scholarly journals TB-04 TERT PROMOTER MUTATION AS A SUSCEPTIBLE MOLECULAR MARKER OF BCNU LOCAL THERAPY

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii10-ii11
Author(s):  
Shigeta Miyake ◽  
Kensuke Tateishi ◽  
Joe Sasame ◽  
Yohei Miyake ◽  
Shinichirou Matsuyama ◽  
...  
Keyword(s):  
Molecular Marker ◽  
Methylation Status ◽  
Malignant Gliomas ◽  
Local Therapy ◽  
Tert Promoter Mutation ◽  
Mgmt Methylation ◽  
Promoter Mutation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Abstract INTRODUCTION Alkylating agents, including Temozolomide (TMZ) and CCNU (ACNU) have been widely accepted as a standard treatment in malignant gliomas. Several studies also demonstrated that BCNU wafer placement extended survival in glioblastoma patients. However, little study demonstrated gene-specific efficacy of BCNU local therapy in malignant gliomas. Herein, we investigated BCNU sensitivity for patient-derived primary cultured glioma cells. MATERIALS AND METHODS From January 2017 to July 2019, 58 gliomas (grade III, IV) were tested genomic analysis and ATP-based cell viability after BCNU treatment. IDH1/2 mutation and TERT promoter mutation status was determined by Sanger sequencing. MGMT methylation status were evaluated by methylation specific PCR. RESULTS Of 58 cases,10 cases (17.2%) and 32 (55.2%) cases harbored IDH1/2 mutation and TERT mutation (C228T, C250T), respectively. Among them, co-mutation was identified in 5/58 cases (8.6%). MGMT was methylated in 17/58 cases (29.3%). Interestingly, the presence of TERT promoter mutation was positively correlated with BCNU sensitivity, particularly in IDH1/2 wild-type tumors (p<0.05). In contrast, there was no significant relationship between TMZ sensitivity and IDH mutation/MGMT methylation status. CONCLUSION Although sample size is small, our results imply TERT promoter mutations might be a predictive molecular marker for BCNU sensitivity in malignant gliomas. Since TERT mutations are located at two hot spot loci (C228T and C250T), vast majority of TERT promoter mutations can be evaluated during surgery, which may contribute tailored therapeutic strategy in malignant gliomas.

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

Cell-free tumor DNA and TERT promoter mutations in bladder cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 353-353 ◽  
Author(s):  
Franklin W. Huang ◽  
Mikael L. Rinne ◽  
Kevin T. Lundgren ◽  
Stephanie Anne Mullane ◽  
Irene Moreno ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Metastatic Disease ◽  
Tert Promoter Mutation ◽  
Plasma Samples ◽  
Promoter Mutation ◽  
Library Construction ◽  
Non Invasive ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

353 Background: Currently, there are no FDA-approved blood biomarkers for the prognosis or prediction of outcomes in urothelial carcinoma (UC). The telomerase reverse transcriptase ( TERT) promoter is recurrently mutated at high frequency in UC (50%). These mutations have been correlated with tumor recurrence and survival. Tumor cell-free DNA (cfDNA) with somatic genomic alterations can be found in the plasma of cancer patients and has the potential for use as a non-invasive cancer biomarker. Detection of TERT promoter mutations in cfDNA might be used as a prognostic tool to monitor disease outcome in UC patients. We set out to detect tumor cfDNA and TERT promoter mutations in cfDNA from patients with UC at different stages. Methods: UC patients receiving chemotherapy in the neoadjuvant, first or second-line metastatic setting had blood collected either before or during therapy. cfDNA was isolated from ~1ml plasma samples using the QIAmp (Qiagen) kit. Samples underwent ultra-low pass whole genome sequencing (ULP-WGS) to determine whether tumor cfDNA could be detected in these samples. TERT promoter mutations were detected using a sensitive qPCR assay. Results: 40 plasma samples from a total of 32 patients with urothelial carcinoma were analyzed. Sufficient amounts of plasma cfDNA were obtained for library construction and ULP-WGS in 11 patients. 6 of these 11 patients were determined to be positive for detectable tumor cfDNA and of these, all were metastatic and 50% (3/6) were positive for a TERT promoter mutation. In total, 8 out of 40 samples (20%) were positive for a TERT promoter mutation, including samples from two patients where total cfDNA yield was insufficient for library construction. A total of ~20% of patients with metastatic disease were positive for TERT promoter mutations in cfDNA. The low percentage of samples having sufficient cfDNA most likely reflects the low volume of plasma used. Conclusions: TERT promoter mutations were identified in cfDNA of UC patients. ULP-WGS showed tumor cfDNA in patients with a high tumor burden and metastatic disease. TERTpromoter mutations in cfDNA could potentially be used as a non-invasive method for detection of disease. These results have implications for the use of cfDNA in the evaluation of advanced UC.

