Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Genome Med. 2022 Aug 11;14(1):88. doi: 10.1186/s13073-022-01095-x.
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.
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.
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.
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.
端粒维持机制（TMM）的激活是癌细胞永生化的关键驱动因素之一。在神经胶质瘤中，TERT 表达和 TERT 启动子突变被认为可靠地表明端粒酶激活，而 ATRX 突变和/或缺失表明端粒的替代性延长（ALT）。然而，这些关系在肿瘤组织中尚未得到广泛验证。
端粒重复扩增协议（TRAP）和 C 环测定法用于在横截面上（n=412）和时间上（n=133）对神经胶质瘤样本进行 TMM 分析和特征描述。WES、RNA-seq 和 NanoString 分析用于鉴定和验证 TMM 组的遗传特征。
我们通过在大量神经胶质瘤样本中直接测量端粒酶活性和 ALT 表明，无论 TERT 表达、TERT 启动子突变和 ATRX 缺失如何，神经胶质瘤中的 TMM 不能仅通过端粒酶活性和 ALT 的组合来定义。此外，我们观察到相当一部分神经胶质瘤既缺乏端粒酶活性又缺乏 ALT。这种端粒酶激活阴性和 ALT 阴性组表现出潜在生长缓慢的证据。通过分析来自另一组神经胶质瘤患者的一组纵向样本，我们发现 TMM 不是固定的，并且可以随着神经胶质瘤的进展而变化。
本研究表明 TMM 是动态的，反映了肿瘤细胞的可塑性和致癌性。在定义 TMM 时，应考虑直接测量端粒酶酶活性和 ALT 的证据。准确了解神经胶质瘤中的 TMM 有望为制定癌症管理策略提供重要信息。
