Cancer Research and Treatment

Original Articles

CNS cancer

Detection of TERT Promoter Mutations Using Targeted Next-Generation Sequencing: Overcoming GC Bias through Trial and Error: Hyunwoo Lee, Boram Lee, Deok Geun Kim, Yoon Ah Cho, Jung-Sun Kim, Yeon-Lim Suh; Cancer Res Treat. 2022;54(1):75-83. Published online May 3, 2021; DOI: https://doi.org/10.4143/crt.2021.107

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Purpose
Detection of telomerase reverse transcriptase (TERT) promoter mutations is a crucial process in the integrated diagnosis of glioblastomas. However, the TERT promoter region is difficult to amplify because of its high guanine-cytosine (GC) content (> 80%). This study aimed to analyze the capturing of TERT mutations by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tissues.
Materials and Methods
We compared the detection rate of TERT mutations between targeted NGS and Sanger sequencing in 25 cases of isocitrate dehydrgenase (IDH)-wildtype glioblastomas and 10 cases of non-neoplastic gastric tissues. Our customized panel consisted of 232 essential glioma-associated genes.
Results
Sanger sequencing detected TERT mutations in 17 out of 25 glioblastomas, but all TERT mutations were missed by targeted NGS. After the manual visualization of the NGS data using an integrative genomics viewer, 16 cases showed a TERT mutation with a very low read depth (mean, 21.59; median, 25), which revealed false-negative results using auto-filtering. We optimized our customized panel by extending the length of oligonucleotide baits and increasing the number of baits spanning the coverage of the TERT promoter, which did not amplify well due to the high GC content.
Conclusion
Our study confirmed that it is crucial to consider the recognition of molecular bias and to carefully interpret NGS data.

Citations

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Quality metrics for enhanced performance of an NGS panel using single-vial amplification technology
Subit Barua, Susan Hsiao, Emily Clancy, Christopher Freeman, Mahesh Mansukhani, Helen Fernandes
Journal of Clinical Pathology.2024; 77(1): 46. CrossRef
Diagnostic utility of genetic alterations in distinguishing IDH‐wildtype glioblastoma from lower‐grade gliomas: Insight from next‐generation sequencing analysis of 479 cases
Boram Lee, Soohyun Hwang, Hyunsik Bae, Kyue‐Hee Choi, Yeon‐Lim Suh
Brain Pathology.2024;[Epub] CrossRef
Novel method for detecting frequent TERT promoter hot spot mutations in bladder cancer samples
Ákos Kovács, Farkas Sükösd, Levente Kuthi, Imre M. Boros, Balázs Vedelek
Clinical and Experimental Medicine.2024;[Epub] CrossRef
Changes in Mutations of Cell-Free DNA and Liver Tumor Tissue in Patients with Advanced Hepatocellular Carcinoma before and after Introduction of Lenvatinib
Mio Tsuruoka, Masashi Ninomiya, Jun Inoue, Tomoaki Iwata, Akitoshi Sano, Kosuke Sato, Masazumi Onuki, Satoko Sawahashi, Atsushi Masamune
Oncology.2024; 102(12): 1072. CrossRef
Melanoma genomics – will we go beyond BRAF in clinics?
Justyna Mirek, Wiesław Bal, Magdalena Olbryt
Journal of Cancer Research and Clinical Oncology.2024;[Epub] CrossRef
Deep Learning Prediction of TERT Promoter Mutation Status in Thyroid Cancer Using Histologic Images
Jinhee Kim, Seokhwan Ko, Moonsik Kim, Nora Jee-Young Park, Hyungsoo Han, Junghwan Cho, Ji Young Park
Medicina.2023; 59(3): 536. CrossRef
Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules
Guodong Fu, Ronald S. Chazen, Eric Monteiro, Allan Vescan, Jeremy L. Freeman, Ian J. Witterick, Christina MacMillan
JAMA Network Open.2023; 6(7): e2323500. CrossRef
Molecular Biomarkers and Recent Liquid Biopsy Testing Progress: A Review of the Application of Biosensors for the Diagnosis of Gliomas
Yuanbin Wu, Xuning Wang, Meng Zhang, Dongdong Wu
Molecules.2023; 28(15): 5660. CrossRef
Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas
Gábor Bedics, Péter Szőke, Bence Bátai, Tibor Nagy, Gergő Papp, Noémi Kránitz, Hajnalka Rajnai, Lilla Reiniger, Csaba Bödör, Bálint Scheich
Scientific Reports.2023;[Epub] CrossRef

