The telomere maintenance mechanism spectrum and its dynamics in gliomas

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.

The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases

“…Contrary to conventional assumptions, neither TERT promoter mutations nor ATRX loss reliably predicted TMM categories. These findings underscore the intricate and evolving nature of TMM in gliomas suggesting a complex interplay of factors influencing TMM [ 61 ]. Importantly, recent findings in pediatric high-grade gliomas (pHGGs) like diffuse intrinsic pontine glioma (DIPG), and telomere maintenance mechanisms exhibit a noteworthy heterogeneity.…”

“…Thus, TMM in gliomas cannot be defined solely by the combination of telomerase activity and ALT. In fact, during the progression of the disease, gliomas have the capacity to switch from one telomere maintenance mechanism to another [ 61 ]. In a comprehensive retrospective cohort study by Kim et al, the TMM landscape unfolded across distinct groups—telomerase-positive, ALT-positive, negative for both telomerase and ALT, and a subset exhibiting both activities contributing to profound intratumoral heterogeneity.…”

Techniques for assessing telomere length: A methodological review

“…TRF is considered the gold standard for measuring the absolute telomere length. The wide availability of commercial kits for experimentation allows for the measurement of telomere length in various tissues and cells [25] . However, TRF analysis provides an average measure of telomere length and does not capture the length of the shortest telomeres [22] .…”

The Spectrum of Molecular Pathways in Gliomas—An Up-to-Date Review

“…TERT mutations are found in many glioblastomas, whereas mutations of the X-linked gene of α-thalassemia (ATRX) , leading to inactivation of the ATRX protein and induction of ALT, are found in many IDH-mutated astrocytomas. Of note, TERT mutations and ATRX mutations are mutually exclusive in gliomas, and the exact mechanism of how ATRX mutations, in particular, induce ALT in gliomas is still under investigation [ 72 , 73 , 74 , 75 ]. Apoptosis in gliomas is still a topic with many unresolved issues, and a major problem is finding the reason for the frequent TRAIL resistance of glioma tumor cells.…”