Telomerase Reverse Transcriptase Promoter Status Research Articles

Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients

The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients. We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and-146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients. Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P= 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant. Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.

Immunohistochemical and mutational status of telomerase reverse transcriptase in conjunctival squamous cell carcinoma.

Purpose:Mutations in human telomerase reverse transcriptase (TERT) are associated with increased telomerase activity in cutaneous melanomas. Conjunctival squamous cell carcinoma, also referred to as ocular surface squamous cell carcinoma, is cancer on the surface of the eye. Recent studies have identified UV signature mutations in TERT promoters in ocular melanoma and ocular surface squamous neoplasia. However, its immunohistochemical status has not been reported in ocular surface squamous cell carcinoma. This study aimed to explore the immunohistochemical and mutational status of TERT in ocular surface SCC.Methods:The immunohistochemical expression of TERT and mutational status of TERT promoter was evaluated in 19 ocular surface squamous cell carcinoma cases. Conjunctival melanoma tissue was used as a positive control.Results:The cytoplasmic overexpression of TERT was detected in 11/19 (57%), and TERT promoter mutations were identified in 6/19 (31%) of ocular surface squamous cell carcinoma. Out of these, 66% had a C228T mutation, and 33% had a C250T mutation. The TERT expression was found to be associated with a high (≥T3) AJCC category (P = 0.023), and TERT immunoexpression was significantly correlated with reduced disease-free survival (P = 0.024, log-rank analysis) in ocular surface squamous cell carcinoma patients.Conclusion:The present study demonstrates that TERT promoter mutations with UV signatures are frequent in ocular surface squamous cell carcinoma. The increased expression of TERT could be of biological significance in aggressive ocular surface squamous cell carcinoma.

CSIG-04. UNCOUPLING OF ETS1 FROM MAPK PATHWAY SIGNALS AS RESISTANCE MECHANISM TOWARDS BRAF INHIBITORS IN BRAF-MUTATED CHILDHOOD GLIOMA

Abstract BACKGROUND High-grade gliomas are among the most aggressive brain tumors across all age groups. BRAF is within the most frequently altered genes in pediatric glioma, sometimes connected with telomerase reverse transcriptase (TERT) promoter mutations, predicting a particularly aggressive course of disease. Precision medicine approaches targeting the MAPK pathway have shown promising results in patients with BRAF-mutated glioma. Although acquired insensitivity to BRAF inhibitors appears as major issue for therapy failure, underlying molecular mechanisms are still poorly understood. METHODS Cell models from an anaplastic pleomorphic xanthoastrocytoma with BRAF V600E and TERT promoter mutations and the recurrent tumor, operated following MAPK pathway-targeting therapy, were established. Furthermore, a dabrafenib-resistant subline of the recurrent tumor was generated. The patient-derived cell models were genetically characterized using array-based genomic hybridization (aCGH). Sensitivity of the cells towards different MAPK pathway inhibitors was tested. Basal expression and activation of MAPK pathway and downstream signals were analyzed by qRT-PCR and Western blots. RESULTS Screening a panel of both primary and immortalized glioma cell models with different BRAF and TERT promoter status revealed significantly induced MAPK pathway activation and enhanced TERT levels in BRAF V600E and TERT promoter double-mutant gliomas. Furthermore, cells with both mutations were hyper-sensitive towards BRAF-targeting agents and BRAF inhibition resulted in reduced TERT levels. ETS1 expression was strongly increased in the recurrent tumor and identified as important player in telomerase re-activation. aCGH revealed gains of chromosomal regions encoding for different ETS-factors in the dabrafenib-resistant subline. Western blot analyses suggested a BRAF/ERK-independent survival mechanism in the dabrafenib-resistant subline. Accordingly, dabrafenib insensitivity triggered cross-resistance towards the MEK inhibitor trametinib. Uncoupled from the MAPK pathway, ETS1 expression was further upregulated in the dabrafenib-resistant subline. CONSLUSION: Taken together, our data demonstrate that MAPK-independent ETS transcription factor upregulation is a central mechanism of BRAF inhibitor therapy failure in BRAF-mutated pediatric glioma 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

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

Preoperative detection of the TERT promoter mutations in papillary thyroid carcinomas.

