Frequency Of TERT Promoter Mutations Research Articles

Genomic profiling of lymph node and distant metastases from papillary and poorly differentiated thyroid carcinomas.

To perform a molecular profiling of the metastases from papillary thyroid carcinomas (PTCs) and poorly differentiated thyroid carcinomas (PDTCs). We retrieved and analyzed the molecular and clinical features of 136 metastases from PTCs and 35 metastases from PDTCs subjected to targeted DNA sequencing, from cBioPortal. The clinicopathological data included the number and location of the metastases, and genomic data included mutations, translocations, copy number alterations and fraction of the genome altered (FGA). Bone metastases from PTCs had a lower frequency of BRAF mutations than the lymph node metastases (LNMs) (43% vs 88%, p < 0.01), and a higher frequency of RBM10 and NRAS mutations than the LNMs (21% vs 3% for both, p < 0.05). The FGA of the bone metastases was higher than the FGA of the lung metastases (5.6% vs 1.3%, p < 0.05). The frequency of RET translocations was higher in the lung metastases from PTCs than the LNMs (15% vs 3%, p < 0.05). The LNMs from PTC patients harboring 4 or more distant metastases (DMs) had a higher frequency of TERT promoter mutations than the LNMs from patients harboring less than 4 DMs (96% vs 65%, p < 0.001). SDHA gene amplifications were enriched in the bone metastases from PDTCs and absent in the LNMs (38% vs 0%, p < 0.05). Metastases from PTCs and PDTCs harbor clinically relevant alterations affecting distinct body locations, such as NRAS and RBM10 mutations, RET translocations and SDHA amplifications that may be explored therapeutically.

Small cell neuroendocrine carcinoma and poorly differentiated rhabdomyosarcomas of the urinary bladder in adults-A comparative analysis in favor of a common histogenesis.

Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like)small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related othergenes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.

Papillary thyroid carcinoma tall cell subtype (PTC-TC) and high-grade differentiated thyroid carcinoma tall cell phenotype (HGDTC-TC) have different clinical behaviour: aretrospective study of 1456 patients.

Papillary thyroid carcinoma, tall cell subtype (PTC-TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high-grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC-TC). We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC-TC and HGDTC-TC. HGDTC-TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC-TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC-TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis-free survival (DMFS; P < 0.001). The 10-year DSS was 72 and 99%, the 10-year LRDFS was 61 and 92% and the 10-year DMFS was 53 and 97%, respectively, for HGDTC-TC and PTC-TC. On multivariate analysis, the classification (HGDTC-TC versus PTC-TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. Compared with PTC-TC, HGDTC-TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC-TC versus 34% in PTC-TC) and incurs a significantly worse prognosis. HGDTC-TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas.

TERT Promoter and BRAF V600E Mutations in Papillary Thyroid Cancer: A Single-Institution Experience in Korea.

Simple SummaryTERT promoter mutation has recently emerged as a promising prognostic biomarker for aggressive papillary thyroid cancer (PTC), along with BRAF B600E mutation. The prevalence of the TERT promoter mutations has been reported as relatively uncommon in Asian countries. We report on a prospective study of the TERT promoter and BRAF V600E mutation in the largest number of subjects with PTC in Korea. We assume that our specific clinical settings and the favorable healthcare environment in Korea led to several distinct findings: the lowest prevalence of TERT promoter mutation ever reported, multifocal gene mutations in bilateral PTCs, and more early-stage papillary microcarcinomas included in this study. This study indicates that relevant evaluation and treatment strategies should be investigated continuously based on different circumstances.Telomerase reverse transcriptase (TERT) promoter mutation has been investigated for its clinical and prognostic significance in aggressive papillary thyroid cancer (PTC). In this study, we aimed to assess the prevalence, clinicopathologic features, and treatment outcomes of TERT mutation-positive PTCs along with the common BRAF V600E mutation. We performed mutational analyses for BRAF and the TERT promoter in thyroid cancer patients who had undergone surgery at our institution since 2019. We reviewed and analyzed 7797 patients with PTC in this study. The prevalence of BRAF V600E and TERT promoter mutations was 84.0% and 1.1%, respectively. Multifocal gene mutations in bilateral PTCs were identified. TERT promoter mutations were associated with older age, larger tumor size, tumor multifocality, tumor variants, advanced stages, more adjuvant radioactive iodine treatment (RAI), higher stimulated serum thyroglobulin level before RAI, and more uptakes in the regions outside the surgical field on a post-RAI whole-body scan. The coexistence of BRAF V600E and TERT promoter mutations exacerbated all clinicopathologic characteristics. The frequency of TERT promoter mutations was the lowest in this study, compared to previous studies. TERT promoter mutations consistently correlated with aggressive PTCs, and the synergistic effect of both mutations was evident. Specific clinical settings in our institution and in Korea may have led to these distinctive results. Prospective multicenter studies with longer follow-up periods are required to establish valuable oncologic outcomes.

