Yohei Miyake1, Jun-Ichi Adachi2, Tomonari Suzuki1, Kazuhiko Mishima1, Ryuichiro Araki3, Reina Mizuno1, Ryo Nishikawa1. 1. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan. 2. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan. jadachi@saitama-med.ac.jp. 3. Community Health Science Center, Saitama Medical University, Moroyama, Saitama, Japan.
Abstract
PURPOSE: Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables. METHODS: We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR. RESULTS: TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters. CONCLUSIONS: This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.
PURPOSE: Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables. METHODS: We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR. RESULTS:TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters. CONCLUSIONS: This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.
Authors: Tobias Hallén; Gudmundur Johannsson; Rahil Dahlén; Camilla A M Glad; Charlotte Örndal; Angelica Engvall; Helena Carén; Thomas Skoglund; Daniel S Olsson Journal: J Clin Endocrinol Metab Date: 2022-07-14 Impact factor: 6.134
Authors: Shingo Fujio; Tareq A Juratli; Tomoko Takajo; Kazunori Arita; Yushi Nagano; Koji Yoshimoto; Naema Nayyar; William T Curry; Maria Martinez-Lage; Daniel P Cahill; Fred G Barker; Priscilla K Brastianos Journal: Neurol Med Chir (Tokyo) Date: 2021-05-08 Impact factor: 1.742