Telomerase reverse transcriptase promoter (TERT-p) mutations are strongly associated with tumour aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). Since the TERT-p mutations have been reported to be subclonal, it is unclear how accurately they can be detected by preoperative fine-needle aspiration (FNA). The objective of this study was to analyse the concordance rate of the TERT-p mutations between preoperative FNA and corresponding postoperative surgical specimens. Ninety-six cases of PTC aged 55 years or older were studied. The mutational status of TERT-p was detected by droplet digital polymerase chain reaction assay. The mutational status of the TERT-p in FNA samples was highly concordant with that in postoperative formalin-fixed and paraffin-embedded (FFPE) specimens. The TERT-p mutation was significantly associated with age, tumour size, extrathyroidal extensionand the Ki-67 labelling index in multivariate analysis in both FNA and FFPE samples. The detection of the TERT-p mutations using FNA samples has a good ability to predict disease aggressiveness and, therefore, could be clinically useful in the determination of PTC management.

Diagnostic Performance of [11C]Methionine Positron Emission Tomography in Newly Diagnosed and Untreated Glioma Based on the Revised World Health Organization 2016 Classification

The relationship between uptake of amino acid tracer with positron emission tomography (PET) and glioma subtypes/gene status is still unclear. To assess the relationship between uptake of [11C]methionine using PET and pathology, IDH (isocitrate dehydrogenase) mutation, 1p/19q codeletion, and TERT (telomerase reverse transcriptase) promoter status in gliomas. The participants were 68 patients with newly diagnosed and untreated glioma who underwent surgical excision and preoperative [11C]methionine PET examination at Osaka City University Hospital between July 2011 and March 2018. Clinical and imaging studies were reviewed retrospectively based on the medical records at our institution. The mean lesion/contralateral normal brain tissue (L/N) ratio of diffuse astrocytomas was significantly lower than that of anaplastic astrocytomas (P= 0.00155), glioblastoma (P < 0.001), and oligodendrogliomas (P=0.0157). The mean L/N ratio of IDH mutant gliomas was significantly lower than that of IDH wild-type gliomas (median 1.75 vs. 2.61; P= 0.00162). A mean L/N ratio of 2.05 provided the best sensitivity and specificity for distinguishing between IDH mutant and IDH wild-type gliomas (69.2% and 76.2%, respectively). The mean L/N ratio of TERT promoter mutant gliomas was significantly higher than that of TERT promoter wild-type gliomas (P=0.0147). Multiple regression analysis showed that pathologic diagnosis was the only influential factor on L/N ratio. Distinguishing glioma subtypes based on the revised 2016 World Health Organization classification of the central nervous system tumors on the basis of [11C]methionine PET alone seems to be difficult. However, [11C]methionine PET might be useful for predicting the IDH mutation status in newly diagnosed and untreated gliomas noninvasively before tumor resection.

NIMG-34. QUANTITATIVE MR PARAMETERS FOR THE PREDICTION OF EGFR AMPLIFICATION AND THE TERT PROMOTER MUTATION STATUS OF IDH-WILDTYPE LOWER-GRADE GLIOMAS

Abstract OBJECTIVES To assess the predictive role of quantitative MRI parameters from DTI, dynamic susceptibility contrast (DSC), and dynamic contrast-enhanced (DCE) imaging in determining the epidermal growth factor receptor (EGFR) amplification and telomerase reverse transcriptase promoter (TERTp) mutation status of isocitrate dehydrogenase-wildtype (IDHwt) lower-grade gliomas (LGGs). METHODS A total of 49 patients with IDHwt LGGs with either known EGFR amplification (39 EGFR non-amplified, 10 EGFR-amplified) or TERTp mutation (19 TERTp wildtype, 21 TERTp mutant) statuses underwent preoperative MRI. The mean apparent diffusion coefficient (ADC), fractional anisotropy (FA), normalized cerebral blood volume (nCBV), normalized cerebral blood flow (nCBF), volume transfer constant (Ktrans), rate transfer coefficient (Kep), extravascular extracellular volume fraction (Ve), and plasma volume fraction (Vp) values were assessed. Univariate and multivariate logistic regression models were constructed to predict EGFR amplification and TERTp status. RESULTS EGFR-amplified tumors showed lower mean ADC values than EGFR non-amplified tumors (p = 0.019). Mean ADC was an independent predictor of EGFR amplification, with an AUC of 0.75. TERTp mutant tumors showed higher mean nCBV (p = 0.020), higher mean nCBF (p = 0.017), and higher mean Vp (p = 0.002) than TERTp wildtype tumors. With multivariate logistic regression, mean Vp was the only independent predictor of TERTp mutation status, with an AUC of 0.85. CONCLUSION Lower ADC values may be a useful marker for the prediction of EGFR amplification, whereas higher Vp values may be a useful marker for the prediction of the TERTp mutation status of IDHwt LGGs.

Highly sensitive detection of TERT promoter mutations in recurrent glioblastomas using digital PCR

Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.

