scholarly journals Targeted Next-Generation Sequencing Identifies Molecular and Genetic Events in Dedifferentiated Chondrosarcoma

2020 ◽  
Author(s):  
Calixto-Hope G. Lucas ◽  
James P. Grenert ◽  
Andrew Horvai
Keyword(s):  
Dna Sequencing ◽  
Copy Number ◽  
High Grade ◽  
Copy Number Alterations ◽  
Next Generation ◽  
Dedifferentiated Chondrosarcoma ◽  
Tert Promoter ◽  
Pathologic Features ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Context.— Dedifferentiated chondrosarcoma is a rare adult bone tumor with a dismal prognosis and is composed of a conventional chondrosarcoma juxtaposed to high-grade nonchondrogenic sarcoma. Dedifferentiated chondrosarcomas may represent tumor progression from a differentiated to a primitive histotype. Objective.— To determine the genetic and molecular events that drive progression from a conventional chondrosarcoma to high grade nonchondrogenic sarcoma. Design.— We analyzed the genomic landscape of paired conventional and dedifferentiated components of 11 dedifferentiated chondrosarcoma using targeted next-generation DNA sequencing with immunohistochemical validation. Clinical, radiographic, and pathologic features of tumors were reviewed. Capture-based DNA sequencing targeting the coding regions of 479 cancer genes and select introns was performed. Results.— The tumors arose in the femur (n = 4; 36%), scapula (n = 3; 27%), pelvis (n = 3; 27%), and humerus (n = 1; 9%) of 7 men (64%) and 4 women (36%; median age, 61 years). DNA was adequate for sequencing from all 11 dedifferentiated components (100%) and 9 paired conventional chondrosarcoma components (82%). All tumors (100%) harbored either IDH1 p.R132 or IDH2 p.R172S hotspot mutations. Seven tumors (64%) displayed COL2A1 alterations. TERT promoter mutations were present in 5 of 9 pairs (56%) and 2 (22%) additional unpaired dedifferentiated components. IDH1/2, COL2A1, and TERT mutations were identical in both components of the paired samples. Pathogenic missense or truncating mutations in TP53 and large-scale copy number alterations were more common in dedifferentiated components than in those of matched conventional components. Conclusions.— The results support IDH1/2, COL2A1, and TERT promoter mutations being common in dedifferentiated chondrosarcoma and as likely early events in progression, whereas inactivating mutation of TP53 and high-level copy number alterations may be later events in the dedifferentiated phenotype.

Comparison of genomic alterations in bladder urothelial tumors with and without telomerase reverse transcriptase promoter mutation using a next-generation sequencing assay.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 310-310 ◽  
Author(s):  
Sumit Isharwal ◽  
Francois Audenet ◽  
Eugene J. Pietzak ◽  
Eugene K. Cha ◽  
Gopa Iyer ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Copy Number ◽  
Promoter Region ◽  
Telomerase Reverse Transcriptase ◽  
Copy Number Alterations ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Urothelial Tumors ◽  
Altered Gene ◽  
Promoter Mutations

