Analysis of genetic aberrations in pediatric high-grade gliomas

Background. High-grade gliomas are characterized by a wide range of genetic abnormalities. The heterogeneous genomic landscape of pediatric high-grade gliomas allows identifying distinct subgroups of the disease in children and young adults. Most importantly, these subgroups differ by clinical course and prognosis, as well as treatment response to standard therapy.Objective: to assess the profile of molecular genetic markers of high-grade gliomas in children.Materials and methods. In the current study, we examine the frequency of H3F3A, Hist1H3B, BRAF, IDH1 / 2 mutations, the copy number alterations of CDKN2A / 2B genes and the expression of ETV6‑NTRK3 fusion gene in a cohort of 53 pediatric high-grade gliomas.Results. Driver mutations and CDKN2A / 2B deletions were observed in 24 (45 %) and 15 (28 %) of 53 tumors, respectively. Overall, the studied high-grade gliomas harbored 41 genetic aberrations including 24 (58.5 %) somatic missense mutations, 1 (2.4 %) genetic variant of unknown clinical significance, 1 (2.4 %) oncogenic fusion gene and 15 (36.6 %) deletions of the tumor suppressor genes.Conclusion. These findings point to the importance of molecular profiling of tumors for the optimal clinical care and development of new approaches to treatment aimed at molecular targets for personalized anticancer therapies.

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GENE-01. TUMOR MUTATION BURDEN AND DRIVER MUTATIONS: FURTHER INSIGHT INTO THE GENOMIC LANDSCAPE OF PEDIATRIC HIGH GRADE GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/nox083.072 ◽

2017 ◽

Vol 19 (suppl_4) ◽

pp. iv18-iv18 ◽

Cited By ~ 1

Author(s):

Lauren Weintraub ◽

Vikramjit Kanwar ◽

Jeffrey Ross

Keyword(s):

Driver Mutations ◽

High Grade ◽

Tumor Mutation Burden ◽

Genomic Landscape ◽

Mutation Burden ◽

High Grade Gliomas ◽

Insight Into

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Altered Expression of MGMT in High-Grade Gliomas Results from the Combined Effect of Epigenetic and Genetic Aberrations

PLoS ONE ◽

10.1371/journal.pone.0058206 ◽

2013 ◽

Vol 8 (3) ◽

pp. e58206 ◽

Cited By ~ 25

Author(s):

João Ramalho-Carvalho ◽

Malini Pires ◽

Susana Lisboa ◽

Inês Graça ◽

Patrícia Rocha ◽

...

Keyword(s):

Combined Effect ◽

High Grade ◽

Altered Expression ◽

Genetic Aberrations ◽

High Grade Gliomas

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GENETIC POLYMORPHISM OF RETROPERITONEAL MYXOID LIPOSARCOMA

Siberian Journal of Oncology ◽

10.21294/1814-4861-2020-19-3-89-96 ◽

2020 ◽

Vol 19 (3) ◽

pp. 89-96

Author(s):

A. Yu. Volkov ◽

V. M. Safronova ◽

S. N. Nered ◽

L. N. Lyubchenko ◽

I. S. Stilidi

Keyword(s):

