The telomere maintenance mechanism spectrum and its dynamics in gliomas

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.This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (NRF-2018M3A9H3021707), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI21C0239)

서로 다른 조직학적 단계의 동시성 뇌수막종의 유전체 변이 특성 비교

학위논문 (석사)-- 서울대학교 대학원 : 의학과, 2017. 2. 이상형.Meningioma is the most common tumor of the central nervous system. Although several genetic studies of meningioma reveals various significant mutation related to meningioma development but still further studies are needed for confirming specific mutations. Here whole exome study was done on two meningioma samples of different histological grade obtained from a patient with multiple meningioma. This study shows that the each meningioma shows distinct tumor mutation despite from the same patient. Also both the meningioma shows distinct separate relations with different pathways. The common genetic abnormal incidence was the loss of Heterozygosity of the chromosome 22 in both tumors which maybe the cause of the tumor development and the subsequent mutations plays a role in progression towards different grades.Chapter 1. Introduction 1 1.1 Study Background 1 1.2. Purpose of Research 2 Chapter 2. Materials and Methods 3 2.1 Case History 3 2.2 Sample Collection 9 2.3 Whole Exome Sequencing 9 2.4 RNA Sequencing 10 2.5 Processing of Sequenced Data 10 Chapter 3. Results 12 3.1 Quality Control Assessment and Tumor Purity analysis 12 3.2 No common gene mutations between synchronous meningiomas 14 3.3. Common genetic event of Loss of heterozygosity in 22 in synchronous meningiomas 19 3.4 Differential gene expression analysis 21 3.5 Hypothesis of genomic evolution process of meningioma development and progression 32 Chapter 4. Discussion 35 Chapter 5. Conclusion 39 Abstract in Korean 43Maste

The telomere maintenance mechanism spectrum and its dynamics in gliomas

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.N