The telomere maintenance mechanism spectrum and its dynamics in gliomas

Sojin Kim, Tamrin Chowdhury, Hyeon Jong Yu, Jee Ye Kahng, Chae Eun Lee, Seung Ah Choi, Kyung Min Kim, Ho Kang, Joo Ho Lee, Soon Tae Lee, Jae Kyung Won, Kyung Hyun Kim, Min Sung Kim, Ji Yeoun Lee, Jin Wook Kim, Yong Hwy Kim, Tae Min Kim, Seung Hong Choi, Ji Hoon Phi, Young Kyoung ShinJa Lok Ku, Sungyoung Lee, Hongseok Yun, Hwajin Lee, Dokyoung Kim, Kyoungmi Kim, Junho K. Hur, Sung Hye Park, Seung Ki Kim, Chul Kee Park

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number88
JournalGenome Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Keywords

  • ALT
  • Glioma
  • Telomere maintenance mechanism
  • TERT

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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