Frequency of TERT Promoter Mutations in Real-World Analysis of 2,092 Thyroid Carcinoma Patients.

BackgroundTelomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients.MethodsWe prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma.ResultsOf 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences.ConclusionThis study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

Abstract 5280: TERT promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma

Abstract Background: Papillary thyroid microcarcinomas (PTMCs) have been attributed to the recent increased incidence of thyroid cancer. Although indolent, a subset of PTMC could potentially develop distant metastasis (DM). This study aimed to evaluate the clinico-pathological features and molecular characteristics of PTMC and identify the risk factors for DM in PTMC patients from Middle Eastern ethnicity. Methods: We retrospectively analyzed 210 patients with histologically confirmed PTMC. Clinico-pathological associations for DM, BRAF mutation and TERT mutation were analyzed successfully in 184 patients. Multivariate analysis was performed using Cox proportional hazards model and logistic regression analysis. Results: Among the PTMC patients included in this cohort, DM was noted in 6.0%(11/184), whereas tumor relapse occurred in 29/184 (15.8%). Of the 11 cases with DM, lung metastasis occurred in 8 cases, bone metastasis in 2 cases and brain metastasis in 1 case. Presence of extrathyroidal extension and older age were significantly associated with DM. Molecular analysis showed BRAF V600E mutations to be the most frequent, being detected in 45.7% (84/184). TERT promoter mutations were detected in 16 (8.7%) cases and were significantly associated with DM and shorter metastasis-free survival in multivariate analysis. Conclusions: Our study indicates a surprisingly high frequency of TERT promoter mutation in Saudi patients with PTMC. Identifying TERT promoter mutations as an independent predictor of DM in patients with microcarcinoma could explain the inherent aggressive nature of PTMC from Middle Eastern ethnicity and magnify its role in patient risk stratification, which might help in improving therapeutic strategy for these patients. Citation Format: Saeeda Omer Ahmed, Abdul K. Siraj, Sandeep K. Parvathareddy, Kaleem Iqbal, Zeeshan Qadri, Maha Al-Rasheed, Sarah Siraj, Saravanan Thangavel, Roxanne Diaz, Allianah Benito, Ingrid F. Victoria, Khawla S. AlKuraya. TERT promoter mutations are an independent predictor of distant metastasis in Middle Eastern papillary thyroid microcarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5280.

Clinicopathological indicators for TERT promoter mutation in papillary thyroid carcinoma.

Mutations in the telomerase reverse transcriptase (TERT) promoter have been reported as a convincing prognostic factor in papillary thyroid carcinomas (PTCs). We aimed to investigate the frequency of TERT promoter mutations in patients with thyroid cancer and identify the clinicopathological factors associated with them in PTCs. A total of 1086 consecutive cases of thyroid cancer composed of mostly PTCs were included in this study. TERT promoter and BRAF mutations were detected by pyrosequencing and their associations with clinicopathological features of tumour were analyzed. TERT promoter mutations were observed in 1.9% of PTCs, 6.7% of follicular thyroid carcinomas, 8.3% of Hurthle cell carcinomas and 25.0% of poorly differentiated thyroid carcinomas and in a single case of anaplastic thyroid carcinoma. In PTCs, aggressive clinicopathological features, higher stage and BRAF V600E mutation were all found to be associated with TERT promoter mutations. Distant metastasis and disease recurrence were more frequent in TERT promoter-mutated PTCs. In multivariate analysis, age ≥55 years, tall cell variant, mitoses ≥3/10 high-power fields, tumour necrosis, and gross extrathyroidal extension (ETE) were identified as independent factors associated with TERT promoter mutations in PTCs. This study revealed a relatively low frequency of TERT promoter mutations in Korean patients with PTC. Certain clinicopathological features including old age, tall cell variant, increased mitoses, tumour necrosis and gross ETE were found to be indicative of TERT promoter mutations in PTCs, suggesting that mutational analysis in a particular group of PTCs can be effective in regions with low mutation rates.

