High expression of DNA methyltransferases in primary human medulloblastoma

Pócza, Tímea; Krenács, Tibor; Turányi, Eszter; Csáthy, János; Jakab, Zsuzsanna; Hauser, Péter

doi:10.5114/fn.2016.60365

Cited by 15 publications

(10 citation statements)

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“…In tumor cells, the hypermethylation of suppressor genes and global hypomethylation is observed [ 86 , 87 ]. DNA methylation profile changes are induced by environmental and endogenous factors [ 88 ]. In medulloblastoma, one can observe that the activation of the SHH signaling pathway is connected with DNMT1 overexpression [ 89 ].…”

Section: Epigenetic Changes In Medulloblastomamentioning

confidence: 99%

Epigenetic-Based Therapy—A Prospective Chance for Medulloblastoma Patients’ Recovery

Strejczek

Woszczyk

Urbaniak

et al. 2021

IJMS

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Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient’s age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects that influence the central nervous system’s function and cause neurocognitive deficits. Therefore, they substantially lower the quality of life, which is especially severe in a developing organism. Thus, there is a need for new therapies that are less toxic and even more effective. Recently, knowledge about the epigenetic mechanisms that are responsible for medulloblastoma development has increased. Epigenetics is a phenomenon that influences gene expression but can be easily modified by external factors. The best known epigenetic mechanisms are histone modifications, DNA methylation, or noncoding RNAs actions. Epigenetic mechanisms comprehensively explain the complex phenomena of carcinogenesis. At the same time, they seem to be a potential key to treating medulloblastoma with fewer complications than past therapies. This review presents the currently known epigenetic mechanisms that are involved in medulloblastoma pathogenesis and the potential therapies that use epigenetic traits to cure medulloblastoma while maintaining a good quality of life and ensuring a higher median overall survival rate.

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Section: Epigenetic Changes In Medulloblastomamentioning

confidence: 99%

Epigenetic-Based Therapy—A Prospective Chance for Medulloblastoma Patients’ Recovery

Strejczek

Woszczyk

Urbaniak

et al. 2021

IJMS

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“…Интенсивность экспрессии белка проводилась по системе Score 0-12 (Score 0-3 -отсутствие или низкий уровень экспрессии белка, Score 4-8 -средний уровень, Score 9-12 -высокий уровень). Score=a×b, где a -интенсивность окраски (1+, 2+, 3+), b -процент позитивных клеток (1 -до 25%, 2 -от 26 до 50%, 3 -от 51 до 75%, 4 -от 76 до 100%) [19].…”

Section: материалы и методыunclassified

Treatment of children with medulloblastoma without metastatic involvement in the age group older than 3 years: international experience and results of intercenter trial

et al. 2020

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Background. During the past 20 years, some large international studies have been conducted that evaluated the effectiveness of treatment programs for children with medulloblastoma. At the same time, in the standard risk group, fairly high rates of 5-year overall survival (OS) and event-free survival (EFS) were achieved, which amounted to 85% and 80%, respectively. At the present time some risk-adaptive therapeutic programs are developed according to molecular-biological features of tumor cells and possibility of chemotherapy and craniospinal radiation (CSI) therapy dose reduction. Materials and methods. From 2008 to 2018 fifty one pediatric patients with primary diagnosed medulloblastoma in the age group 318 years were included in trial, 38 in standard risk group, 13 in high risk group (without metastatic disease). Treatment program consisted of surgical removal of the primary tumor site with subsequent chemotherapy (with high-dose cyclophosphamide or thiophosphamide) and radiation therapy (with CSI of 23.4 Gy or 36 Gy, depending on the risk group). In order to detect morphological and molecular biological distinctive features of tumor cells, the following criteria were evaluated: histological variant, molecular subgroup, methyltransferase status by DNMT and MGMT proteins expression, presence of C-MYC/N-MYC gene amplification, Iso17q and TP53 gene mutation. Results. As a result of this study, sufficiently high rates of overall survival and progression/relapse-free survival (PRFS) were achieved in standard and high-risk groups patients, which amounted to 76.08.8% and 83.310.8% with median follow-up 62.96.2 months and 52.27.8 months, respectively. There was revealed patients group in the age 37 years with 100% PRFS and median follow-up 66.98.9 months. At the same time, morphological and molecular biological factors of an unfavorable outcome of the disease were absent in the tumor samples (large cell anaplastic histology, C-MYC/N-MYC gene amplification, Iso17q and TP53 gene mutation). We have also achieved 100% PRFS in patients with desmoplastic tumor histology and in patients, who were treated with thiphosphamide-based chemotherapy regimen. Molecular-biological characteristics analysis of tumor cells showed a negative effect on PRFS of DNMT-positive status (Score 4, by 3 markers) and presence of N-MYC gene amplification (SHH molecular subgroup). Conclusion. There was identified a group of patients aged 3 to 7 years, for whom the possibility for reducing of CSR dose down to 18 Gy opens. Understanding of tumor cells methyltransferase status creates the prerequisites for using of epigenetic demethylating therapy. It is necessary more observations to assess the effect of the chemotherapy regimen with high-dose thiophosphamide on the PRFS.

