Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma

Nayuta Higa; Toshiaki Akahane; Seiya Yokoyama; Ryutaro Makino; Hajime Yonezawa; Hiroyuki Uchida; Tomoko Takajo; Mari Kirishima; Taiji Hamada; Naoki Noguchi; Ryosuke Otsuji; Daisuke Kuga; Shohei Nagasaka; Hitoshi Yamahata; Junkoh Yamamoto; Koji Yoshimoto; Akihide Tanimoto; Ryosuke Hanaya

doi:10.1093/noajnl/vdad078

Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma

Neurooncol Adv. 2023 Jun 28;5(1):vdad078. doi: 10.1093/noajnl/vdad078. eCollection 2023 Jan-Dec.

Authors

Nayuta Higa^{1

2}, Toshiaki Akahane^{3

4}, Seiya Yokoyama³, Ryutaro Makino¹, Hajime Yonezawa¹, Hiroyuki Uchida¹, Tomoko Takajo¹, Mari Kirishima³, Taiji Hamada³, Naoki Noguchi², Ryosuke Otsuji², Daisuke Kuga², Shohei Nagasaka⁵, Hitoshi Yamahata¹, Junkoh Yamamoto⁵, Koji Yoshimoto², Akihide Tanimoto^{3

4}, Ryosuke Hanaya¹

Affiliations

¹ Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
² Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Pathology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
⁴ Center for Human Genome and Gene Analysis, Kagoshima University Hospital, Kagoshima, Japan.
⁵ Department of Neurosurgery, University of Occupational and Environmental Health, Kitakyushu, Japan.

Abstract

Background: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas.

Methods: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH.

Results: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients.

Conclusions: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.

Keywords: PTEN; TERTp; TERTp-wild-type glioblastoma; prognostic markers.