310 Background: Telomerase reverse transcriptase (TERT) is the most frequently altered gene in urothelial cancer (UC), detected across all grades and stages of disease. We sought to characterize TERT alterations within a prospective cohort of UC treated at our institute and compare the frequency of genomic alterations in TERT promoter mutant vs wild-type UC specimens. Methods: Patients diagnosed with bladder urothelial tumors were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed for somatic point mutations, truncations, copy number alterations, and insertions/deletions using the MSK-IMPACT NGS assay that detects alterations in all exons and select introns of 410 oncogenes and tumor suppressor genes as well as the entire TERT promoter region. Results: 329 UC were sequenced of which 236 (71.7%) harbored TERT mutations, the majority being promoter region hotspots (chr5: 1295228 G > A [81%] and chr5:1295250 G > A [16%]). Patients with TERT promoter mutations were significantly older than those without (69.01±10.70 years vs. 65.44±11.78 years, p = 0.0317). UC with TERT promoter mutations had significantly higher mutation count [median 10 (range: 2-76) vs median 5 (range: 0-119)] as well as copy number alterations [median 0.11 (range: 0-0.68) vs median 0.047 (range: 0-0.65)]. Between UC with and without TERT promoter mutations, there was a very significant difference in mutation frequencies of ARID1A(33% vs 11%), PIK3CA(28% vs 13%), FGFR3(32% vs 16%), CREBBP(19% vs 4%), CDKN1A(17% vs 2%), ERBB2(26% vs 9%), ERCC2(15% vs 3%), TSC1(11% vs 0%), MT2C(17% vs 9%) (all with p < 0.005). Conclusions: TERT is the most frequently altered gene in bladder cancer with the majority of TERT alterations comprised of two hotspot mutations. UC with TERT promoter mutations tends to occur in older patients and is associated with overall higher mutation count and copy number alterations. A number of genes are differentially mutated in UC with and without TERT promoter mutations and may suggest a link between TERT promoter mutations and distinct mutations profiles in UC.

PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi124-vi124
Author(s):  
Danielle Golub ◽  
Peter C Pan ◽  
Benjamin Liechty ◽  
Cheyanne Slocum ◽  
Tejus Bale ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
High Grade Glioma ◽  
Proliferation Index ◽  
Molecular Profile ◽  
Low Grade ◽  
High Grade ◽  
Molecular Features ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.

scholarly journals The genetic landscape of choroid plexus tumors in children and adults

2020 ◽  
Author(s):  
Christian Thomas ◽  
Patrick Soschinski ◽  
Melissa Zwaig ◽  
Spyridon Oikonomopoulos ◽  
Konstantin Okonechnikov ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Rna Sequencing ◽  
Copy Number ◽  
Clinical Course ◽  
Copy Number Alterations ◽  
Choroid Plexus Tumors ◽  
Tp53 Mutations ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Choroid Plexus Papillomas

Abstract Background Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs). Methods DNA methylation profiling and RNA-sequencing was performed in a series of 47 CPTs. Samples comprised 35 choroid plexus papillomas (CPPs), 6 atypical choroid plexus papillomas (aCPPs) and 6 CPCs plus three recurrences thereof. Targeted TP53 and TERT promotor sequencing was performed in all samples. Whole exome sequencing (WES) and linked-read whole genome sequencing (WGS) was performed in 25 and 4 samples, respectively. Results Tumors comprised the molecular subgroups “pediatric A” (N=11), “pediatric B” (N=12) and “adult” (N=27). Copy-number alterations mainly represented whole-chromosomal alterations with subgroup-specific enrichments (gains of Chr1, 2 and 21q in “pediatric B” and gains of Chr5 and 9 and loss of Chr21q in “adult”). RNA sequencing yielded a novel CCDC47-PRKCA fusion transcript in one adult choroid plexus papilloma patient with aggressive clinical course; an underlying Chr17 inversion was demonstrated by linked-read WGS. WES and targeted sequencing showed TP53 mutations in 7/47 CPTs (15%), five of which were children. On the contrary, TERT promoter mutations were encountered in 7/28 adult patients (25%) and associated with shorter progression-free survival (log-rank test, p=0.015). Conclusion Pediatric CPTs lack recurrent driver alterations except for TP53, whereas CPTs in adults show TERT promoter mutations or a novel CCDC47-PRKCA gene fusion, being associated with a more unfavorable clinical course.

scholarly journals Noninvasive Prediction of TERT Promoter Mutations in High-Grade Glioma by Radiomics Analysis Based on Multiparameter MRI

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Hongan Tian ◽  
Hui Wu ◽  
Guangyao Wu ◽  
Guobin Xu
Keyword(s):  
High Grade Glioma ◽  
High Grade ◽  
Lasso Regression ◽  
Decision Curve Analysis ◽  
Clinical Evaluations ◽  
Net Reclassification Improvement ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Integrated Discrimination Improvement

