한빛사논문
- 조회1,037
Sojin Kim1†, Tamrin Chowdhury1,2†, Hyeon Jong Yu1,2, Jee Ye Kahng2, Chae Eun Lee1, Seung Ah. Choi1,3, Kyung‑Min Kim1,2, Ho Kang1,2, Joo Ho Lee2,4, Soon‑Tae Lee2,5, Jae‑Kyung Won2,6, Kyung Hyun Kim1,3, Min‑Sung Kim1, Ji Yeoun Lee1,3,7, Jin Wook Kim1,2, Yong‑Hwy Kim1,2, Tae Min Kim2,8, Seung Hong Choi2,9, Ji Hoon Phi2,3, Young‑Kyoung Shin2,10, Ja‑Lok Ku2,10, Sungyoung Lee11, Hongseok Yun11, Hwajin Lee12, Dokyoung Kim13, Kyoungmi Kim14, Junho K. Hur15, Sung‑Hye Park2,6, Seung‑Ki Kim1,2,3 and Chul‑Kee Park1,2,16*
1Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak‑ro, Jongno‑gu, Seoul 03080, Republic of Korea. 2Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 3Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul 03080, Republic of Korea. 4Department of Radiation Oncology, Seoul National University Hospital, Seoul 03080, Republic of Korea. 5Department of Neurology, Seoul National University Hospital, Seoul 03080, Republic of Korea. 6Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea. 7Department of Anatomy and Cell Biol‑ogy, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 8Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea. 9Department of Radiology, Seoul National University Hospital, Seoul 03080, Republic of Korea. 10Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 11Department of Genomic Medicine, Seoul National University Hospital, Seoul 03080, Repub‑lic of Korea. 12Biomedical Knowledge Engineering Laboratory and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea. 13Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea. 14Department of Biomedical Sciences and Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea. 15Department of Genetics, College of Medi‑cine, Hanyang University, Seoul 04763, Korea. 16Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
†Sojin Kim and Tamrin Chowdhury contributed equally.
*Correspondence
Abstract
Background
The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues.
Methods
Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups.
Results
We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression.
Conclusions
This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.
논문정보
- Research article
- 2022년 08월 (BRIC 등록일 2022-08-24)
- 국내 연구진
- 의약학 > 종양의학
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