Conventional magnetic resonance imaging-based radiomic signature predicts telomerase reverse transcriptase promoter mutation status in grade II and III gliomas.

Telomerase reverse transcriptase (TERT) promoter mutation status is an important biomarker for the precision diagnosis and prognosis prediction of lower grade glioma (LGG). This study aimed to construct a radiomic signature to noninvasively predict the TERT promoter status in LGGs. Eighty-three local patients with pathology-confirmed LGG were retrospectively included as a training cohort, and 33 patients from The Cancer Imaging Archive (TCIA) were used as for independent validation. Three types of regions of interest (ROIs), which covered the tumor, peri-tumoral area, and tumor plus peri-tumoral area, were delineated on three-dimensional contrast-enhanced T1 (3D-CE-T1)-weighted and T2-weighted images. One hundred seven shape, first-order, and texture radiomic features from each modality under each ROI were extracted and selected through least absolute shrinkage and selection operator. Radiomic signatures were constructed with multiple classifiers and evaluated using receiver operating characteristic (ROC) analysis. The tumors were also stratified according to IDH status. Three radiomic signatures, namely, tumoral radiomic signature, tumoral plus peri-tumoral radiomic signature, and fusion radiomic signature, were built, all of which exhibited good accuracy and balanced sensitivity and specificity. The tumoral signature displayed the best performance, with area under the ROC curves (AUC) of 0.948 (0.903-0.993) in the training cohort and 0.827 (0.667-0.988) in the validation cohort. In the IDH subgroups, the AUCs of the tumoral signature ranged from 0.750 to 0.940. The MRI-based radiomic signature is reliable for noninvasive evaluation of TERT promoter mutations in LGG regardless of the IDH status. The inclusion of peri-tumoral area did not significantly improve the performance.

Suspicious ultrasound and clinicopathological features of papillary thyroid carcinoma predict the status of TERT promoter.

To investigate the value of ultrasound (US) and clinicopathological features of papillary thyroid cancer (PTC) in predicting Telomerase Reverse Transcriptase (TERT) promoter mutations. Preoperative US images of 351 surgically confirmed PTCs were evaluated in terms of PTCs size and US features. The basic clinicopathological features were also retrieved. Univariate and multivariate analyses were performed to identify the risk factors for TERT promoter mutations. A scoring system was developed based on the cumulative number of risk factors. The area under the receiver operating characteristic curve (AUC) and cut-off value were calculated to evaluate the diagnostic performance of the scoring system for predicting TERT promoter mutations. TERT promoter mutations were found in 4.84% (17/351) of patients with PTCs. Patient age >50 years (OR: 6.244, P = 0.006), multifocality (OR: 21.071, P = 0.022), taller-than-wide shape (OR: 4.934, P = 0.029), microlobulated margin (OR: 4786, P = 0.032), and capsule contact or involvement (OR: 4.668, P = 0.030) were independent risk factors for TERT promoter mutations. TERT promoter mutations were relevant to more suspicious US and clinicopathological features than TERT promoter wild-type PTC (median, 4 vs. 1, P < 0.001). The cut-off value was 2.5 and the associated AUC was 0.908 (P < 0.001). The probability of TERT promoter mutations increases along with the suspicious US features and clinicopathological characteristics, which may help to recognize patients who deserve a different approach, in terms of management and follow-up, in view of the worst outcome associated to this mutation.

TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma.

To evaluate the prevalence of two recurrent somatic mutations(-124 C>T and -146 C>T) within thepromoterof the gene encoding telomerase reverse transcriptase (TERT) as well as their relationship with TERT level, telomeres length, and outcome in patients with head and neck squamous cell carcinomas (HNSCCs). We evaluate the prevalence of TERT promoter mutations, TERT levels, and telomere length in paired cancer tissue and adjacent mucosa (AM) in a series of HNSCCs. Cancer tissue and AM specimens from 105 patients were analyzed. Telomere length and TERT mRNA levels were estimated using real-time polymerase chain reaction. TERT promoter mutations were assessed using Sanger sequencing. Out of 105 cases, 101 were considered suitable for the analysis. TERT promoter harbored mutations in 12 tumors (11.9%), with -124 C>T and -146 C>T accounting for 83.3% and 16.7% of the alterations, respectively. No mutations were detected in AM samples. The prevalence of TERT promoter mutations was significantly higher in oral cavity SCCs (10 out of 27 tumors; 37%), and telomere length in AM was shorter in patients with tumors carrying TERT promoter mutations than in patients with unmutated TERT promoter cancers (p = 0.023). TERT levels in tumor did not significantly differ according to the mutational status of TERT promoter. No significant association was found between TERT promoter status and overall survival. TERT promoter mutations are most likely a late event in tumor development, occurring in a context of critically short telomeres, mostly in patients with oral cavity SCC. TERT levels, but not TERT promoter mutational status impact clinical outcome.