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Clinical Targeted Next-Generation sequencing Panels for Detection of Somatic Variants in Gliomas: Hyemi Shin, Jason K. Sa, Joon Seol Bae, Harim Koo, Seonwhee Jin, Hee Jin Cho, Seung Won Choi, Jong Min Kyoung, Ja Yeon Kim, Yun Jee Seo, Je-Gun Joung, Nayoung K. D. Kim, Dae-Soon Son, Jongsuk Chung, Taeseob Lee, Doo-Sik Kong, Jung Won Choi, Ho Jun Seol, Jung-Il Lee, Yeon-Lim Suh, Woong-Yang Park, Do-Hyun Nam; Cancer Res Treat. 2020;52(1):41-50. Published online May 7, 2019; DOI: https://doi.org/10.4143/crt.2019.036

Abstract PDF Supplementary Material PubReader ePub

Purpose
Targeted next-generation sequencing (NGS) panels for solid tumors have been useful in clinical framework for accurate tumor diagnosis and identifying essential molecular aberrations. However, most cancer panels have been designed to address a wide spectrum of pan-cancer models, lacking integral prognostic markers that are highly specific to gliomas.
Materials and Methods
To address such challenges, we have developed a glioma-specific NGS panel, termed “GliomaSCAN,” that is capable of capturing single nucleotide variations and insertion/deletion, copy number variation, and selected promoter mutations and structural variations that cover a subset of intron regions in 232 essential glioma-associated genes. We confirmed clinical concordance rate using pairwise comparison of the identified variants from whole exome sequencing (WES), immunohistochemical analysis, and fluorescence in situ hybridization.
Results
Our panel demonstrated high sensitivity in detecting potential genomic variants that were present in the standard materials. To ensure the accuracy of our targeted sequencing panel, we compared our targeted panel to WES. The comparison results demonstrated a high correlation. Furthermore, we evaluated clinical utility of our panel in 46 glioma patients to assess the detection capacity of potential actionable mutations. Thirty-two patients harbored at least one recurrent somatic mutation in clinically actionable gene.
Conclusion
We have established a glioma-specific cancer panel. GliomaSCAN highly excelled in capturing somatic variations in terms of both sensitivity and specificity and provided potential clinical implication in facilitating genome-based clinical trials. Our results could provide conceptual advance towards improving the response of genomically guided molecularly targeted therapy in glioma patients.

