title: TERT promoter mutations contribute to subset prognostication of lower-grade gliomas.
abstract: 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.
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Aden Ka-Yin
authors.initials: AK
authors.lastname: Chan
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Nellie Yuk-Fei
authors.initials: NY
authors.lastname: Chung
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Joseph Shu-Ming
authors.initials: JS
authors.lastname: Liu
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Kay Ka-Wai
authors.initials: KK
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Neurosurgery Division, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Danny Tat-Ming
authors.initials: DT
authors.lastname: Chan
authors.affiliation: Neurosurgery Division, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Liangfu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Ho-Keung
authors.initials: HK
authors.lastname: Ng
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D019098:Telomerase / Q000235:genetics*
chemical_list: C509186:TERT protein, human; D019098:Telomerase
references.citation: Science. 2013 Feb 22;339(6122):957-9
references.pmid: 23348506
references.citation: Acta Neuropathol. 2013 Dec;126(6):907-15
references.pmid: 24154961
references.citation: Science. 2013 Feb 22;339(6122):959-61
references.pmid: 23348503
references.citation: Crit Rev Oncol Hematol. 2008 Jun;66(3):262-72
references.pmid: 18272388
references.citation: Br J Cancer. 2004 Sep 13;91(6):1105-11
references.pmid: 15475940
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: Acta Neuropathol. 2013 Aug;126(2):267-76
references.pmid: 23764841
references.citation: Am J Pathol. 1994 Nov;145(5):1175-90
references.pmid: 7977648
references.citation: Mod Pathol. 2014 Mar;27(3):332-42
references.pmid: 24030748
references.citation: Am J Pathol. 2009 Apr;174(4):1149-53
references.pmid: 19246647
references.citation: J Clin Oncol. 2000 Feb;18(3):636-45
references.pmid: 10653879
references.citation: Acta Neuropathol. 2010 Apr;119(4):509-11
references.pmid: 20044756
references.citation: Acta Neuropathol. 2013 Dec;126(6):917-29
references.pmid: 24174164
references.citation: Acta Neuropathol. 2013 Dec;126(6):931-7
references.pmid: 23955565
references.citation: Lancet Oncol. 2013 May;14(6):534-42
references.pmid: 23598174
references.citation: Int J Cancer. 2002 Oct 1;101(4):335-41
references.pmid: 12209957
references.citation: Cancer J. 2008 Nov-Dec;14(6):352-7
references.pmid: 19060598
references.citation: Acta Neuropathol. 2013 Dec;126(6):939-41
references.pmid: 24174165
references.citation: Acta Neuropathol. 2010 Sep;120(3):297-304
references.pmid: 20644945
references.citation: J Clin Oncol. 2013 Jan 20;31(3):337-43
references.pmid: 23071247
references.citation: N Engl J Med. 2009 Feb 19;360(8):765-73
references.pmid: 19228619
references.citation: BMC Cancer. 2010 Jun 09;10:271
references.pmid: 20534141
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6021-6
references.pmid: 23530248
references.citation: Acta Neuropathol. 2011 Feb;121(2):241-52
references.pmid: 21069360
references.citation: Acta Neuropathol. 2010 Dec;120(6):719-29
references.pmid: 21080178
references.citation: J Clin Oncol. 2013 Jan 20;31(3):344-50
references.pmid: 23071237