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.

scholarly journals Prospective Analysis of TERT Promoter Mutations in Papillary Thyroid Carcinoma at a Single Institution

2021 ◽  
Vol 10 (10) ◽  
pp. 2179
Author(s):  
Yun-Suk Choi ◽  
Seong-Woon Choi ◽  
Jin-Wook Yi
Keyword(s):  
Thyroid Cancer ◽  
Surgical Margin ◽  
Tert Promoter Mutation ◽  
Papillary Thyroid ◽  
Brafv600e Mutation ◽  
Promoter Mutation ◽  
Large Tumor ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Background: Papillary thyroid cancer (PTC) has the highest cancer incidence in Korea. It is known that some thyroid cancers have aggressive clinical behavior and a poor prognosis. Genomic studies have described some somatic mutations that are related to the aggressive features of thyroid cancer, such as the BRAFV600E mutation. Recently, TERT promoter mutations were identified and reported as poor prognostic factors in PTC. Our aim was to identify the frequency and clinical impact of TERT promoter mutation in PTC. Methods: Analysis of both BRAFV600E and TERT promoter mutations in thyroidectomy specimens began in February 2019. As of December 2020, 622 patients had been tested. Data were prospectively collected and retrospectively reviewed to ascertain clinical and pathologic variables. Results: TERT promoter mutations were identified in 13 patients (2.09%); 12 had the C228T mutation, and one had the C216T mutation. In total, ten patients had the BRAFV600E mutation. TERT promoter mutation was significantly associated with advanced age (46.795 ± 12.616 versus 65.692 ± 13.628 years, p < 0.001), large tumor size (1.006 ± 0.829 versus 2.285 ± 1.938 cm, p = 0.035), extrathyroidal extension, surgical margin involvement, angioinvasion, BRAFV600E mutation and advanced TNM stage, a higher MACIS score and a high proportion of radioactive iodine therapy application. Logistic regression showed that lymphatic and angioinvasion and BRAFV600E mutation were predictive of TERT promoter mutation. Conclusions: Our study is the first to report the prospective results of TERT promoter mutations at a single tertiary hospital in Incheon, Korea. PTC with TERT promoter mutation was associated with more aggressive behavior than PTC with wild-type TERT gene status.

scholarly journals TERT Promoter Mutation is a Diagnostic and Differential Diagnostic Marker for Tumors with Urothelial Origin

2020 ◽  
Vol 4 (2) ◽  
Author(s):  
Shaobo Zhang
Keyword(s):  
Differential Diagnosis ◽  
Diagnostic Marker ◽  
Clinical Implications ◽  
Telomerase Reverse Transcriptase ◽  
Tert Promoter Mutation ◽  
Promoter Mutation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Telomerase reverse transcriptase (TERT) promoter mutations have been found in approximately 60–80% of bladder urothelial cancers and its variants of all grades anywhere in the urinary tract. The TERT promoter mutations occur early in urothelial neoplasia and are biomarkers for neoplasm development, recurrence, diagnosis, differential diagnosis, and potentially a therapeutic target. This review highlighted the role of TERT promoter mutations in urothelial tumorigenesis, and the potential clinical implications.

scholarly journals BIOM-59. TERT PROMOTER MUTATION AND MGMT PROMOTER METHYLATION-MEDIATED SENSITIVITY TO TEMOZOLOMIDE IN IDH-WILDTYPE GLIOBLASTOMA: IS THERE A LINK?

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii14-ii14
Author(s):  
Dorothee Gramatzki ◽  
Jörg Felsberg ◽  
Bettina Hentschel ◽  
Marietta Wolter ◽  
Gabriele Schackert ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Tert Promoter Mutation ◽  
Promoter Mutation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Mgmt Promoter ◽  
Hotspot Mutations ◽  
Promoter Mutations ◽  
The Impact

Abstract BACKGROUND Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Recent studies suggest that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations. METHODS MGMT promoter methylation and TERT promoter mutation status were assessed in an exploratory prospective cohort of IDH-wildtype glioblastoma patients of the German Glioma Network (GGN) (n=298) and validated in a retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n=302). RESULTS In the prospective GGN discovery cohort of patients with MGMT promoter-unmethylated tumors, TERT promoter mutation showed inferior outcome (p=0.044). In contrast, TERT promoter mutations were not associated with improved outcome in patients with MGMT promoter-methylated tumors. Different TERT promoter hotspot mutations were not associated with distinct outcomes. The association of TERT promoter mutation in MGMT promoter-unmethylated tumors was not confirmed in the retrospective validation cohort. CONCLUSIONS Analysis of two independent cohorts of glioblastoma patients, including the prospective GGN cohort, did not confirm previous data suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in IDH-wildtype glioblastoma patients.

PL02.5.A 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 IDHwildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii1-ii2
Author(s):  
G Lombardi ◽  
S Giunco ◽  
F Cavallin ◽  
C Angelini ◽  
M 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

Abstract 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 monoinstitutional study to better investigate their impact and their interaction on clinical outcomes MATERIAL AND 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 CONCLUSION 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

scholarly journals MPTH-12. TERT PROMOTER MUTATION IS A POOR PROGNOSTIC MARKER FOR GBMS AND INTERACTS WITH MGMT METHYLATION STATUS

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi108-vi108
Author(s):  
Hideyuki Arita ◽  
Kai Yamasaki ◽  
Taishi Nakamura ◽  
Mitsuaki Shirahata ◽  
Keiichi Kobayashi ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Methylation Status ◽  
Tert Promoter Mutation ◽  
Mgmt Methylation ◽  
Promoter Mutation ◽  
Tert Promoter
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