TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma

doi:10.1007/s00401-021-02337-9

. 2021 Aug;142(2):323-338.

doi: 10.1007/s00401-021-02337-9. Epub 2021 Jun 20.

TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma

Kenji Fujimoto^{1

2}, Hideyuki Arita^{1

3}, Kaishi Satomi^{1

4}, Kai Yamasaki^{1

5}, Yuko Matsushita^{1

6}, Taishi Nakamura^{1

7}, Yasuji Miyakita⁶, Toru Umehara³, Keiichi Kobayashi⁸, Kaoru Tamura⁹, Shota Tanaka¹⁰, Fumi Higuchi¹¹, Yoshiko Okita¹², Yonehiro Kanemura¹³, Junya Fukai¹⁴, Daisuke Sakamoto¹⁵, Takehiro Uda¹⁶, Ryunosuke Machida¹⁷, Aya Kuchiba¹⁸, Taketoshi Maehara⁹, Motoo Nagane⁸, Ryo Nishikawa¹⁸, Hiroyoshi Suzuki¹⁹, Makoto Shibuya²⁰, Takashi Komori²¹, Yoshitaka Narita⁶, Koichi Ichimura^{22

23}

Affiliations

¹ Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
² Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
³ Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁵ Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.
⁶ Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
⁸ Department of Neurosurgery, Faculty of Medicine, Kyorin University, Tokyo, Japan.
⁹ Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁰ Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan.
¹² Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan.
¹³ Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan.
¹⁴ Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan.
¹⁵ Department of Neurosurgery, Hyogo College of Medicine, Hyogo, Japan.
¹⁶ Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
¹⁷ Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan.
¹⁸ Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
¹⁹ Department of Pathology and Laboratory Medicine, National Hospital Organization, Sendai Medical Center, Sendai, Japan.
²⁰ Central Clinical Laboratory, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
²¹ Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
²² Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. k.ichimura.uk@juntendo.ac.jp.
²³ Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. k.ichimura.uk@juntendo.ac.jp.

PMID: 34148105
DOI: 10.1007/s00401-021-02337-9

TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma

Kenji Fujimoto et al. Acta Neuropathol. 2021 Aug.

. 2021 Aug;142(2):323-338.

doi: 10.1007/s00401-021-02337-9. Epub 2021 Jun 20.

Authors

Affiliations

¹ Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
² Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
³ Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁵ Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.
⁶ Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
⁸ Department of Neurosurgery, Faculty of Medicine, Kyorin University, Tokyo, Japan.
⁹ Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁰ Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan.
¹² Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan.
¹³ Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan.
¹⁴ Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan.
¹⁵ Department of Neurosurgery, Hyogo College of Medicine, Hyogo, Japan.
¹⁶ Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
¹⁷ Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan.
¹⁸ Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
¹⁹ Department of Pathology and Laboratory Medicine, National Hospital Organization, Sendai Medical Center, Sendai, Japan.
²⁰ Central Clinical Laboratory, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
²¹ Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
²² Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. k.ichimura.uk@juntendo.ac.jp.
²³ Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. k.ichimura.uk@juntendo.ac.jp.

PMID: 34148105
DOI: 10.1007/s00401-021-02337-9

Abstract

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM.

Keywords: Copy-number alteration; IDH-wildtype; Lower grade glioma; TERT promoter mutation.

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References

1. Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T et al (2018) Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 20:66–77. https://doi.org/10.1093/neuonc/nox132 - DOI - PubMed
1. Arita H, Narita Y, Takami H, Fukushima S, Matsushita Y, Yoshida A et al (2013) TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. Acta Neuropathol 126:939–941. https://doi.org/10.1007/s00401-013-1203-9 - DOI - PubMed
1. Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H et al (2016) A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun 4:79. https://doi.org/10.1186/s40478-016-0351-2 - DOI - PubMed - PMC
1. Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139:603–608. https://doi.org/10.1007/s00401-020-02127-9 - DOI - PubMed
1. Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB et al (2018) cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.” Acta Neuropathol 136:805–810. https://doi.org/10.1007/s00401-018-1913-0 - DOI - PubMed - PMC

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[1] Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T et al (2018) Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 20:66–77. https://doi.org/10.1093/neuonc/nox132 - DOI - PubMed

[2] Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T et al (2018) Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. Neuro Oncol 20:66–77. https://doi.org/10.1093/neuonc/nox132 - DOI - PubMed

[3] Arita H, Narita Y, Takami H, Fukushima S, Matsushita Y, Yoshida A et al (2013) TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. Acta Neuropathol 126:939–941. https://doi.org/10.1007/s00401-013-1203-9 - DOI - PubMed

[4] Arita H, Narita Y, Takami H, Fukushima S, Matsushita Y, Yoshida A et al (2013) TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. Acta Neuropathol 126:939–941. https://doi.org/10.1007/s00401-013-1203-9 - DOI - PubMed

[5] Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H et al (2016) A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun 4:79. https://doi.org/10.1186/s40478-016-0351-2 - DOI - PubMed - PMC

[6] Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H et al (2016) A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun 4:79. https://doi.org/10.1186/s40478-016-0351-2 - DOI - PubMed - PMC

[7] Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139:603–608. https://doi.org/10.1007/s00401-020-02127-9 - DOI - PubMed

[8] Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139:603–608. https://doi.org/10.1007/s00401-020-02127-9 - DOI - PubMed

[9] Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB et al (2018) cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.” Acta Neuropathol 136:805–810. https://doi.org/10.1007/s00401-018-1913-0 - DOI - PubMed - PMC

[10] Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB et al (2018) cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.” Acta Neuropathol 136:805–810. https://doi.org/10.1007/s00401-018-1913-0 - DOI - PubMed - PMC

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TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma

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TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma

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