scholarly journals Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5678
Author(s):  
Lia Pinto ◽  
Hanane Baidarjad ◽  
Natacha Entz-Werlé ◽  
Eric Van Dyck
Keyword(s):  
Dna Repair ◽  
Treatment Resistance ◽  
Genetic Alterations ◽  
Telomere Maintenance ◽  
High Grade ◽  
Tumor Resistance ◽  
Chromatin Dynamics ◽  
Repair Pathways ◽  
High Grade Gliomas ◽  
The Impact

Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs. Notably, mutations in H3.3 are frequently associated with mutations affecting ATRX and DAXX, which encode a chaperone complex that deposits H3.3 into heterochromatic regions, including telomeres. The K27M and G34R/V mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations. Contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, with the current mainstays of therapy—genotoxic chemotherapy and ionizing radiation (IR)—facing the development of tumor resistance driven by complex DNA repair pathways. Chromatin and nucleosome dynamics constitute important modulators of the DNA damage response (DDR). Here, we summarize the major DNA repair pathways that contribute to resistance to current DNA damaging agent-based therapeutic strategies and describe the telomere maintenance mechanisms encountered in pHGGs. We then review the functions of H3.3 and its chaperones in chromatin dynamics and DNA repair, as well as examining the impact of their mutation/alteration on these processes. Finally, we discuss potential strategies targeting DNA repair and epigenetic mechanisms as well as telomere maintenance mechanisms, to improve the treatment of pHGGs.

scholarly journals Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas

2014 ◽  
Vol 117 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Kathleen Dorris ◽  
Matthew Sobo ◽  
Arzu Onar-Thomas ◽  
Eshini Panditharatna ◽  
Charles B. Stevenson ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Telomere Maintenance ◽  
High Grade ◽  
High Grade Gliomas

Long survival and therapeutic responses in patient histologically disparate high-grade gliomas demonstrating chromosome 1p loss

2000 ◽  
Vol 92 (6) ◽  
pp. 983-990 ◽  
Author(s):  
Yasushi Ino ◽  
Magdalena C. Zlatescu ◽  
Hikaru Sasaki ◽  
David R. Macdonald ◽  
Anat O. Stemmer-Rachamimov ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Genetic Alterations ◽  
Allelic Loss ◽  
High Grade ◽  
Prognostic Information ◽  
Content Type ◽  
Chromosome 1P ◽  
Oligodendroglial Tumors ◽  
High Grade Gliomas ◽  
Fine Print

Object. Allelic loss of chromosome 1p is a powerful predictor of tumor chemosensitivity and prolonged survival in patients with anaplastic oligodendrogliomas. Chromosome 1p loss also occurs in astrocytic and oligoastrocytic gliomas, although less commonly than in pure oligodendroglial tumors. This observation raises the possibility investigated in this study that chromosome 1p loss might also provide prognostic information for patients with high-grade gliomas with astrocytic components.Methods. The authors report on seven patients with high-grade gliomas composed of either pure astrocytic or mixed astrocytic-oligodendroglial phenotypes, who had remarkable neuroradiological responses to therapy or unexpectedly long survivals. All of the tumors from these seven patients demonstrated chromosome 1p loss, whereas other genetic alterations characteristic of high-grade gliomas (p53 gene mutations, EGFR gene amplification, chromosome 10 loss, chromosome 19q loss, or CDKN2A/p16 deletions) were only found in occasional cases. The authors also assessed the frequency of chromosome 1p loss in a series of anonymous high-grade astrocytoma samples obtained from a tumor bank and demonstrate that this genetic change is uncommon, occurring in only 10% of cases.Conclusions. Although any prognostic importance of chromosome 1p loss in astrocytic or mixed astrocytic—oligodendroglial gliomas can only be determined in larger and prospective series, these findings raise the possibility that some high-grade gliomas with chromosome 1p loss, in addition to pure anaplastic oligodendrogliomas, may follow a more favorable clinical course.

scholarly journals Central Role of Ubiquitination in Genome Maintenance: DNA Replication and Damage Repair

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Soma Ghosh ◽  
Tapas Saha
Keyword(s):  
Dna Repair ◽  
Posttranslational Modifications ◽  
Excision Repair ◽  
Genetic Alterations ◽  
Conjugation System ◽  
Protein Ubiquitination ◽  
Independent Functions ◽  
Repair Mechanisms ◽  
Repair Pathways