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“…The cancerogenic Hh signalling also occurs in many sporadic malignant tumours including gastro-intestinal, haematological, breast, prostate, lung, brain and skin cancers [3,26,35,38]. Hh alterations in paediatric cancer concern a proportion of medulloblastomas (Hh-activated molecular subtype), some rhabdomyosarcomas, neuroblastomas and several others [16,18,26,29,40]. The oncogenic signalling stimulates proliferation and survival of cancer stem cells, affects their differentiation, controls angiogenesis and tumour-stroma interactions.…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

Kuleszo

Lipska‐Ziętkiewicz

Koczkowska

et al. 2019

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Introduction: Germ cell tumours (GCTs) in the children comprise a group of tumours that originate from primordial germ cells but their pathogenesis is not clear. Intracranial GCTs represent a special subset of these paediatric neoplasms. Hedgehog (Hh) pathway gene status in GCTs is generally unexplored, while Hh signalling is involved in germ cell biology. Material and methods: Comparative genomic profiling analysis with a microarray-comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) technique in a group of intracranial paediatric GCTs was performed. The analysis included evaluation of genes being ligands, receptors, regulators, effectors, and targets of Hh signalling. Results: Chromosomal aberrations were found in 62% of examined tumours, showing their heterogeneity. A number of private genomic imbalances were observed, but only a few recurrent ones. The most common numerical changes were trisomies 19, 21 and monosomies 13, 18 while the most frequent structural aberration was gain/ amplification of the chromosome 12p. The analysis of the gene status of Hh network elements showed imbalances in a proportion of tumours. PTCH1, GLI2, IHH and ZIC2 gene aberrations occurred most frequently. Moreover, six tumours had various copy gains or losses of several other genes involved in the pathway, including HHIP, GLI1, GLI3, DHH, SHH, SMO, PTCH2, and several genes from the WNT group. Interestingly, four cases showed losses of pathway repressors, with parallel gains of activators in two of them. Correlations with patho-clinical tumour features were not found, most probably due to the heterogeneity of the examined limited group. Conclusions: Our results show few genomic alterations related to the Hh signalling pathway genes in paediatric intracranial GCTs. Further analysis of Hedgehog pathway alterations can potentially disclose its biological significance and define new prognostic factors and/or therapeutic targets for high-risk patients.

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High expression of DNA methyltransferases in primary human medulloblastoma

Abstract: A b s t r a c t

Cited by 15 publications

References 36 publications

Epigenetic-Based Therapy—A Prospective Chance for Medulloblastoma Patients’ Recovery

Epigenetic-Based Therapy—A Prospective Chance for Medulloblastoma Patients’ Recovery

Treatment of children with medulloblastoma without metastatic involvement in the age group older than 3 years: international experience and results of intercenter trial

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

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