TERT Promoter Mutations Are an Independent Predictor of Distant Metastasis in Middle Eastern Papillary Thyroid Microcarcinoma.

BackgroundPapillary thyroid microcarcinomas (PTMCs) have been attributed to the recent increased incidence of thyroid cancer. Although indolent, a subset of PTMC could potentially develop distant metastasis (DM). This study aimed to evaluate the clinico-pathological features and molecular characteristics of PTMC and identify the risk factors for DM in PTMC patients from Middle Eastern ethnicity.MethodsWe retrospectively analyzed 210 patients with histologically confirmed PTMC. Clinico-pathological associations for DM, BRAF mutation and TERT mutation were analyzed successfully in 184 patients. Multivariate analysis was performed using Cox proportional hazards model and logistic regression analysis.ResultsAmong the PTMC patients included in this cohort, DM was noted in 6.0% (11/184), whereas tumor relapse occurred in 29/184 (15.8%). Of the 11 cases with DM, lung metastasis occurred in 8 cases, bone metastasis in 2 cases and brain metastasis in 1 case. Presence of extrathyroidal extension and male sex were significantly associated with DM. Molecular analysis showed BRAF V600E mutations to be the most frequent, being detected in 45.7% (84/184). TERT promoter mutations were detected in 16 (8.7%) cases and were significantly associated with DM and shorter metastasis-free survival in multivariate analysis.ConclusionsOur study indicates a surprisingly high frequency of TERT promoter mutation in Saudi patients with PTMC. Identifying TERT promoter mutations as an independent predictor of DM in patients with microcarcinoma could explain the inherent aggressive nature of PTMC from Middle Eastern ethnicity and magnify its role in patient risk stratification, which might help in improving therapeutic strategy for these patients.

Frequency of TERT promoter mutations in hepatocellular carcinoma

The TERT gene encodes its catalytic subunit that is essential for telomere length at the chromosome ends. The expression of TERT is highly associated with the risk of human cancers. Recurrent mutations in the promoter of the TERT gene are identified as a mechanism to activate telomerase in cancer. This study aims to determine the rate of TERT promoter mutations in hepatocellular carcinoma (HCC) tissue samples and the association between the TERT promoter mutations and some risk factors of HCC. The study was conducted on 84 patients diagnosed with HCC by pathological surgery. Gene sequencing technique was used to identify TERT promoter mutations. Results exhibited 21 samples (25%) carried TERT promoter mutation at -124C&gt;T site and no mutation at -146C&gt;T site. At the same time, there was no association between -124C&gt;T mutation and risks of HCC found in this study.

Telomerase Reverse Transcriptase Promoter Mutations in A Cohort Of Adult Gliomas - Clinicopathological Correlates.

Introduction: Gliomas were previously classified histologically, although now the latest WHO classification incorporates several molecular markers to classify these. Detection of TERT promoter mutations is assuming increased importance due to its relevance to prognostication. : The aim of this study was to determine the frequency of TERT promoter mutations, association of TERT promoter mutations with other molecular alterations and to assess the role of TERT promoter mutations in overall survival and progression-free survival in relation to histological and molecular glioma subtypes. This study analyzed a cohort of 107 adult patients with diffuse gliomas, WHO grades II and III and glioblastoma, by immunohistochemistry for IDH and ATRX mutations, FISH for 1p/19q co-deletions and PCR sequencing for TERT promoter mutation. Further, five glioma molecular sub-groups were derived using three molecular alteration and included the sub-groups with: i) IDH mutations only, ii) IDH and TERT mutations only, iii) IDH and 1p/19q co-deletion only, iv) Triple negative, and v) Triple positive. IDH mutations and 1p/19q co-deletions were individually and significantly associated with an improved progression free (P = 0.001 and P = 0.002, respectively) and overall survival (P = 0.000 and P = 0.005, respectively) in the present cohort of gliomas. TERT promoter mutations occurred frequently in anaplastic oligodendrogliomas (94%), oligodendrogliomas (87.5%) and glioblastomas (54%). Sub-division into molecular sub-groups showed that the triple-positive tumors carried the best prognosis, followed by IDH only, triple negative and finally the TERT mutation only tumors (P < 0.000). : This indicates that sub-classification using these molecular markers separates tumors into prognostically relevant categories.

