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 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 and temporarily across 412 glioma samples. WES, RNA-seq, and nanostring analysis were done to identify and validate the genetic characteristics of 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 in the dichotomy of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX mutation. Moreover, we observed that a considerable proportion of gliomas lack both telomerase activity and ALT (Neither group). And this Neither group exhibited evidence of slow growth potential. From a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed but changes with glioma progression.
This study suggests that the TMM is a dynamic entity that reflects the plasticity of the tumor cells and their oncogenicity. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. Accurate understanding of TMM in glioma is expected to be important information for establishing strategies to manage cancer. Less...