie Ding, Zhi-Yong Qin, Christopher S. Hong, Ling-Chao Chen, Xin Zhang, Fang-Ping Zhao, Yin Wang, Yang Wang, Liang-Fu Zhou, Zhengping Zhuang, Ho-Keung Ng, Hai Yan, Yu Yao _ and Ying Mao

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Oncotarget. 2015; 6:24871-24883. https://doi.org/10.18632/oncotarget.4549

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Abstract

Zhen-Yu Zhang1,*, Aden Ka-Yin Chan2,*, Xiao-Jie Ding1, Zhi-Yong Qin1, Christopher S. Hong3, Ling-Chao Chen1, Xin Zhang1, Fang-Ping Zhao4, Yin Wang5, Yang Wang1, Liang-Fu Zhou1, Zhengping Zhuang3, Ho-Keung Ng2, Hai Yan6, Yu Yao1, Ying Mao1

1Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China

2Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China

3Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

4Genetron Health, Inc., Chaoyang District, Beijing, China

5Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China

6Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA

*These authors have contributed equally to this work

Correspondence to:

Yu Yao, e-mail: [email protected]

Hai Yan, e-mail: [email protected]

Ho-Keung Ng, e-mail: [email protected]

Keywords: TERT promoter, IDH, gliomas, radiation therapy, chemotherapy

Received: March 29, 2015     Accepted: June 26, 2015     Published: July 09, 2015

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.


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