The Place and Prognostic Value of TERT Promoter Mutation in Molecular Classification in Grade II-III Glial Tumors and Primary Glioblastomas.

Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class II-IV gliomas. After 2016, two mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were identified in addition to the IDH, 1p / 19q, and ATRX status. We identified 84 patients with grade II-IV glioma with IDH, ATRX, 1p / 19q and TERT status. All tumor samples were subjected to molecular genetic screening (Sanger sequencing for IDH and TERT mutations, fluorescence in situ hybridization for 1p/19q status) after histological diagnosis (immunohistochemistry for IDH1 R132H, ATRX, and p53) for a more precise molecular diagnosis. The confidence intervals were calculated at the 95% confidence level, and differences at p < 0.05 were considered statistically significant. Primary glioblastomas had the highest frequency of TERT promoter mutations (25 of 28, 89.2%, p=0.006) followed by oligodendrogliomas (29 of 35, 82.8%, p < 0.001) while astrocytomas showed the lowest frequency (3 of 15, 20%, p=0.107), and the positivity significantly differed among these three groups (p < 0.001). TERT promoter mutations were more frequent in patients older than 55 years of age at diagnosis (p=0.023). The group with TERT promoter mutations, and without IDH mutations showed the worst overall survival. However, the presence of both TERT promoter and IDH mutations, which resembled oligodendroglial progression, showed best overall survival (p=0.042). The discovery of TERT promoter mutations in numerous gliomas has opened the door for a better molecular classification of gliomas, and TERT status is associated with survival. Further studies will help in elucidating the value of TERT promoter mutations as biomarkers in clinical practice, and eventual therapeutic targets.

Significance of telomerase reverse-transcriptase promoter mutations in differentiated thyroid cancer

Background: Telomerase reverse-transcriptase (TERT) encodes the reverse transcriptase of telomerase, and TERT promoter mutations are enriched in advanced thyroid cancer. In this study, we aimed to characterize the clinicopathologic biology of differentiated thyroid cancer harboring TERT promoter mutations in Taiwan. Materials and Methods: Consecutive adult patients treated with differentiated thyroid cancer between 2017 and 2019 were included in this study. Mutational testing for the TERT promoter was performed by DNA-based polymerase chain reaction. Results: Among 389 patients included in the analysis, 22 (5.7%) had papillary or follicular thyroid cancer harboring TERT promoter mutations, including C228T (n = 18), C250T (n = 3), and CC242TT (n = 1). The frequency of BRAF V600E mutation was 73%. TERT promoter mutations were significantly associated with older age, tall cell variant of papillary thyroid cancer, extrathyroidal extension, positive surgical margins, lymphovascular invasion, perineural invasion, and distant metastasis. The generalized additive model showed that patient age was positively and almost linearly correlated with the likelihood of the presence of TERT promoter mutations. Conclusion: The frequency of TERT promoter mutations is relatively low in patients with differentiated thyroid cancer in Taiwan. These tumors carry unfavorable clinicopathologic features, present in a more advanced stage, and probably predict worse prognosis.

BRAF mutation, TERT promoter mutation, and HER2 amplification in sporadic or neurofibromatosis-related neurofibromas and malignant peripheral nerve sheath tumors: do these molecules have a signature in malignant transformation?

