scholarly journals Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2160
Author(s):  
Jeong-Won Jang ◽  
Jin-Seoub Kim ◽  
Hye-Seon Kim ◽  
Kwon-Yong Tak ◽  
Soon-Kyu Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Telomere Length ◽  
Differentially Expressed Gene ◽  
Genetic Alterations ◽  
Tissue Samples ◽  
Protein Protein Interaction ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Tert Expression

Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein–protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.

BIOM-14. METABOLIC BIOMARKERS OF TERT-TARGETED THERAPY FOR HUMAN GLIOBLASTOMA DETECTED BY MAGNETIC RESONANCE SPECTROSCOPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi13-vi13
Author(s):  
Noriaki Minami ◽  
Donghyun Hong ◽  
Nicholas Stevers ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
1H Mrs ◽  
Significant Drop ◽  
Knock Down ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Metabolic Data ◽  
Metabolic Biomarkers ◽  
Promoter Mutations ◽  
Tert Expression

Abstract BACKGROUND TERT promoter mutations that result in TERT expression are observed in over 80% of GBM. Moreover, the upstream transcription factor GABPB1 was recently identified as an ideal therapeutic target for tumors with TERT promoter mutations. In that context, non-invasive reliable biomarkers that can help detect TERT expression are needed. The aim of this research was to assess the value of MRS-detectable metabolic changes as biomarkers of TERT expression and TERT-targeted therapy in GBM. METHODS Genetically engineered GBM cells (NHARas/TERT) treated with TERT siRNA were compared to siCtrl-treated cells, and stable TERT and GABPB1 knock down GBM cells (U251, GBM1) were compared to shCtrl. 1H-MRS and 13C-MRS metabolic data was acquired from cell extracts using a Bruker 500MHz scanner. Hyperpolarized MRS studies of live cells used a HyperSense DNP polarizer and data was acquired using a Varian 500MHz scanner. Spectra were analyzed using Mnova and Matlab software. Multivariate data analysis was performed using SIMCA software. RESULTS Unbiased PCA analysis of 1H-MRS metabolic data showed separation of TERT or GABPB1 knock down and control cells. VIP predictive scores revealed that lactate and GSH were the top altered metabolites with a significant drop observed in both metabolites in every model following TERT silencing. Consistent with the reduction in GSH, spectrophotometric assays showed a significant drop in NADPH and NADH. 2-13C glucose flux analysis revealed that both glycolysis and PPP-related metabolites were reduced in TERT knock down cells. Hyperpolarized [1-13C]-pyruvate flux to lactate was also reduced, confirming that the glycolytic pathway was altered following TERT knock down. CONCLUSION 1H MRS-detectable lactate and GSH, combined with hyperpolarized 13C MRS-detectable metabolic fluxes, could serve as metabolic biomarkers of TERT-targeted therapy for human GBM with TERT promoter mutations. These biomarkers could be translated to the clinical, improve the monitoring of GBM patients and advance precision medicine.

scholarly journals TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas

Oncotarget ◽  
2015 ◽  
Vol 7 (8) ◽  
pp. 8712-8725 ◽  
Author(s):  
Ke Gao ◽  
Gang Li ◽  
Yiping Qu ◽  
Maode Wang ◽  
Bo Cui ◽  
...  
Keyword(s):  
Telomere Length ◽  
Poor Survival ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Radiotherapy Resistance ◽  
Promoter Mutations

BIOM-21. THE SIGNIFICANCE OF TERT PROMOTER MUTATIONS, TELOMERE LENGTH AND MGMT PROMOTER METHYLATION IN NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA (GBM): A LARGE MONO-INSTITUTIONAL STUDY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi15-vi15
Author(s):  
Giuseppe Lombardi ◽  
Silvia Giunco ◽  
Francesco Cavallin ◽  
Chiara Angelini ◽  
Mario Caccese ◽  
...  
Keyword(s):  
Telomere Length ◽  
Clinical Outcomes ◽  
Methylation Status ◽  
Multivariable Analysis ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
The Impact

Abstract BACKGROUND the significance of TERT promoter mutations, telomere length and their interactions with MGMT methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a monoinstitutional study to better investigate their impact and their interaction on clinical outcomes. METHODS TERTmutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation were assessed in 278 newly-diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated from Dec2016 to Jan2020. We explored association between gene characteristics and neuroradiological response, PFS, OS. Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio. RESULTS characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMTmet in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). ORR was reported in 15% of PTS, medianOS was 15 ms (95% CI 13-18 ms), medianPFS was 8 ms (95% CI 7-9 ms). At multivariable analysis, TERT mutations and RTL were not associated with clinical outcomes; about OS, TERT mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMTmet tumors showed significant improved PFS and OS with a HR of 0.54(95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT-status, TERT-mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS0-1 in 60% of PTS, MGMTmet in 37%, TERT mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMTmet tumors resulted significantly associated to prolonged OS(HR0.16;95%CI0.07-0.40). No gene interaction was significant. CONCLUSIONS we analyzed the impact of TERT mutations, RTL and MGMT in newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT status and RTL were not associated with clinical outcomes. MGMT was the only prognostic factor. No significant interaction was demonstrated between TERT mutations, RTL and MGMT

