Association of loss of heterozygosity with shorter survival in primary glioblastoma patients

Jesionek-Kupnicka, Dorota; Szybka, Malgorzata; Potemski, Piotr; Kulczycka-Wojdala, Dominika; Jaskólski, Dariusz J.; Bieńkowski, Michał; Skowronski, Wiesław; Papierz, W; Kordek, Radzisław; Zawlik, Izabela

doi:10.5114/pjp.2013.39335

Cited by 16 publications

(14 citation statements)

References 36 publications

(80 reference statements)

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“…The significance of differences in the frequencies of molecular events in the chromosome region 10q23. 3 17 Our experience with the original protocol demonstrated that endogenous control system included loci whose copy numbers are frequently altered in glioblastoma according to our observations (not shown) and previously published data. 4,19 We developed an original endogenous control system and designed specific primer pairs (Supporting Information Table 2) based on the GRCh37/hg19 genome assembly with comprehensive annotations and the data accumulated in the past decade for alterations in copy numbers of genomic regions in glioblastoma.…”

Section: Discussionsupporting

confidence: 59%

See 1 more Smart Citation

Loss of heterozygosity and uniparental disomy of chromosome region 10q23.3–26.3 in glioblastoma

Алексеева

Kuznetsova

Танас

et al. 2017

Genes Chromosomes & Cancer

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Glioblastoma is the most frequent and aggressive brain tumor in the adult population. Loss of heterozygosity (LOH) at markers of the long arm of chromosome 10 is the most common genetic alteration in glioblastoma, being detectable in up to 80% of cases. We have tested 124 glioblastoma samples for LOH by microsatellite analysis of the 10q23.3-26.3 region which contains the cancer related genes PTEN, FGFR2, MKI67, and MGMT. Then, a real-time quantitative microsatellite analysis (QuMA) was used to qualitatively estimate the change in copy number of this region in the samples with LOH. LOH was detected in 62.1% of the glioblastoma samples. A total of 64 samples with LOH in this region were examined by QuMA. LOH was attributed to a deletion in 37.5% of cases, and uniparental disomy (UPD) in 25% of cases. In 37.5% of cases, deletion and UPD segments alternated within the region: deletions being more frequent than UPD in its proximal part (encompassing PTEN and FGFR2) and both deletions and UPD occurring at the same frequency in its distal part (MGMT). Thus, we have investigated mechanisms of structural alterations of the chromosome region 10q23.3-26.3 in glioblastoma. In addition to a structural deletion of this region, UPD was identified as a frequent cause of LOH. We resume that more detailed studies of glioblastoma at the molecular genetic level are essential in search for potential markers suitable for predicting the disease outcome and the response to treatment. | I N TR ODU C TI ONGlioblastoma is the most frequent and aggressive brain tumor in the adult population. Glioblastomas account for 80% of primary neoplasms of the central nervous system and are thereby among the most vital problems of neuro-oncology. At the molecular level, glioblastoma has been studied rather comprehensively and is characterized by many genetic and epigenetic alterations, which affect various cancer related genes.1 In spite of the vast data accumulated in the molecular genetics of glioblastoma, only few markers are known to predict the prognosis and response to therapy, the set including abnormal methylation of the MGMT promoter region and IDH1 mutations, which are used in clinical practice.

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Section: Discussionsupporting

confidence: 59%

“…Loss of heterozygosity (LOH) at markers of the long arm of chromosome 10 is the most frequent (up to 80%) molecular genetic alteration in glioblastoma. 3 Two regions, 10q23-24 and 10q25-pter, are most often affected by LOH. 4 A high LOH frequency is associated with the presence of many tandem and interspersed repeats in the regions.…”

mentioning

confidence: 99%

Loss of heterozygosity and uniparental disomy of chromosome region 10q23.3–26.3 in glioblastoma

Алексеева

Kuznetsova

Танас

et al. 2017

Genes Chromosomes & Cancer

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“…Because we did not observe any improvement in the OS of patients with both MGMT methylation and 10q LOH, we hypothesize that the positive effect of complete MGMT silencing on therapy response can be counterbalanced by the loss of other tumor suppressor genes (e.g. PTEN , ERCC6 and DMBT1 ) mapping to the same region of chromosome 10q and associated with reduced OS (39, 40). …”

Section: Discussionmentioning

confidence: 65%

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

Fontana¹,

Tabano²,

Bonaparte³

et al. 2016

J Neuropathol Exp Neurol

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Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these 2 events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.

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“…The molecular criteria confirming the primary GB were frequency of EGFR amplification (37.5%), IDH1 mutation (2.44%), and TP53 mutation (26.2%). The results for EGFR amplification, IDH1, and TP53 were partly published before ( Jesionek-Kupnicka et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

TP53Promoter Methylation in Primary Glioblastoma: Relationship withTP53mRNA and Protein Expression and Mutation Status

Jesionek-Kupnicka

Szybka

Małachowska

et al. 2014

DNA and Cell Biology

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Reduced expression of TP53 by promoter methylation has been reported in several neoplasms. It remains unclear whether TP53 promoter methylation is associated with reduced transcriptional and protein expression in glioblastoma (GB). The aim of our work was to study the impact of TP53 methylation and mutations on TP53 mRNA level and protein expression in 42 molecularly characterized primary GB tumors. We also evaluate the impact of all molecular alterations on the overall patient survival. The frequency of TP53 promoter methylation was found in 21.4%. To the best of our knowledge, this is the first report showing such high frequency of TP53 promoter methylation in primary GB. There was no relation between TP53 promoter methylation and TP53 mRNA level ( p = 0.5722) and between TP53 promoter methylation and TP53 protein expression ( p = 0.2045). No significant associations were found between TP53 mRNA expression and mutation of TP53 gene ( p = 0.9076). However, significant association between TP53 mutation and TP53 protein expression was found ( p = 0.0016). Our data suggest that in primary GB TP53 promoter methylation does not play a role in silencing of TP53 transcriptional and protein expression and is probably regulated by other genetic and epigenetic mechanisms associated with genes involved in the TP53 pathway.

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Association of loss of heterozygosity with shorter survival in primary glioblastoma patients

Cited by 16 publications

References 36 publications

Loss of heterozygosity and uniparental disomy of chromosome region 10q23.3–26.3 in glioblastoma

Loss of heterozygosity and uniparental disomy of chromosome region 10q23.3–26.3 in glioblastoma

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

TP53Promoter Methylation in Primary Glioblastoma: Relationship withTP53mRNA and Protein Expression and Mutation Status

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