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Neuro-oncology. 2015 Feb 13. pii: nov010. doi: 10.1093/neuonc/nov010

Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis.

Spiegl-Kreinecker S¹, Lötsch D², Ghanim B³, Pirker C⁴, Mohr T⁵, Laaber M⁶, Weis S⁷, Olschowski A⁸, Webersinke G⁹, Pichler J¹⁰, Berger W¹¹

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¹Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
²Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
³Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
⁴Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
⁵Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
⁶Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
⁷Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
⁸Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
⁹Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
¹⁰Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
¹¹Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).

Abstract

BACKGROUND: Expression of the telomerase reverse transcriptase (TERT) might be altered by activating mutations of the rs2853669 polymorphism within the promoter region. Here we investigate the impact of these genomic alterations on telomerase activation and dissect their prognostic potential in glioblastoma (GBM).

METHODS: The respective TERT promoter region was sequenced in 126 GBM tissues and compared with clinical parameters and glioma biomarkers MGMT promoter methylation and IDH1 mutation. TERT mRNA expression, telomerase activity, and telomere lengths were determined by reverse transcriptase PCR, TRAP assay, and real-time PCR, respectively.

RESULTS: Seventy-three percent of GBM patients harbored TERT promoter mutations associated with enhanced telomerase activity and TERT mRNA expression but reduced telomere lengths (P < .001 for all). Patients with mutated tumors exhibited significantly shorter overall survival in the entire cohort (11.5 vs 23.1 months; P < .0001) and in the primary GBM patient subgroup lacking IDH1 mutations (n = 120; P = .0084). This prognostic impact was confined to younger patients (aged <65 years), while the negative prognostic power of enhanced age at diagnosis was limited to those patients lacking TERT promoter mutations. Presence of the common single nucleotide polymorphism rs2853669, disrupting an endogenous Ets2 transcription factor-binding site, was associated with improved survival exclusively in patients with a wild-type TERT promoter. On the contrary, the shortest mean overall survival was detected in those patients harboring both an activating TERT promoter mutation and homozygous rs2853669 alleles.

CONCLUSION: In summary, TERT promoter mutations are powerful prognosticators for worse course of disease in human GBM patients but their prognostic value is influenced by the rs2853669 polymorphism and age at diagnosis.

KEYWORDS: glioblastoma, prognostic marker, rs2853669, TERT promoter mutations, telomerase

Publikations ID: 25681309
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