TERT promoter status and gene copy number gains: effect on TERT expression and association with prognosis in breast cancer.

Upregulation of the telomerase reverse transcriptase (TERT) gene in human cancers leads to telomerase activation, which contributes to the growth advantage and survival of tumor cells. Molecular mechanisms of TERT upregulation are complex, tumor-specific and can be clinically relevant. To investigate these mechanisms in breast cancer, we sequenced the TERT promoter, evaluated TERT copy number changes and assessed the expression of the MYC oncogene, a known transcriptional TERT regulator, in two breast cancer cohorts comprising a total of 122 patients. No activating TERT promoter mutations were found, suggesting that this mutational mechanism is not likely to be involved in TERT upregulation in breast cancer. The T349C promoter polymorphism found in up to 50% of cases was not correlated with TERT expression, but T349C carriers had significantly shorter disease-free survival. TERT gains (15-25% of cases) were strongly correlated with increased TERT mRNA expression and worse patient prognosis in terms of disease-free and overall survival. Particularly aggressive breast cancers were characterized by an association of TERT gains with MYC overexpression. These results evidence a significant effect of gene copy number gain on the level of TERT expression and provide a new insight into the clinical significance of TERT and MYC upregulation in breast cancer.

The TERT promoter mutation incidence is modified by germline TERT rs2736098 and rs2736100 polymorphisms in hepatocellular carcinoma.

Telomerase activation via induction of the catalytic component telomerase reverse transcriptase (TERT) plays essential roles in malignant transformation. TERT promoter-activating mutations were recently identified as a novel mechanism to activate telomerase in hepatocellular carcinoma (HCC) and many other malignancies. In addition, single nucleotide polymorphisms (SNPs) in the TERT rs2736098 and rs2736100 are significantly associated with cancer susceptibility. It is currently unclear whether different germline TERT variants modify TERT promoter mutations. Here we analyzed the TERT promoter status and genotyped the TERT SNPs at rs2736098 and rs2736100 in patients with HCC. Thirty percent of HCCs harbored TERT promoter mutations and there was a significant difference in rs2736098 and rs2736100 genotypes between wt and mutant TERT promoter-bearing HCC tumors (P = 0.007 and 0.018, respectively). For rs2736100, the cancer risk genotype CC was significantly associated with a reduced incidence of TERT promoter mutations compared to AA + AC variants [Odds ratio (OR): 0.181, 95% Confidence interval (CI): 0.0543–0.601, P = 0.004]. The rs2736098_CT genotype was significantly associated with the TERT promoter mutation-positive tumors compared to the TT genotype (OR: 5.391, 95% CI: 1.234–23.553, P = 0.025). These differences in genotype distribution did not differ between patients with a wt TERT promoter and controls. The presence of TERT promoter mutations was not associated with clinico-pathological variables. Taken together, the germline TERT genetic background may significantly affect the onset of TERT promoter mutations in HCCs, which provides a better understanding of HCC-related TERT promoter mutations and telomerase regulation in cancer.

Prognostic Significance of TERT Promoter Mutations in Papillary Thyroid Carcinomas in a BRAF(V600E) Mutation-Prevalent Population.

The role of telomerase reverse transcriptase (TERT) promoter mutations in differentiated thyroid cancer has been well established. These mutations have a significantly higher prevalence in aggressive thyroid tumors, including widely invasive oncocytic carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas. Interestingly, in some studies, TERT mutations were found to be more common in tumors with a BRAF(V600E) mutation. However, mutational analysis of TERT promoter mutations in thyroid tumors has not been previously performed for patients in Korea, where the BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is particularly prevalent. This study analyzed TERT promoter mutations in various thyroid tumors and examined their relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases. Using 242 preoperative fine-needle aspiration biopsy specimens (including 207 PTCs) with confirmed histopathological diagnosis of the biopsied thyroid nodules, the TERT promoter status (C228T and C250T) was analyzed, and the relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases was examined. Of 242 patients, 14.5% (30/207), 26.7% (4/15), 50% (1/2), and 60% (2/5) of PTCs, follicular thyroid carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas harbored a TERT(C228T) mutation, respectively. The TERT(C228T) mutation was associated with recurrence (p = 0.03). However, no association with other clinicopathologic factors in PTC was found. Coexistence of TERT(C228T) and BRAF(V600E) mutations was found in 13.0% of PTCs and was significantly associated with older age and advanced stage compared with the group negative for either mutation. The TERT(C228T) mutation status was an independent prognostic factor for recurrence-free survival (hazard ratio = 3.08 [confidence interval 1.042-9.079]; p = 0.042) in patients with PTC in multivariate analysis. Identification of TERT promoter mutations in preoperative fine-needle aspiration biopsy specimens may help in better characterizing the prognosis and triaging thyroid cancer patients for appropriate treatment.

TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma.

Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (P<0.001) and are associated with oligodendroglial histology (P<0.001). Kaplan–Meier's survival analysis showed that TERT promoter mutation (P=0.037), Isocitrate dehydrogenase (IDH) mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P=0.007) and OS (P=0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.

P04.06 * TERT PROMOTER MUTATIONS CONTRIBUTE TO SUBSET PROGNOSTICATION OF LOWER GRADE GLIOMAS

Recurrent mutations in the promoter region of TERT (telomerase reverse transcriptase) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behaviour in glioblastomas. However, the clinical significance of TERT promoter mutations in lower grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 181 lower grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 12/89 (14%) diffuse astrocytomas, 8/23 (35%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (p < 0.001), IDH mutation (p = 0.025) and are associated with oligodendroglial histology (p < 0.001). Kaplan-Meier's survival analysis showed that TERT promoter mutation (p = 0.017), IDH mutation (p = 0.004) and 1p/19q codeletion (p < 0.001) were associated with favorable overall survival. In the subset of 90 IDH mutated lower grade gliomas lacking 1p/19q codeletion, 16 TERT promoter mutated tumors exhibited longer overall survival (p = 0.017). Consistent with this observation, in the subset of 71 IDH mutated astrocytomas, 11 TERT promoter mutated tumors showed longer progression-free survival (p = 0.003) and overall survival (p = 0.005). In contrast, among the subset of 46 IDH wild type lower grade gliomas, TERT promoter mutation was associated with shorter progression-free survival (p = 0.001) and overall survival (p = 0.001). Similarly, in the subset of 37 IDH wild type lower grade gliomas with intact 1p/19q, 8 TERT promoter mutated tumors exhibited unfavorable progression-free survival (p = 0.005) and overall survival (p = 0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower grade astrocytic tumors or 1p/19q intact lower grade gliomas and this may further refine future molecular classification of lower grade gliomas.

TERT PROMOTER MUTATIONS CONTRIBUTE TO PROGNOSTIC SUBGROUPS OF LOWER GRADE ASTROCYTOMAS

BACKGROUND: Recurrent mutations in the promoter region of TERT (telomerase reverse transcriptase) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behaviour in glioblastomas. However, the prognostic impact of TERT promoter mutations in lower grade gliomas remains undetermined. METHODS: The aim of this study is to evaluate the status of TERT promoter and the respective clinical significance in a cohort of 181 lower grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas and oligoastrocytomas. RESULTS: Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 12/89 (14%) diffuse astrocytomas, 8/23 (35%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (p < 0.001), IDH mutation (p = 0.025) and are associated with oligodendroglial histology (p < 0.001). Kaplan-Meier's survival analysis showed that IDH mutation (p = 0.027) and 1p/19q codeletion (p = 0.001) were associated with longer progression-free survival. TERT promoter mutation (p = 0.017), IDH mutation (p = 0.004) and 1p/19q codeletion (p < 0.001) were associated with favorable overall survival. In the subset of 90 IDH mutated lower grade gliomas lacking 1p/19q codeletion, 16 TERT promoter mutated tumors exhibited longer overall survival (p = 0.017). Consistent with this observation, in the subset of 71 IDH mutated astrocytomas, 11 TERT promoter mutated tumors showed longer progression-free survival (p = 0.003) and overall survival (p = 0.005). In contrast, among the subset of 46 IDH wild type lower grade gliomas, TERT promoter mutation was associated with shorter progression-free survival (p = 0.001) and overall survival (p = 0.001). Similarly, in the subset of 37 IDH wild type lower grade gliomas with intact 1p19q, 8 TERT promoter mutated tumors exhibited unfavorable progression-free survival (p = 0.005) and overall survival (p = 0.008). IDH included IDH1 and IDH2. CONCLUSIONS: Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower grade astrocytic tumors (1p/19q intact low grade gliomas) and this may further refine future molecular classification of lower grade gliomas. SECONDARY CATEGORY: Clinical Neuro-Oncology.

Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system

Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.