Molecular Genetic ◽

Myxoid Liposarcoma ◽

Molecular Genetic Analysis ◽

Term Treatment ◽

Missense Mutations ◽

Synonymous Mutations ◽

Erbb2 Gene ◽

Long Term Treatment ◽

Wide Range ◽

Next Generation Sequencing Ngs

Objective: to detect new molecular genetic markers and therapeutic targets in retroperitoneal myxoid liposarcoma.Material and Methods. DNA samples isolated from tumor tissue and obtained from formalinfixed paraffin-embedded (FFPE) slides were used. DNA was extracted using the GeneRead DNA FFPE Kit (50) (Qiagen). High-throughput next generation sequencing (NGS) using the GeneReader Actionable Insights Tumor Panel (GRTP – 101X) on the QCI Analyzer version 1.1 platform (Qiagen) was used for molecular genetic analysis of 12 genes involved in carcinogenesis: KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, RAF1.Results. Targeted sequencing of retroperitoneal extra-organ myxoid liposarcoma demonstrated genetic heterogeneity. Our study was the first to describe mutations and polymorphic variants in genes, such as EGFR, PIK3CA, ALK, BRAF, ERBB2 / 3, ESR1, KIT, PDGFRA in myxoid liposarcoma.Conclusion. This study demonstrated a wide range of molecular genetic rearrangements in retroperitoneal extra-organ myxoid liposarcoma. Synonymous mutations in the EGFR (Q787Q) and PDGFRA (P567P) genes were detected in all cases (100 %). Missense mutations in the ERBB2 gene (P1170A) and synonymous mutations in the ALK (G845G) and BRAF genes were identified in 75 % of cases. Missense mutation in the PIK3CA gene (I391M) was detected in 25 % of cases. The gene polymorphisms presented in this paper are most likely involved in the carcinogenesis of retroperitoneal myxoid liposarcoma. Further studies with larger patient groups and multivariate analysis of long-term treatment results are required.

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Leukemia- and lymphoma-associated flow cytometric, cytogenetic, and molecular genetic aberrations in healthy individuals

Orvosi Hetilap ◽

10.1556/oh.2012.29334 ◽

2012 ◽

Vol 153 (14) ◽

pp. 531-540

Author(s):

János Jakó ◽

László Szerafin

Keyword(s):

B Cell ◽

Fusion Gene ◽

Molecular Genetic ◽

Jak2 V617f ◽

Chromosomal Translocations ◽

Jak2 V617f Mutation ◽

Healthy Individuals ◽

Specific Flow ◽

Genetic Aberrations ◽

Flow Cytometric

Most leukemia and lymphoma cases are characterized by specific flow cytometric, cytogenetic and molecular genetic aberrations, which can also be detected in healthy individuals in some cases. The authors review the literature concerning monoclonal B-cell lymphocytosis, and the occurrence of chromosomal translocations t(14;18) and t(11;14), NPM-ALK fusion gene, JAK2 V617F mutation, BCR-ABL1 fusion gene, ETV6-RUNX1(TEL-AML1), MLL-AF4 and PML-RARA fusion gene in healthy individuals. At present, we do not know the importance of these aberrations. From the authors review it is evident that this phenomenon has both theoretical and practical (diagnostic, prognostic, and therapeutic) significance. Orv. Hetil., 2012, 153, 531–540.

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PDTM-11. GAINING INSIGHTS INTO THE INFLAMMATORY MICROENVIRONMENT OF PEDIATRIC HIGH-GRADE GLIOMAS USING GEMMs AND PATIENT SAMPLES

Neuro-Oncology ◽

10.1093/neuonc/noz175.787 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi189-vi189

Author(s):

James Ross ◽

Zhihong Chen ◽

Cameron Herting ◽

Frank Szulzewsky ◽

Oren Becher ◽

...

Keyword(s):

Immune Cell ◽

Cell Mass ◽

Driver Mutations ◽

Specific Gene ◽

High Grade ◽

Human Patient ◽

Inflammatory Microenvironment ◽

Inflammatory Monocytes ◽

High Grade Gliomas

Abstract Pediatric high-grade gliomas (pHGG) account for the most cancer-related deaths in children, as there are no effective therapies available. It is known tumor associated macrophages (TAM) can make up 30–40% of the total tumor cell mass in adult high-grade gliomas, promoting tumor growth and immune evasion. This raises the question of whether pHGGs possess a distinct constituency of TAMs due to their unique genetic and epigenetic landscapes. To uncover the composition and behavior of TAMs in pHGG we utilize RCAS/tva, a somatic cell-type specific gene transfer system which allows us to recapitulate all major subtypes of pHGG in newborn immunocompetent mice, including histone wild-type and histone-mutant tumors. We combine RCAS-H3.3K27M, RCAS-H3.3G34R/V, or RCAS-H3.3WT along with their driver mutations such as RCAS-shp53 and RCAS-PDGFA or RCAS-PDGFB. These tumors are induced in Nestin-positive cells, each in their respective locations found in the human population. Tumors driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumors and have increased infiltration of lymphocytes and TAMs, specifically inflammatory monocytes. In vitro bone marrow derived monocyte and microglial cultures demonstrate the BMDM population is most responsible for the production of inflammatory chemokines and angiogenic factors in the tumor microenvironment. We performed histological analyses on over 40 human patient samples to determine the role of the stromal population in TAM infiltration. Matched human samples were also utilized for pan-cancer immune profiling with NanoString to further characterize the innate and adaptive immune microenvironments. These analyses indicate DIPG/K27M tumors have a higher immune cell infiltrate compared to G34R/V and histone wildtype tumors. Further, we observe higher infiltration of T-cell populations in pHGGs compared to adult HGGs, suggesting these tumors may be amenable to immunotherapy despite being considered “immune cold.” These studies provide the critical foundation needed for the development of novel therapeutics targeting these tumors.

