TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

• Published in: Modern pathology Vol. 28; no. 2; pp. 177 - 186
• Main Authors: Chan, Aden Ka-Yin, Yao, Yu, Zhang, Zhenyu, Chung, Nellie Yuk-Fei, Liu, Joseph Shu-Ming, Li, Kay Ka-Wai, Shi, Zhifeng, Chan, Danny Tat-Ming, Poon, Wai Sang, Zhou, Liangfu, Ng, Ho-Keung
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.02.2015; Nature Publishing Group US; Elsevier Limited
• Subjects: 631/208/737; 692/699/67/1922; 692/700/1750; Adult; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Classification; Dehydrogenases; Disease-Free Survival; DNA Mutational Analysis; Female; Glioma - genetics; Glioma - mortality; Glioma - pathology; Histology; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Laboratory Medicine; Male; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Mutation; Neoplasm Grading; Neurosurgery; original-article; Pathology; Prognosis; Promoter Regions, Genetic - genetics; Proportional Hazards Models; Survival analysis; Telomerase; Telomerase - genetics; Tumors; Hong Kong China; China
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2014.94

Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (P<0.001) and are associated with oligodendroglial histology (P<0.001). Kaplan–Meier's survival analysis showed that TERT promoter mutation (P=0.037), Isocitrate dehydrogenase (IDH) mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P=0.007) and OS (P=0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.