Peripheral nerve sheath tumors may occur sporadically or related to neurofibromatosis (NF). Unless the mechanisms of tumorigenesis in NF related malignant peripheral nerve sheath tumors (MPNST) are better understood, it remained unclear in sporadic cases. We aimed to investigate the genetic route for malignancy in both individuals with NF-1 and sporadic ones to open a way for targeted therapies in the future. We investigated the role of HER2 with Dual ISH DNA Probe Cocktail test, BRAF mutation (exon 15) and TERT promoter mutation frequency with Sanger sequencing method in respectively 25 sporadic neurofibromas, 25 NF-1 related neurofibromas and 25 MPNST cases from two institutes. Categorical data were analyzed and summarized as frequency and percentage. Statistical analysis was done with SPSS v.22 statistical package, and the statistical significance level was considered as 0.05. We identified TERT promoter mutation only in one sporadic MPNST (4%) and no BRAF mutation in any case. HER2 amplification is found in 10/25 (40%) MPNST cases. No mutations or gene amplification detected in neurofibromas (p < 0.001). MPNSTs are sarcomas with poor prognosis and limited treatment options. TERT promoter mutations and HER2 amplification may play a putative role in therapeutic purposes.

Highly prevalent BRAF V600E and low-frequency TERT promoter mutations underlie papillary thyroid carcinoma in Koreans.

BackgroundThe presence of telomerase reverse transcriptase (TERT) promoter mutations have been associated with a poor prognosis in patients with papillary thyroid carcinomas (PTC). The frequency of TERT promoter mutations varies widely depending on the population and the nature of the study.MethodsData were prospectively collected in 724 consecutive patients who underwent thyroidectomy for PTC from 2018 to 2019. Molecular testing for BRAF V600E and TERT promoter mutations was performed in all cases.ResultsTERT promoter alterations in two hotspots (C228T and C250T) and C216T were found in 16 (2.2%) and 4 (0.6%) of all PTCs, respectively. The hotspot mutations were significantly associated with older age at diagnosis, larger tumor size, extrathyroidal extension, higher pathologic T category, lateral lymph node metastasis, and higher American Thyroid Association recurrence risk. The patients with C216T variant were younger and had a lower American Thyroid Association recurrence risk than those with hotspot mutations. Concurrent BRAF V600E was found in 19 of 20 cases with TERT promoter mutations. Of 518 microcarcinomas measuring ≤1.0 cm in size, hotspot mutations and C216T variants were detected in five (1.0%) and three (0.6%) cases, respectively.ConclusionsOur study indicates a low frequency of TERT promoter mutations in Korean patients with PTC and supports previous findings that TERT promoter mutations are more common in older patients with unfavorable clinicopathologic features and BRAF V600E. TERT promoter mutations in patients with microcarcinoma are uncommon and may have a limited role in risk stratification. The C216T variant seems to have no clinicopathologic effect on PTC.

Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype.

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.

Prognostic and radiographic correlates of a prospectively collected molecularly profiled cohort of IDH1/2-wildtype astrocytomas.

In the molecular era, the relevance of tumor grade for prognostication of IDH1/2-wildtype (WT) gliomas has been debated. It has been suggested that histologic grade II and III astrocytomas with molecular features of glioblastoma, IDH1/2-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. We integrated prospective clinical sequencing from 564 patients with IDH1/2-WT gliomas (26 grade II, 71 grade III and 467 grade IV) with clinical and radiographic data to assess associations between molecular features, grade and outcome. Compared to histologic grade IV IDH1/2-WT astrocytomas, histologic grade II astrocytomas harbor fewer chromosome 7/10 alterations (P=0.04), EGFR amplifications (P=0.022) and alterations in cell-cycle effectors (P=1.9e-11), but a similar frequency of TERT promoter mutations. In contrast, there is no difference in the frequency of these canonical molecular features in histologic grade III vs. IV IDH1/2-WT disease. Progression-free (PFS) and overall survival (OS) for histologic grade II tumors were significantly longer than grade III tumors (P=0.02 and P=0.008, respectively), whereas there was no difference in PFS and OS for histologic grade III compared to grade IV tumors. Median PFS for histologic grade II, III and IV tumors was 19, 11 and 9months, respectively. Median OS for the same tumors was 44, 23 and 23months, respectively. In histologic grade II and III IDH1/2 WT tumors, gliomatosis is associated with the absence of cell-cycle alterations (P=0.008) and enriched in grade II features (P=0.1) and alterations in the PI3K-AKT pathway (P=0.09). Grade II histology has genotypic and phenotypic associations with prognostic implications in IDH1/2-WT astrocytomas.