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PATH-10. PROGNOSTIC RELEVANT IMMUNOPHENOTYPES OF PEDIATRIC HIGH-GRADE NON-BRAINSTEM GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.646 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii426-iii426

Author(s):

Taisiya Mikhaleuskaya ◽

Natalya Konoplya ◽

Alena Valochnik

Keyword(s):

Parietal Lobe ◽

Adult Population ◽

Braf V600e ◽

Biological Behavior ◽

Prognostic Impact ◽

High Grade ◽

Neuronal Markers ◽

Wide Range ◽

Cdkn2a Deletion ◽

High Grade Gliomas

Abstract Pediatric diffuse astrocytomas comprise a wide range of malignancies with variable prognosis. The 4th grading system used now not always correctly characterizes the biological behavior of these tumors. We collected 24 pediatric supratentorial non-brainstem high grade glioma cases. Patient age ranged from 1 to 18 years old (median 11y). Main tumor locations were as follows: parietal lobe 8 cases; temporal lobe, 10 cases; frontal lobe, 3 cases; occipital lobe 3 cases. Eight of them were totally removed. All patients were treated with standard CT and RT. The main objective was to assess the prognostic impact of histopathological and molecular criteria on progression-free(PFS) and overall survival (OS) of high grade gliomas. The following criteria were analyzed: IDH1 R132H, BRAF V600E expression, ALT-phenotype, CDKN2A deletion, 1p/19q co-deletion, glial and neuronal markers expression. RESULTS: IDHR132H mutation was identified in 3 cases. 4 cases carried BRAFV600E mutation with CDKN2A deletion and displayed PXA phenotype. 5 cases showed undifferentiated glial morphology and ALT–phenotype. Also there was a group of tumors without any of the above mentioned genetic changes. Interestingly 3 of them were post radiation tumors. Statistical analysis showed that low OS correlated with ALT-phenotype(p-0.015), absence of neuronal markers expression and absence of molecular changes (p-0.03). Mutation of IDH1R132H was a favorable prognostic factor as in the adult population. PFS was affected only by the presence of neuronal expression (p-0.015). Employing immunohistochemical analysis with surrogate molecular markers in complex with FISH can provide additional prognostic information in case of pediatric high grade gliomas.

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FBN1 Mutation Screening in a Marfan Syndrome Patient

Medica Hospitalia : Journal of Clinical Medicine ◽

10.36408/mhjcm.v3i1.211 ◽

2017 ◽

Vol 3 (1) ◽

Author(s):

Amallia Setyawati ◽

Nani Maharani ◽

Sultana Faradz ◽

Gerard Pals ◽

Sodiqur Rifqi ◽

...

Keyword(s):

