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Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss

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Abstract

Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55 %). The frequency of mutation was particularly high among primary glioblastomas (70 %) and pure oligodendroglial tumors (74 %), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25 %, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98 %). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92 %) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.

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Acknowledgments

This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan [No. 24659650 (H.A.)], and by the National Cancer Center Research and Development Fund [23-A-50 (K.I.)]. The authors thank Dr Danita Pearson for excellent technical assistance and Dr Sylvia Kocialkowski for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Neurosurgery and Neuro-Oncology, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hideyuki Arita, Yoshitaka Narita, Yuko Matsushita, Yasuji Miyakita, Makoto Ohno & Soichiro Shibui

  2. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Shintaro Fukushima & Koichi Ichimura

  3. Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan

    Kensuke Tateishi & Nobutaka Kawahara

  4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan

    Akihiko Yoshida

  5. Department of Pathology, University of Cambridge, Cambridge, UK

    V. Peter Collins

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  1. Hideyuki Arita
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  2. Yoshitaka Narita
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Correspondence to Koichi Ichimura.

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401_2013_1141_MOESM3_ESM.pptx

Supplementary Figure 1: Relationships between TERT promoter status and other genetic profiles in the Validation cohort. The Venn diagram shows the relationship between TERT promoter mutation and other genetic profiles in the Validation cohort. a. Relationship between TERT mutations, IDH mutations and TP53 mutations according to the tumor type. b. Relationship between TERT mutations, EGFR amplification and PTEN mutations/homozygous deletions in all pGBM (154) in which alterations of EGFR and/or PTEN predominantly occur. DA, diffuse astrocytoma; AA, anaplastic astrocytoma; pGBM, primary glioblastoma; OL, oligodendroglioma grade II; AO, anaplastic oligodendroglioma; OA, oligoastrocytoma grade II; AOA, anaplastic oligoastrocytoma. None, no alterations in the genes indicated. (PPTX 87 kb)

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Arita, H., Narita, Y., Fukushima, S. et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126, 267–276 (2013). https://doi.org/10.1007/s00401-013-1141-6

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