Faithful transmission of genetic information through generations ensures genomic stability and integrity. However, genetic alterations occur every now and then during the course of genome duplication. In order to repair these genetic defects and lesions, nature has devised several repair pathways which function promptly to prevent the cell from accumulating permanent mutations. These repair mechanisms seem to be significantly impacted by posttranslational modifications of proteins like phosphorylation and ubiquitination. Protein ubiquitination is emerging as a critical regulatory mechanism of DNA damage response. Non-proteolytic, proteasome-independent functions of ubiquitin involving monoubiquitination and polyubiquitination of DNA repair proteins contribute significantly to the signaling of DNA repair pathways. In this paper, we will particularly highlight the work on ubiquitin-mediated signaling in the repair processes involving the Fanconi anemia pathway, translesional synthesis, nucleotide excision repair, and repair of double-strand breaks. We will also discuss the role of ubiquitin ligases in regulating checkpoint mechanisms, the role of deubiquitinating enzymes, and the growing possibilities of therapeutic intervention in this ubiquitin-conjugation system.

scholarly journals The Relevance of G-Quadruplexes for DNA Repair

2021 ◽  
Vol 22 (22) ◽  
pp. 12599
Author(s):  
Rebecca Linke ◽  
Michaela Limmer ◽  
Stefan Juranek ◽  
Annkristin Heine ◽  
Katrin Paeschke
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genome Instability ◽  
Genetic Disorders ◽  
Telomere Maintenance ◽  
Dna Structures ◽  
G4 Dna ◽  
G Quadruplex ◽  
Repair Pathways

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

Post-operative concomitant radiochemotherapy in the treatment of primitive CNS high grade gliomas. A retrospective analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 11528-11528
Author(s):  
P. Costa ◽  
F. Braga ◽  
C. Sottomayor ◽  
M. Honavar ◽  
M. Resende ◽  
...  
Keyword(s):  
Adjuvant Treatment ◽  
Haematological Toxicity ◽  
Small Sample ◽  
Routine Practice ◽  
High Grade ◽  
Tumour Control ◽  
Concomitant Radiochemotherapy ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
The Impact

11528 Background: The authors analyse retrospectively the impact on tumour control and toxicity of concomitant radiotherapy (RT) and Temozolomide (TMZ) in high grade gliomas (HGG) of the CNS, in patients treated in the Clínica de Radioterapia do Porto - Portugal. Methods: This cohort represents all patients with HGG treated between January 2002 and January 2006, with concomitant RT a median total dose of 60 Gy, 2 Gy per treatment given once daily 5-days/week and TMZ 75mg/m2 for 42 days, followed by adjuvant treatment with TMZ 5-days schedule every 28 days (150 mg/m2 for the first cycle increased to 200mg/m2). The cohort was retrospectively analyzed for gender distribution, age, extent of surgical resection, initial KPS, median overall survival (OS) and haematological toxicity. Results: 23 with HGG (6 females, 17 males) were treated with concomitant RT (44–72 Gy) and TMZ followed by adjuvant TMZ; median age was 58 (ranging from 17–72); median KPS was 80 (ranging from 40–90); 3 patients had complete resection, 17 partial resection and 3 biopsy. All patients except one, who had treatment interruption for thrombocytopenia, completed the concomitant phase of treatment; 19 patients continued to received adjuvant treatment with TMZ (median number of cycles was 5 (ranging from 1–20). Median OS (measured from the date of diagnosis to the date of death) was 20.4 month and 1 yr OS was 54%. During concomitant phase, one patient had grade 3–4 thrombocytopenia. During the adjuvant TMZ therapy 4 patients had grade 3–4 haematological toxicity (anaemia: 1; thrombocytopenia: 1; leucopoenia and thrombocytopenia: 2). Conclusions: The results of concomitant RT+TMZ followed by TMZ in these patients with HGG showed values in accordance with the latest data published on literature for this association. Differences observed might be due to the small sample size.RT+TMZ followed by adjuvant TMZ is a well tolerated treatment with better results in median OS comparatively with previous results of RT only treatment in HGG. Treatment related toxicity was within acceptable levels, and this approach became routine practice in this set of patients. No significant financial relationships to disclose.

scholarly journals Erratum to: Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas

2014 ◽  
Vol 119 (1) ◽  
pp. 223-224
Author(s):  
Kathleen Dorris ◽  
Matthew Sobo ◽  
Arzu Onar-Thomas ◽  
Eshini Panditharatna ◽  
Charles B. Stevenson ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Telomere Maintenance ◽  
High Grade ◽  
High Grade Gliomas

scholarly journals RONC-21. IDENTIFICATION OF EPIGENETIC DRUGS AS RADIOSENSITIZERS IN PEDIATRIC HIGH-GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii459-iii459
Author(s):  
Dennis Metselaar ◽  
Giovanna ter Huizen ◽  
Michaël Hananja Meel ◽  
Joshua Goulding ◽  
Piotr Waranecki ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
Growth Characteristics ◽  
High Grade ◽  
Rna Seq ◽  
Multilevel Regression ◽  
Epigenetic Drugs ◽  
Spheroid Growth ◽  
Repair Pathways ◽  
High Grade Gliomas ◽  
Combinational Therapies

Abstract Pediatric high-grade gliomas (pHGG) are malignant brain tumors with a high mortality rate. Radiotherapy (RT) is one of the cornerstones of current pHGG treatment, while the efficacy of chemotherapeutics remains inferior. The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increase the effect of RT in pHGG treatment. Since recent studies revealed pHGG to be epigenetically dysregulated, we tested 148 epigenetic drugs on eight primary pHGG models in the presence and absence of RT, to assess their radiosensitizing potential. Based on synergy scores, we found 22 compounds that resulted in enhanced cytotoxicity in the presence of RT. The effect of these compounds on pHGG was further investigated by tracking spheroid growth microscopically for 30 days, identifying four molecules that stopped spheroid-expansion solely in combination with RT (p=<0.001, multilevel regression). Parallel cell-viability assays reported identical results. Furthermore, tumor migration in 3D matrigel growth assays, using non-toxic doses of the four identified compounds, revealed that two compounds (the selective HDAC-inhibitors; chidamide and entinostat) stop the infiltrative growth characteristics of pHGG cells, exclusively in combination with RT. RNA-Seq data showed that entinostat and chidamide inhibit DNA-repair pathways like the Fanconi anemia cascade and homologous recombination. Since we anticipate that entinostat- or chidamide-induced radiosensitization can be enhanced by blocking kinase-driven escape mechanisms, we are currently conducting a kinome-wide CRISPR/Cas9 knockout screen in three primary pHGG models to develop combinational therapies. These results highlight entinostat and chidamide as potential radiosensitizers in pHGG treatment.

scholarly journals Image-based personalization of computational models for predicting response of high-grade glioma to chemoradiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David A. Hormuth ◽  
Karine A. Al Feghali ◽  
Andrew M. Elliott ◽  
Thomas E. Yankeelov ◽  
Caroline Chung
Keyword(s):  
Mathematical Models ◽  
Computational Models ◽  
Tumor Response ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Information Criteria ◽  
Patient Specific ◽  
Model Parameters ◽  
High Grade ◽  
High Grade Gliomas

AbstractHigh-grade gliomas are an aggressive and invasive malignancy which are susceptible to treatment resistance due to heterogeneity in intratumoral properties such as cell proliferation and density and perfusion. Non-invasive imaging approaches can measure these properties, which can then be used to calibrate patient-specific mathematical models of tumor growth and response. We employed multiparametric magnetic resonance imaging (MRI) to identify tumor extent (via contrast-enhanced T1-weighted, and T2-FLAIR) and capture intratumoral heterogeneity in cell density (via diffusion-weighted imaging) to calibrate a family of mathematical models of chemoradiation response in nine patients with unresected or partially resected disease. The calibrated model parameters were used to forecast spatially-mapped individual tumor response at future imaging visits. We then employed the Akaike information criteria to select the most parsimonious member from the family, a novel two-species model describing the enhancing and non-enhancing components of the tumor. Using this model, we achieved low error in predictions of the enhancing volume (median: − 2.5%, interquartile range: 10.0%) and a strong correlation in total cell count (Kendall correlation coefficient 0.79) at 3-months post-treatment. These preliminary results demonstrate the plausibility of using multiparametric MRI data to inform spatially-informative, biologically-based predictive models of tumor response in the setting of clinical high-grade gliomas.

Sign in / Sign up

Export Citation Format

Share Document