Objectives. To investigate the predictors of telomerase reverse transcriptase (TERT) promoter mutations in adults suffered from high-grade glioma (HGG) through radiomics analysis, develop a noninvasive approach to evaluate TERT promoter mutations. Methods. 126 adult patients with HGG (88 in the training cohort and 38 in the validation cohort) were retrospectively enrolled. Totally 5064 radiomics features were, respectively, extracted from three VOIs (necrosis, enhanced, and edema) in MRI. Firstly, an optimal radiomics signature (Radscore) was established based on LASSO regression. Secondly, univariate and multivariate logistic regression analyses were performed to investigate important potential variables as predictors of TERT promoter mutations. Besides, multiparameter models were established and evaluated. Eventually, an optimal model was visualized as radiomics nomogram for clinical evaluations. Results. 6 radiomics features were selected to build Radscore signature through LASSO regression. Among them, 5 were from necrotic VOIs and 1 was from enhanced ones. With univariate and multivariate analysis, necrotic volume percentages of core (CNV), Age, Cho/Cr, Lac, and Radscore were significantly higher in TERTm than in TERTw (p<0.05). 4 models were built in our study. Compared with Model B (Age, Cho/Cr, Lac, and Radscore), Model A (Age, Cho/Cr, Lac, Radscore, and CNV) has a larger AUC in both training (0.955 vs. 0.917, p=0.049) and validation (0.889 vs. 0.868, p=0.039) cohorts. It also has higher performances in net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA) evaluation. Conclusively, Model A was visualized as a radiomics nomogram. Calibration curve shows a good agreement between estimated and actual probabilities. Conclusions. Age, Cho/Cr, Lac, CNV, and Radscore are important indicators for TERT promoter mutation predictions in HGG. Tumor necrosis seems to be closely related to TERT promoter mutations. Radiomics nomogram based on multiparameter MRI and CNV has higher prediction accuracies.

Prognostic significance of TERT promoter mutations in follicular cell-derived thyroid carcinomas

2014 ◽  
Author(s):  
Miguel Melo ◽  
Rocha Adriana Gaspar da ◽  
Joao Vinagre ◽  
Rui Batista ◽  
Joana Peixoto ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Follicular Cell ◽  
Thyroid Carcinomas ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

In papillary thyroid cancer TERT promoter mutations have a worst impact on outcome than BRAF mutations

2015 ◽  
Author(s):  
Marina Muzza ◽  
Carla Colombo ◽  
Maria Carla Proverbio ◽  
Stefania Rossi ◽  
Delfina Tosi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Papillary Thyroid ◽  
Braf Mutations ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals Human TERT promoter mutations as a prognostic biomarker in glioma

2021 ◽  
Vol 147 (4) ◽  
pp. 1007-1017
Author(s):  
Branka Powter ◽  
Sarah A. Jeffreys ◽  
Heena Sareen ◽  
Adam Cooper ◽  
Daniel Brungs ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Nucleotide Polymorphism ◽  
Liquid Biopsies ◽  
Single Nucleotide ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Potential Clinical Utility ◽  
Promoter Mutations ◽  
The Relationship ◽  
Potential Use

AbstractThe TERT promoter (pTERT) mutations, C228T and C250T, play a significant role in malignant transformation by telomerase activation, oncogenesis and immortalisation of cells. C228T and C250T are emerging as important biomarkers in many cancers including glioblastoma multiforme (GBM), where the prevalence of these mutations is as high as 80%. Additionally, the rs2853669 single nucleotide polymorphism (SNP) may cooperate with these pTERT mutations in modulating progression and overall survival in GBM. Using liquid biopsies, pTERT mutations, C228T and C250T, and other clinically relevant biomarkers can be easily detected with high precision and sensitivity, facilitating longitudinal analysis throughout therapy and aid in cancer patient management.In this review, we explore the potential for pTERT mutation analysis, via liquid biopsy, for its potential use in personalised cancer therapy. We evaluate the relationship between pTERT mutations and other biomarkers as well as their potential clinical utility in early detection, prognostication, monitoring of cancer progress, with the main focus being on brain cancer.

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