OS02.6.A The TeloDIAG: How telomeric parameters can help in glioma rapid diagnosis and liquid biopsies approaches

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii5-ii6
Author(s):  
P Billard ◽  
C Guerriau ◽  
C Carpentier ◽  
F Juillard ◽  
N Grandin ◽  
...  
Keyword(s):  
Telomere Maintenance ◽  
Molecular Characteristics ◽  
Low Grade ◽  
New Classification ◽  
Liquid Biopsies ◽  
Efficient Tool ◽  
Isocitrate Dehydrogenase 1 ◽  
Mutational Status ◽  
Alternative Lengthening

Abstract BACKGROUND The integration of molecular markers into the WHO 2016 classification has clarified the complex diagnosis of gliomas. Among these biomarkers, the TERT promoter mutation and the loss of ATRX (ATRX loss) are mutually exclusive alterations associated with re-activation of telomerase or alternative lengthening of telomeres (ALT), respectively. Strangely, 25% of gliomas display neither or both these alterations, a situation referred to as abnormal telomere maintenance mechanism (aTMM). MATERIAL AND METHODS To investigate the TMM actually involved in gliomas, the C-circle (CC) assay was adapted to tumor (FFPE and frozen) samples. RESULTS We constructed a CC-based algorithm able to identify the TMM of 284 gliomas with either TERT or ATRX alteration, with a sensitivity of 100% and a specificity of 97.3%, and succeeded in deciphering the TMM involved in 122 aTMM gliomas. Additionally, the combination of the TMM, the mutational status of the Isocitrate dehydrogenase 1/2 (IDH) gene, and the histological grading was used as base for a new classification: TeloDIAG. Six subtypes are defined in this classification: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma, respectively, the last class gathers ALT+ IDHwt glioma. The TeloDIAG diagnosis is 99% concordant with the WHO classification for glioma displaying typical molecular characteristics (N=312). It modified the classification of 38% (N=156) discordant tumors, such as IDHwt Astrocytoma, aTMM tumors, or gliomas with unexpected TMM (e.g. TERTwt oligodendroglioma, ATRX loss GBM). Interestingly, 20% (N=69) of TERTwt, ATRXwt, or IDHwt GBM were actually tAIV, which is remarkable as tAIV-glioma patients’ survival tended to be longer (21.2 months) than tGBM patients’ survival (16.5 months). Importantly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 95% (N = 206). CONCLUSION In sum, the TeloDIAG is a new, simple, and efficient tool helping in glioma diagnosis and a promising option for liquid biopsy

scholarly journals Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

2020 ◽  
Vol 147 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Monica Sofia Ventura Ferreira ◽  
Mia Dahl Sørensen ◽  
Stefan Pusch ◽  
Dagmar Beier ◽  
Anne-Sophie Bouillon ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Isocitrate Dehydrogenase 1 ◽  
Maintenance Mechanism ◽  
Alternative Lengthening

scholarly journals Molecular Classification of Diffuse Gliomas

2020 ◽  
Vol 47 (4) ◽  
pp. 464-473
Author(s):  
Navya Kalidindi ◽  
Rosemarylin Or ◽  
Sam Babak ◽  
Warren Mason
Keyword(s):  
Dna Methylation ◽  
Molecular Markers ◽  
World Health ◽  
Low Grade ◽  
Diffuse Glioma ◽  
Isocitrate Dehydrogenase 1 ◽  
Anaplastic Gliomas ◽  
Diffuse Gliomas ◽  
The Impact

ABSTRACT:Technological advances in the field of molecular genetics have improved the ability to classify brain tumors into subgroups with distinct clinical features and important therapeutic implications. The World Health Organization’s newest update on classification of gliomas (2016) incorporated isocitrate dehydrogenase 1 and 2 mutations, ATRX loss, 1p/19q codeletion status, and TP53 mutations to allow for improved classification of glioblastomas, low-grade and anaplastic gliomas. This paper reviews current advances in the understanding of diffuse glioma classification and the impact of molecular markers and DNA methylation studies on survival of patients with these tumors. We also discuss whether the classification and grading of diffuse gliomas should be based on histological findings, molecular markers, or DNA methylation subgroups in future iterations of the classification system.