scholarly journals Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1625
Author(s):  
Alexandra Posch ◽  
Sarah Hofer-Zeni ◽  
Eckhard Klieser ◽  
Florian Primavesi ◽  
Elisabeth Naderlinger ◽  
...  
Keyword(s):  
Telomere Length ◽  
Hot Spot ◽  
Expression Profiles ◽  
Ffpe Tissue ◽  
Telomere Maintenance ◽  
Neuroendocrine Neoplasms ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.

scholarly journals Clinical significance of combined circulating TERT promoter mutations and miR-122 expression for screening HBV-related hepatocellular carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ngo Tat Trung ◽  
Nghiem Xuan Hoan ◽  
Pham Quang Trung ◽  
Mai Thanh Binh ◽  
Hoang Van Tong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Significance ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression

PLoS ONE ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. e0231418 ◽  
Author(s):  
Catarina Salgado ◽  
Celine Roelse ◽  
Rogier Nell ◽  
Nelleke Gruis ◽  
Remco van Doorn ◽  
...  
Keyword(s):  
Chromatin Accessibility ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Tert Expression

The clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in newly diagnosed and recurrent IDH-wildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2053-2053
Author(s):  
Giuseppe Lombardi ◽  
Silvia Giunco ◽  
Francesco Cavallin ◽  
Chiara Angelini ◽  
Mario Caccese ◽  
...  
Keyword(s):  
Telomere Length ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Mgmt Promoter ◽  
Promoter Mutations ◽  
Mgmt Promoter Methylation Status

2053 Background: the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large mono-institutional study to better investigate their impact and their interaction on clinical outcomes Methods: TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio Results: characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0-1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07-0.40). No gene interaction was significant. Conclusions: for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status.

CSIG-30. TARGETING TELOMERASE VIA MEK INHIBITION IN AGGRESSIVE TERT PROMOTER MUTATED BRAIN TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi39-vi40
Author(s):  
Daniela Lötsch-Gojo ◽  
Lisa Gabler ◽  
Carola Jaunecker ◽  
Kerstin Fürnweger ◽  
Katharina Bruckner ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Cellular Senescence ◽  
Promoter Activity ◽  
Luciferase Reporter ◽  
Mek Inhibition ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Cell Immortalization ◽  
Promoter Mutations ◽  
Tert Expression

Abstract Activating point mutations within the TERT promoter (C228T or C250T) account for the most frequent alteration in aggressive brain tumors. Presence of these alterations results in the generation of binding sites for E-twenty-six (ETS) transcription factors accompanied by enhanced TERT expression. Accordingly, TERT promoter mutations foster cellular immortalization and subsequently tumor aggressiveness. Due to the limitation of treatment options in aggressive brain tumors, including glioblastoma and medulloblastoma, new therapeutic targets need to be discovered. As we previously described a strong interaction of oncogenic MEK/ETS signaling and TERT promoter mutations, we hypothesize that inhibition of these factors halters cell immortalization in TERT-driven brain tumors. Our study included three TERT promoter wild-type (TERTwt), six mutated (TERTmut) glioblastoma and three TERTmut medulloblastoma cell models and tested the effect of MEK inhibitors (U0126 and trametinib) and the ETS inhibitor YK-4-279 on cell viability and clone formation. Cellular senescence upon treatment was evaluated by beta-galactosidase assays. Impact on TERT mRNA expression and TERT promoter activity were analyzed by quantitative real-time PCR and luciferase reporter assays, respectively. Furthermore, the effects on MAPK- and PI3K pathway activation were evaluated by Western blot. Amongst the investigated inhibitors, tumor cells harboring C228T mutation were distinctly more sensitive against trametinib as compared to TERTwt and C250T TERTmut cells. Similar effects were observed on clonogenicity upon long-term exposure to this inhibitor. Regarding MAPK signaling activation, trametinib treatment completely blocked ERK phosphorylation in every cell model, while activation of ETS1 was more effectively reduced in C228T TERTmutcells. Accordingly, exposure to trametinib reduced TERT expression and promoter activity accompanied by induction of cellular senescence in cells with C228T mutation. Impact of trametinib is currently investigated in preclinical experiments using TERTmut brain tumor models. Summarizing, MEK inhibition represents a novel strategy to overcome cell immortalization especially in C228T TERTmut brain tumors.

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