Highly sensitive detection of TERT promoter mutations in recurrent glioblastomas using digital PCR
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Highly sensitive detection of TERT promoter mutations in recurrent glioblastomas using digital PCR Shunichiro Miki1,2,4 · Kaishi Satomi1,3 · Makoto Ohno2 · Yuko Matsushita1,2 · Mai Kitahara1 · Yasuji Miyakita2 · Masamichi Takahashi2 · Masahide Matsuda4 · Eiichi Ishikawa4 · Akira Matsumura4 · Akihiko Yoshida3 · Yoshitaka Narita2 · Koichi Ichimura1 Received: 22 May 2020 / Accepted: 27 July 2020 © The Japan Society of Brain Tumor Pathology 2020
Abstract Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment. Keywords Glioblastoma · Recurrent · TERT promoter · Mutations · Digital PCR
Introduction The telomerase reverse transcriptase (TERT) gene encodes for the catalytic domain of the telomerase and is involved in maintaining telomere length. Except for germ and stem cells, TERT is not expressed in normal somatic cells but can be activated in diverse types of cancer, leading cells to escape Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10014-020-00375-x) contains supplementary material, which is available to authorized users. * Koichi Ichimura [email protected] 1
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan
2
Department of Neurosurgery and Neuro‑Oncology, National Cancer Center Hospital, Tokyo, Japan
3
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
4
Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
replicative senescence and conferring the potential for indefinite proliferation. Recent studies have shown that mutations in the TERT promoter (TERTp) play a key role in regulating and reinstating TERT expression [1, 2]. In treatment-naïve tumors, we and others have reported that two TERTp hotspot mutations, C228T and C250T (also designated c.-124C>T and c.-146C>T, respectively), are the most frequent mut
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