PATH-23. PROGNOSTIC AND RADIOGRAPHIC CORRELATES OF A PROSPECTIVELY COLLECTED MOLECULARLY PROFILED COHORT OF IDH-WILDTYPE ASTROCYTOMAS

Abstract BACKGROUND In the molecular era, the relevance of tumor grade for prognostication of IDH-wildtype (WT) astrocytomas has been debated. It has been suggested that lower-grade gliomas with molecular features of glioblastoma, IDH-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. METHODS We integrated prospective clinical sequencing via the FDA-approved genomic sequencing assay MSK-IMPACT from 564 patients with IDH-WT astrocytomas (26 grade II, 71 grade III, and 467 grade IV) with clinical data. RESULTS Compared to grade III IDH-WT astrocytomas, grade II tumors harbor fewer chromosome 7/10 alterations and EGFR amplifications (p=0.07 and 0.03), but the same frequency of TERT promoter mutation. In contrast, there is no difference in the frequency of these canonical molecular features in grade III versus grade IV IDH-WT disease. Additionally, grade II astrocytomas harbor fewer cell cycle-pathway alterations than grade III tumors (p=6.9e-7). Progression-free (PFS) and overall survival (OS) for grade II astrocytomas were significantly longer than grade III tumors (p=0.02 and p=0.008, respectively), whereas there was no difference in PFS and OS for grade III compared to grade IV tumors. Median PFS for grade II vs. III vs. IV: 19 mo vs. 11 mo vs. 9 mo; median OS: 44 mo vs. 23 mo vs. 23 mo. In lower-grade IDH-WT astrocytomas, gliomatosis is associated with grade II histology (p=0.04), the absence of cell-cycle alterations (p=0.008), and more alterations in the PI3K-AKT pathway (p=0.09). CONCLUSION Histologic grade has genotypic and phenotypic associations, remains prognostically important in IDH-WT astrocytomas, and should be considered when enrolling patients to clinical trials.

TERT mRNA Expression as a Novel Prognostic Marker in Papillary Thyroid Carcinomas.

Background: Telomerase reverse transcriptase (TERT) promoter mutations have been found in a subset of papillary thyroid carcinomas (PTCs) and are associated with tumor aggressiveness and worse prognosis. However, little is known about the status of TERT mRNA expression and its relationship between TERT promoter mutations and clinicopathological features. Methods: We analyzed 159 PTC samples for TERT promoter mutations using direct DNA sequencing. TERT expression was measured using quantitative reverse transcription polymerase chain reaction. To examine low allelic frequency of TERT promoter mutations with high sensitivity, we used droplet digital polymerase chain reaction (ddPCR). The relationship between the status of the TERT promoter mutation/expression and clinicopathological features including recurrence risk was statistically analyzed. Results:TERT promoter mutations were found in 20 cases (12.6%). However, TERT expression was observed not only in the mutation-positive tumors but also in 56 of 139 (40.3%) mutation-negative tumors. Among them, we detected low allelic frequency of TERT promoter mutations in three samples (5.4%) using ddPCR. We confirmed a significant association between TERT promoter mutations and aggressive clinicopathological features in this series. The risk of recurrence of TERT mutation-negative/expression-positive tumors was significantly higher than that of the mutation-negative/expression-negative tumors, suggesting that TERT expression even in absence of a mutation confers a negative influence on PTCs. Moreover, when we reclassified the mutation-negative cases into two groups based on the TERT expression levels: expression-negative/expression levels <80th percentile and expression levels >80th percentile because minimal expression may have a negligible clinical impact, a higher hazard ratio for recurrence was observed. Interestingly, TERT expression levels in the mutation-negative PTCs were inversely correlated with patient age and the presence of BRAF mutations. Conclusions: We confirm a strong correlation between the presence of TERT promoter mutations and aggressive clinicopathological features in this PTC series. In addition, there were PTCs showing high TERT mRNA expression even in the absence of TERT promoter mutations. These cases also showed a significantly higher recurrence rate. Since the TERT promoter mutations are observed only in elderly patients, TERT mRNA expression can be a useful prognostic marker especially in younger PTC patients.