Citations

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Comparative genomic landscape of lower-grade glioma and glioblastoma
Xinxin Sun, Qingbin Jia, Kun Li, Conghui Tian, Lili Yi, Lili Yan, Juan Zheng, Xiaodong Jia, Mingliang Gu, Michael C. Burger
PLOS ONE.2024; 19(8): e0309536. CrossRef
Actionable molecular alterations in newly diagnosed and recurrent IDH1/2 wild-type glioblastoma patients and therapeutic implications: a large mono-institutional experience using extensive next-generation sequencing analysis
Marta Padovan, Marta Maccari, Alberto Bosio, Chiara De Toni, Salvatore Vizzaccaro, Ilaria Cestonaro, Martina Corrà, Mario Caccese, Giulia Cerretti, Vittorina Zagonel, Giuseppe Lombardi
European Journal of Cancer.2023; 191: 112959. CrossRef
GPX8 regulates pan-apoptosis in gliomas to promote microglial migration and mediate immunotherapy responses
Zigui Chen, Dandan Zheng, Ziren Lin, Chunyuan Zhang, Cheng Wei, Xiandong Deng, Peng Yan, Chuanhua Zheng, Chuanliu Lan, Chengjian Qin, Xuanlei Wei, Deling Qin, Yongfang Wu, Jun Peng, Changfeng Miao, Liuxue Lu, Ying Xia, Qisheng Luo
Frontiers in Immunology.2023;[Epub] CrossRef
Comprehensive clinical assays for molecular diagnostics of gliomas: the current state and future prospects
Alina Penkova, Olga Kuziakova, Valeriia Gulaia, Vladlena Tiasto, Nikolay V. Goncharov, Daria Lanskikh, Valeriia Zhmenia, Ivan Baklanov, Vladislav Farniev, Vadim Kumeiko
Frontiers in Molecular Biosciences.2023;[Epub] CrossRef
A rapid, multiplex digital PCR assay to detect gene variants and fusions in non‐small cell lung cancer
Bryan Leatham, Katie McNall, Hari K. K. Subramanian, Lucien Jacky, John Alvarado, Dominic Yurk, Mimi Wang, Donald C. Green, Gregory J. Tsongalis, Aditya Rajagopal, Jerrod J. Schwartz
Molecular Oncology.2023; 17(11): 2221. CrossRef
Next generation sequencing in adult patients with glioblastoma in Switzerland: a multi-centre decision analysis
A. M. Zeitlberger, P. M. Putora, S. Hofer, P. Schucht, D. Migliorini, A. F. Hottinger, U. Roelcke, H. Läubli, P. Spina, O. Bozinov, M. Weller, M. C. Neidert, T. Hundsberger
Journal of Neuro-Oncology.2022; 158(3): 359. CrossRef
Targeted next‐generation sequencing of adult gliomas for retrospective prognostic evaluation and up‐front diagnostics
J. K. Petersen, H. B. Boldt, M. D. Sørensen, S. Blach, R. H. Dahlrot, S. Hansen, M. Burton, M. Thomassen, T. Kruse, F. R. Poulsen, L. Andreasen, H. Hager, B. P. Ulhøi, S. Lukacova, G. Reifenberger, B. W. Kristensen
Neuropathology and Applied Neurobiology.2021; 47(1): 108. CrossRef
Development of MR-based preoperative nomograms predicting DNA copy number subtype in lower grade gliomas with prognostic implication
Siwei Zhang, Shanshan Wu, Yun Wan, Yongsong Ye, Ying Zhang, Zelan Ma, Quanlan Guo, Hongdan Zhang, Li Xu
European Radiology.2021; 31(4): 2094. CrossRef
Comprehensive Molecular Characterization of Chinese Patients with Glioma by Extensive Next-Generation Sequencing Panel Analysis
Chun Zeng, Jing Wang, Mingwei Li, Huina Wang, Feng Lou, Shanbo Cao, Changyu Lu
Cancer Management and Research.2021; Volume 13: 3573. CrossRef
Analyzing Genetic Differences Between Sporadic Primary and Secondary/Tertiary Hyperparathyroidism by Targeted Next-Generation Panel Sequencing
Yu Ah Hong, Ki Cheol Park, Bong Kyun Kim, Jina Lee, Woo Young Sun, Hae Joung Sul, Kyung-Ah Hwang, Won Jung Choi, Yoon-Kyung Chang, Suk Young Kim, Soyoung Shin, Joonhong Park
Endocrine Pathology.2021; 32(4): 501. CrossRef
Multisite verification of the accuracy of a multi-gene next generation sequencing panel for detection of mutations and copy number alterations in solid tumours
John Bartlett, Yutaka Amemiya, Heleen Arts, Jane Bayani, Barry Eng, Daria Grafodatskaya, Suzanne Kamel Reid, Mathieu Lariviere, Bryan Lo, Rebecca McClure, Vinay Mittal, Bekim Sadikovic, Seth Sadis, Arun Seth, Jeff Smith, Xiao Zhang, Harriet Feilotter, Alv
PLOS ONE.2021; 16(10): e0258188. CrossRef
Development and validation of an expanded targeted sequencing panel for non-invasive prenatal diagnosis of sporadic skeletal dysplasia
Ching-Yuan Wang, Yen-An Tang, I-Wen Lee, Fong-Ming Chang, Chun-Wei Chien, Hsien-An Pan, H. Sunny Sun
BMC Medical Genomics.2021;[Epub] CrossRef
Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
Kyoungmin Lee, Harim Koo, Yejin Kim, Donggeon Kim, Eunju Son, Heekyoung Yang, Yangmi Lim, Minkyu Hur, Hye Won Lee, Seung Won Choi, Do-Hyun Nam
Cancers.2020; 12(11): 3210. CrossRef