scholarly journals Gastric epithelial neoplasm of fundic-gland mucosa lineage: proposal for a new classification in association with gastric adenocarcinoma of fundic-gland type

2021 ◽  
Author(s):  
Hiroya Ueyama ◽  
Takashi Yao ◽  
Yoichi Akazawa ◽  
Takuo Hayashi ◽  
Koichi Kurahara ◽  
...  
Keyword(s):  
Gastric Adenocarcinoma ◽  
Clinicopathological Features ◽  
Low Grade ◽  
Fundic Gland ◽  
New Classification ◽  
Histopathological Classification ◽  
Gland Type ◽  
Epithelial Neoplasm

Abstract Background Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. Methods One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. Results GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. Conclusions We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.

scholarly journals Update on Endometrial Stromal Tumours of the Uterus

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 429
Author(s):  
Iolia Akaev ◽  
Chit Cheng Yeoh ◽  
Siavash Rahimi
Keyword(s):  
Late Recurrence ◽  
Malignant Potential ◽  
Molecular Techniques ◽  
Molecular Characteristics ◽  
Low Grade ◽  
High Grade ◽  
Endometrial Stromal Cells ◽  
Molecular Features ◽  
Therapeutic Decisions

Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories according to the mitotic count. In the most recent classification by the WHO (2020), ESTs have been divided into four categories: Endometrial Stromal Nodules (ESNs), Low-Grade Endometrial Stromal Sarcomas (LG-ESSs), High-Grade Endometrial Stromal Sarcomas (HG-ESSs) and Undifferentiated Uterine Sarcomas (UUSs). ESNs are clinically benign. LG-ESSs are tumours of low malignant potential, often with indolent clinical behaviour, with some cases presented with a late recurrence after hysterectomy. HG-ESSs are tumours of high malignant potential with more aggressive clinical outcome. UUSs show high-grade morphological features with very aggressive clinical behavior. With the advent of molecular techniques, the morphological classification of ESTs can be integrated with molecular findings in enhanced classification of these tumours. In the future, the morphological and immunohistochemical features correlated with molecular categorisation of ESTs, will become a robust means to plan therapeutic decisions, especially in recurrences and metastatic disease. In this review, we summarise the morphological, immunohistochemical and molecular features of ESTs with particular reference to the most recent molecular findings.

scholarly journals The Evaluation of AREG, MMP-2, CHI3L1, GFAP, and OPN Serum Combined Value in Astrocytic Glioma Patients’ Diagnosis and Prognosis

2020 ◽  
Vol 10 (11) ◽  
pp. 872
Author(s):  
Rūta Urbanavičiūtė ◽  
Kęstutis Skauminas ◽  
Daina Skiriutė
Keyword(s):  
Overall Survival ◽  
Protein Level ◽  
Matrix Metalloproteinase 2 ◽  
Secretory Proteins ◽  
Survival Prediction ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Diagnosis And Prognosis ◽  
Specificity And Sensitivity ◽  
Mutational Status

Gliomas account for approximately 70% of primary brain tumors in adults. Of all gliomas, grade IV astrocytoma, also called glioblastoma, has the poorest overall survival, with <5% of patients surviving five years after diagnosis. Due to the aggressiveness, lethal nature, and impaired surgical accessibility of the tumor, early diagnosis of the tumor and, in addition, prediction of the patient’s survival time are important. We hypothesize that combining the protein level values of highly recognizable glioblastoma serum biomarkers could help to achieve higher specificity and sensitivity in predicting glioma patient outcome as compared to single markers. The aim of this study was to select the most promising astrocytoma patient overall survival prediction variables from five secretory proteins—glial fibrillary acidic protein (GFAP), matrix metalloproteinase-2 (MMP-2), chitinase 3-like 1 (CHI3L1), osteopontin (OPN), and amphiregulin (AREG)—combining them with routinely used tumor markers to create a Patient Survival Score calculation tool. The study group consisted of 70 astrocytoma patients and 31 healthy controls. We demonstrated that integrating serum CHI3L1 and OPN protein level values and tumor isocitrate dehydrogenase 1 IDH1 mutational status into one parameter could predict low-grade astrocytoma patients’ two-year survival with 93.8% accuracy.