Abstract 1577: Telomerase reverse transcriptase (TERT) promoter mutations in cancers derived from multiple organ sites among Middle Eastern population

Abstract Activation of telomerase induced by telomerase reverse transcriptase (TERT) promoter mutations has been implicated in human carcinogenesis. The two mutations termed C228T and C250T in TERT promoter region have been reported in various human tumor entities with different frequencies in Western populations. However, the contribution of these mutations to cancer progression in the Middle Eastern region remains poorly understood. In this study we investigated the frequency of TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in 2113 samples from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancers (68.6%), followed by anaplastic thyroid cancers (50%), Hurthle cell carcinomas (40%), central nervous system (CNS) tumors (28.7%) and follicular thyroid cancers (19%). The low frequency of these mutations was found in medullary thyroid cancers (10%), prostate cancers (9.3%), endometrial carcinomas (3.7%), rhabdomyosarcomas (1.4%), colorectal cancers (CRC) (1%), epithelial ovarian carcinomas (EOC) (0.7%) and breast cancers (0.7%). No mutations were observed in gastric cancers, lung cancers, diffuse large B-cell lymphomas (DLBCL) and acute lymphoblastic leukemias (ALL). In CNS tumors the TERT promoter mutations were significantly associated with older age (p&amp;lt;0.0001), histological subtype (p&amp;lt;0.0001), high grade (p&amp;lt;0.0001) and poor 5 years overall survival (p&amp;lt;0.0001). In gliomas, TERT promoter mutations were more frequently present in cases with old age (p=0.003), high grade (p&amp;lt;0.0001) and poor 5 years overall survival (p&amp;lt;0.0001). Furthermore it was also revealed that co-occurrence of TERT promoter mutations and IDH1 wildtype predicted worst survival (p=0.0001) in gliomas. Our results demonstrate that mutations in TERT promoter is a frequently occurring event in several types of cancers and may be utilized for prognostic prediction in CNS tumors from Middle Eastern Region. Citation Format: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep Parvathareddy, Mark Diaz, Dionne Rala, Ingrid G. Victoria, Khadija Al-Obaisi, Wael Al-Haqawi, Nabil Siraj, Allianah Benito, Khawla S. Al-Kuraya. Telomerase reverse transcriptase (TERT) promoter mutations in cancers derived from multiple organ sites among Middle Eastern population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1577.

High frequency of H3K27M immunopositivity in adult thalamic glioblastoma.

Adult thalamic glioblastomas (GBM) are uncommon tumors with limited available molecular data. One of the reported molecular alterations in these tumors is the H3K27M mutation. It has been documented that H3K27M mutation is found in a high proportion of pediatric thalamic gliomas. In this study, we have analyzed the molecular alterations exclusive to adult thalamic GBM. This is a 6 years retrospective study of adult thalamic GBM patients who underwent surgical decompression of the tumor. Clinical data were obtained from the case records. Immunohistochemistry (IHC) was performed on the tumors using antibodies directed against the gene products of R132H mutant isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), p53, H3K27M, H3K27me3, and V600E mutant BRAF. Molecular analyses were carried out to detect other IDH1 and IDH2 mutations, O6 -methylguanine-DNA-methyltransferase gene (MGMT) promoter methylation, and epidermal growth factor gene (EGFR) and telomerase reverse transcriptase gene (TERT) promoter mutations. A total of 42 cases of adult thalamic GBM were studied. The mean age of presentation was 42 years with age range of 19-58 years. Male predominance was noted. All the tumors were IDH wild-type, BRAF (V600E)-immunonegative and unmethylated for MGMT promoter. H3K27M immunopositivity was noted in 60% of tumors. Of these 33.3% were from older adults above the age of 50 years. Of the H3K27M-immunopositive cases, ATRX loss of expression was seen in 32%, p53 immunopositivity in 24% and EGFR amplification in 12%. Higher frequency of TERT promoter mutations was noted in H3K27M-immunonegative cases (58.8%) compared to immunopositive cases (20%). Ours is one of the few studies elucidating the molecular alterations exclusive to adult thalamic GBM. We show a high frequency of H3K27M immunopositivity, suggestive of its mutational status in these tumors, including in older adults.