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Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Atypical Teratoid/Rhabdoid Tumor: Ki Woong Sung, Do Hoon Lim, Eun Sang Yi, Young Bae Choi, Ji Won Lee, Keon Hee Yoo, Hong Hoe Koo, Ji Hye Kim, Yeon-Lim Suh, Yoo Sook Joung, Hyung Jin Shin; Cancer Res Treat. 2016;48(4):1408-1419. Published online April 1, 2016; DOI: https://doi.org/10.4143/crt.2015.347

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Purpose
We prospectively evaluated the effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in improving the survival of patients with atypical teratoid/rhabdoid tumors while reducing the risks of late adverse effects from radiotherapy (RT).
Materials and Methods
For young children (< 3 years old), tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. RT was deferred until after 3 years of age unless the tumor showed relapse or progression. For older patients (> 3 years old), RT including reduced-dose craniospinal RT (23.4 or 30.6 Gy) was administered either after two cycles of induction chemotherapy or after surgery, and tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy.
Results
A total of 13 patients (five young and eight older) were enrolled from November 2004 to June 2012. Eight patients, including all five young patients, had metastatic disease at diagnosis. Six patients (four young and two older) experienced progression before initiation of RT, and seven were able to proceed to HDCT/auto-SCT without progression during induction treatment. Three of six patients who experienced progression during induction treatment underwent HDCT/auto-SCT as salvage treatment. All five young patients died from disease progression. However, four of the eight older patients remain progression-freewith a median follow-up period of 64 months (range, 39 to 108 months). Treatment-related late toxicities were acceptable.
Conclusion
The required dose of craniospinal RT might be reduced in older patients if the intensity of chemotherapy is increased. However, early administration of RT should be considered to prevent early progression in young patients.

Citations

Citations to this article as recorded by

ESTRO-SIOPE guideline: Clinical management of radiotherapy in atypical teratoid/rhabdoid tumors (AT/RTs)
Beate Timmermann, Claire Alapetite, Karin Dieckmann, Rolf-Dieter Kortmann, Yasmin Lassen-Ramshad, John H. Maduro, Monica Ramos Albiac, Umberto Ricardi, Damien C. Weber
Radiotherapy and Oncology.2024; 196: 110227. CrossRef
Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors
Hana Lim, Minji Im, Eun Seop Seo, Hee Won Cho, Hee Young Ju, Keon Hee Yoo, Sung Yoon Cho, Jong-Won Kim, Do Hoon Lim, Ki Woong Sung, Ji Won Lee
Cancer Research and Treatment.2024; 56(2): 642. CrossRef
Focal versus craniospinal radiation for disseminated atypical teratoid/rhabdoid tumor following favorable response to systemic therapy
Paul D. Aridgides, Anita Mahajan, Bree Eaton, Dongliang Wang, Beate Timmerman, Michael C. Früwald, Karolina Nemes, Jared Deck, Kai Yamasaki, Katja Von Hoff, Lucie Lafay‐Cousin, Alyssa Reddy, Andrea C. Lo
Pediatric Blood & Cancer.2023;[Epub] CrossRef
Comparative treatment results of children with atypical teratoid/rhabdoid tumor of the central nervous system in the younger age group
L. V. Olkhova, O. G. Zheludkova, L. S. Zubarovskaya, A. S. Levashov, A. Yu. Smirnova, Yu. V. Dinikina, Yu. V. Kushel, A. G. Melikyan, S. K. Gorelyshev, M. V. Ryzhova, Yu. Yu. Trunin, A. G. Gevorgyan, O. B. Polushkina, V. E. Popov, L. P. Privalova, N. B. Y
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Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children: Case Reports and Literature Review
Gengyin Guo, Jianfeng Zhuang, Keke Zhang, Zhizhen Zhou, Yanjun Wang, Zhen Zhang
Frontiers in Surgery.2022;[Epub] CrossRef
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Meerim Park, Jung Woo Han, Seung Min Hahn, Jun Ah Lee, Joo-Young Kim, Sang Hoon Shin, Dong-Seok Kim, Hong In Yoon, Kyung Taek Hong, Jung Yoon Choi, Hyoung Jin Kang, Hee Young Shin, Ji Hoon Phi, Seung-Ki Kim, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Hong H
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