scholarly journals New classification of low-grade lymphoma

1996 ◽  
Vol 7 ◽  
pp. S3-S12 ◽  
Author(s):  
T.M. Grogan
Keyword(s):  
Low Grade ◽  
New Classification

scholarly journals Non-invasive assessment of telomere maintenance mechanisms in brain tumors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pavithra Viswanath ◽  
Georgios Batsios ◽  
Joydeep Mukherjee ◽  
Anne Marie Gillespie ◽  
Peder E. Z. Larson ◽  
...  
Keyword(s):  
Genetically Engineered ◽  
Telomere Maintenance ◽  
Imaging Biomarker ◽  
Response Monitoring ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Non Invasive ◽  
Alternative Lengthening ◽  
Metabolic Biomarkers ◽  
Tert Expression

AbstractTelomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-13C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-13C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.

scholarly journals High-frequency oscillations in awake patients undergoing brain tumor-related epilepsy surgery

Neurology ◽  
2018 ◽  
Vol 90 (13) ◽  
pp. e1119-e1125 ◽  
Author(s):  
Anteneh M. Feyissa ◽  
Gregory A. Worrell ◽  
William O. Tatum ◽  
Deependra Mahato ◽  
Benjamin H. Brinkmann ◽  
...  
Keyword(s):  
Brain Tumor ◽  
High Frequency ◽  
Idh1 Mutation ◽  
World Health ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Mutant Genotype ◽  
High Frequency Oscillations ◽  
Mutational Status

ObjectiveTo examine the relationship between high-frequency oscillations (HFOs) and the presence of preoperative seizures, World Health Organization tumor grade, and isocitrate dehydrogenase 1 (IDH1) mutational status in gliomas.MethodsWe retrospectively studied intraoperative electrocorticography recorded in 16 patients with brain tumor (12 presenting with seizures) who underwent awake craniotomy and surgical resection between September 2016 and June 2017. The number and distribution of HFOs were determined and quantified visually and with an automated HFO detector.ResultsFive patients had low-grade (1 with grade I and 4 with grade II) and 11 had high-grade (6 with grade III and 5 with grade IV) brain tumors. An IDH1 mutation was found in 6 patients. Patients with a history of preoperative seizures were more likely to have HFOs than those without preoperative seizures (9 of 12 vs 0 of 4, p = 0.02). The rate of HFOs was higher in patients with IDH1 mutant (mean 7.2 per minute) than IDH wild-type (mean 2.3 per minute) genotype (p = 0.03).ConclusionsHFOs are common in brain tumor-related epilepsy, and HFO rate may be a useful measure of epileptogenicity in gliomas. Our findings further support the notion that IDH1 mutant genotype is more epileptogenic than IDH1 wild-type genotype gliomas.

scholarly journals Prognostic value of mutations in isocitrate dehydrogenase 1 (IDH1) and reverse telomerase transcriptase (TERT) in Argentine patients` gliomas

2021 ◽  
Vol 46 (1) ◽  
pp. 12-19
Author(s):  
Pedro Tomás Funes ◽  
Daniela Moggia ◽  
Diana Lidia Parma ◽  
Marcela Ferrer ◽  
Florencia Giliberto ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pcr Amplification ◽  
Histopathological Analysis ◽  
Low Grade ◽  
High Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Low Grade Gliomas ◽  
Mutational Status ◽  
Idh1 Mutations ◽  
High Grade Gliomas