Disulfide Bonds ◽

Transforming Growth Factor ◽

Early Recognition ◽

Clinical Care ◽

Mutation Screening ◽

Age At Onset ◽

Clinical Manifestations ◽

Missense Mutations ◽

Arm Span ◽

Wide Range

Background : MFS is characterized by variable clinical manifestations mainly in cardiovascular, ocular, and skeletal systems. The major encoding gene of structural constituent of extracellular microfibrils is Fibrillin-1 (FBN1). Approximately 90% of MFS cases are caused by mutations in the FBN1 gene (15q21.1) and the other second is TGFBR2 (3p22) gene. Methods : The UMD database, Ensemble database and VUmc DNA Laboratory database of FBN1 mutations and polymorphisms were used to evaluate the DNA variations. For paternity testing, the PowerPlex system (Promega Corp. USA) was used. A 30-years old was being admitted to the hospital. CKMB and Troponin C serial. A CT angiography was performed and revealed a long type 1 aortic dissection until proximal of bifurcation, the arm span-height ratio is 1.10, high myopia, arachnodactily, positive thumb signs and wrist signs, joint laxity articulation genu, and history of spontaneous pneumothorax. Identified, his mother, two sisters and one brother are clinically MFS. Results : Genetic testing of FBN1 showed a substation at exon 15 of FBN1, c.1924G>T. Discussion: In missense mutations substituting or creating cysteine, the probability of ectopia lentis is significantly higher compared to other missense mutations. The EGF domains are interrupted by seven transforming growth factor (TGF)-binding protein domains characterized by 8 cysteine residues involved in intra-domain disulfide bonds. Conclusion : Untreated, life expectancy of patients with MFS is considerably reduced. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. Early recognition of affected status hopefully will lead to early prevention of complications that may follow.

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Fusion Genes Altered in Adult Malignant Gliomas

Frontiers in Neurology ◽

10.3389/fneur.2021.715206 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gan You ◽

Xing Fan ◽

Huimin Hu ◽

Tao Jiang ◽

Clark C. Chen

Keyword(s):

Genetic Background ◽

Molecular Genetic ◽

Malignant Gliomas ◽

Therapeutic Targets ◽

High Grade ◽

Gene Fusions ◽

Fusion Genes ◽

High Grade Gliomas ◽

The Many

Malignant gliomas are highly heterogeneous brain tumors in molecular genetic background. Despite the many recent advances in the understanding of this disease, patients with adult high-grade gliomas retain a notoriously poor prognosis. Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets to date. Understanding the gene fusions and how they regulate oncogenesis and malignant progression will contribute to explore new approaches for personalized treatment. By now, studies on gene fusions in gliomas remain limited. However, some current clinical trials targeting fusion genes have presented exciting preliminary findings. The aim of this review is to summarize all the reported fusion genes in high-grade gliomas so far, discuss the characterization of some of the most popular gene fusions occurring in malignant gliomas, as well as their function in tumorigenesis, and the underlying clinical implication as therapeutic targets.

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Differential Regulation of the EGFR/PI3K/AKT/PTEN Pathway between Low- and High-Grade Gliomas

Brain Sciences ◽

10.3390/brainsci11121655 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1655

Author(s):

Alveiro Erira ◽

Fernando Velandia ◽

José Penagos ◽

Camilo Zubieta ◽

Gonzalo Arboleda

Keyword(s):

Gene Amplification ◽

Molecular Genetic ◽

Low Grade ◽

High Grade ◽

Central System ◽

Genetic Changes ◽

Akt Phosphorylation ◽

Degree Of Malignancy ◽

High Grade Gliomas ◽

High Degree

Gliomas represent 70% of all central system nervous tumors and are classified according to the degree of malignancy as low- or high-grade. The permanent activation of the EGFR/PI3K/AKT pathway by various genetic or post-translational alterations of EGFR, PI3KCA, and PTEN has been associated with increased proliferation and resistance to apoptosis. The present study aimed to analyze the molecular/genetic changes in the EGFR/PI3K/AKT/PTEN pathway between low-grade and high-grade gliomas in a sample of Colombian patients. A total of 30 samples were tested for PI3K and PTEN mutations, EGFR, PI3K, and AKT gene amplification, AKT, PI3K, BAX, Bcl2 expression levels, and phosphorylation of AKT and PTEN, EGFR and/or PI3K gene amplification was found in 50% of low-grade and 45% of high-grade ones. AKT amplification was found in 25% of the low-grade and 13.6% of the high-grade. The expression of PI3K, AKT, Bcl2, and BAX was increased particularly to a high degree. AKT phosphorylation was found in 66% of low-grade and 31.8% of high-grade. Increased phosphorylation of PTEN was found in 77% low-grade and 66% high-grade. Our results indicate that alterations in the EGFR/PI3K/AKT/PTEN pathway could be important in the initiation and malignant progression of this type of tumor.

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