Background and aim: Gliomas are the most common primary brain tumors, and they are classified according to their histopathological and genetic features. Tumorigenesis depends on alterations in different genes. The aim of this study was to identify mutations in IDH1 and TERT genes in gliomas of Argentine patients and to correlate them with clinical features. Methods. DNA was isolated from 19 biopsies with different glioma grades matched with blood samples. IDH1 and TERT mutations were identified by PCR amplification and sequencing. Results. Six out of seven patients with low-grade glioma (grade II) harbor IDH1 mutations, mainly without tumor growth and an overall survival of more than 12 months. Eleven out of twelve patients with high-grade gliomas (grade III/IV) showed wild type IDH1, mainly with tumor growth and shorter survival than low-grade gliomas. Mutated TERT promoter was present in 5 out of 11 high-grade gliomas, showing the prevalence of polymorphic C allele, whereas, low-grade gliomas showed mutated TERT in 1 out of 5 gliomas and a predominance of T allele. TERT and IDH1 mutations were mutually exclusive in most gliomas. Conclusions: Our results show that genetic tests provided more accurate diagnosis than histopathological analysis. Evolution of gliomas can be predicted primarily by the mutational status of IDH1 and secondarily by other markers, such as TERT mutational status, and the patient´s age.

NIMG-50. DEUTERIUM METABOLIC IMAGING OF THE ALTERNATIVE LENGTHENING OF TELOMERES PATHWAY REPORTS ON TUMOR BURDEN AND PSEUDOPROGRESSION IN LOW-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi140-vi140
Author(s):  
Céline Taglang ◽  
Georgios Batsios ◽  
Joydeep Mukherjee ◽  
Meryssa Tran ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Tumor Burden ◽  
Telomere Maintenance ◽  
Metabolic Imaging ◽  
Glycolytic Flux ◽  
Low Grade ◽  
Non Invasive ◽  
Glucose Flux ◽  
Alternative Lengthening

Abstract Glioma patient management relies heavily on magnetic resonance imaging (MRI). However, MRI is often inadequate for assessment of tumor burden and pseudoprogression. Non-invasive methods that report on molecular pathways such as telomere maintenance that drive tumor proliferation are needed. Among brain tumors, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. The goal of this study was to identify ALT-linked metabolic alterations that can be exploited for non-invasive magnetic resonance spectroscopy (MRS)-based imaging of LGAs. We examined the patient-derived BT257 model and compared neurospheres that are ALT-dependent (BT257 ALT+) with those in which the ALT pathway has been silenced (BT257 ALT-). Our studies suggest that expression and activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 are significantly higher in BT257 ALT+ neurospheres relative to ALT-, an effect that is associated with elevated glucose flux to lactate. Studies indicate that poly(ADP-ribose) polymerase inhibitors such as niraparib selectively induce telomeric fusion and cell death in ALT-dependent cells. We find that the telomeric fusion-mediated cytotoxicity of niraparib is associated with significantly reduced glycolytic flux in BT257 ALT+ neurospheres. We then examined whether 2H-MRS using [6,6’-2H]-glucose, which is a clinically translatable method of imaging glycolytic flux, can be used to monitor the ALT pathway in vivo. [6,6’-2H]-glucose flux to lactate is elevated in tumor relative to normal brain in mice bearing orthotopic BT257 tumors. Importantly, following treatment of BT257 tumor-bearing mice with niraparib, lactate production from [6,6’-2H]-glucose is significantly reduced at early timepoints when alterations in tumor volume cannot be observed by MRI, pointing to the ability of [6,6’-2H]-glucose to report on pseudoprogression in vivo. Collectively, our studies mechanistically link the ALT pathway with elevated glycolytic flux via phosphofructokinase-1 and identify deuterium metabolic imaging as a novel, non-invasive method of imaging tumor burden and treatment response in LGAs in vivo.

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