Identification of der(1;19)(q10;p10) in Five Oligodendrogliomas Suggests Mechanism of Concurrent 1p and 19q Loss

Griffin, Constance A.; Burger, Peter C.; Morsberger, Laura; Yonescu, Raluca; Swierczynski, Sharon L.; Weingart, Jon; Murphy, Kathleen M.

doi:10.1097/01.jnen.0000235122.98052.8f

Cited by 267 publications

(146 citation statements)

References 30 publications

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“…We first screened for combined LOH on 1p and 19q; chromosomal losses that are frequently observed in oligodendrogliomas and relatively rare in astrocytic tumors (Ohgaki and Kleihues 2009;Bromberg and van den Bent 2009)). These losses are caused by an unbalanced translocation between chromosomes 1 and 19 [t(1;19)(q10,p10)] (Griffin et al, 2006;Jenkins et al, 2006). In our entire dataset, 1p/19q LOH was determined in 317 (63.9%) samples.…”

Section: Non-pr132h Mutations In Idh1 Segregate In Distinct Glioma Smentioning

confidence: 99%

Segregation of non-p.R132H mutations inIDH1in distinct molecular subtypes of glioma

et al. 2010

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Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with c.395G>A (p.R132H) representing >90% of all IDH1 mutations. Interestingly, non-p.R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-p.R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between p.R132H and non-p.R132H mutated IDH1 may explain the segregation in distinct glioma subtypes.

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Section: Non-pr132h Mutations In Idh1 Segregate In Distinct Glioma Smentioning

confidence: 99%

Segregation of non-p.R132H mutations inIDH1in distinct molecular subtypes of glioma

et al. 2010

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“…Up to 80% of oligodendrogliomas and B50% of oligoastrocytomas show combined deletions of the chromosomal arms 1p and 19q (Reifenberger and Louis, 2003) mediated by an unbalanced t(1;19)(q10;p10) translocation (Griffin et al, 2006;Jenkins et al, 2006). Deletion of 1p/19q was reported as an independent marker for favourable outcome in patients with anaplastic gliomas treated with chemotherapy and/or radiotherapy (van den Bent et al, 2005;Cairncross et al, 2006;Wick et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

et al. 2011

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Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and linked to radio-and chemotherapy response as well as longer survival. The molecular mechanisms underlying this clinically important association are as yet unknown. Here, we studied the peroxiredoxin 1 (PRDX1) gene at 1p34.1 for promoter methylation and expression in primary gliomas and investigated its role in radio-and chemosensitivity of glioma cells in vitro. In total, we screened primary glioma tissues from 93 patients for methylation of the 5 0 -CpG island of PRDX1 by sodium bisulfite sequencing. PRDX1 mRNA and protein expression levels were determined in subsets of the tumours by quantitative PCR and western blot analysis, respectively. PRDX1 hypermethylation and reduced expression were frequently detected in oligodendroglial tumours and secondary glioblastomas, but not in primary glioblastomas. In oligodendroglial tumours, both PRDX1 hypermethylation and reduced mRNA expression were significantly associated with 1p/19q-deletion. Stable knockdown of PRDX1 by lentiviral transduction of shorthairpin (sh)RNA constructs significantly increased apoptosis and reduced cell viability of Hs683 glioma cells exposed to ionizing irradiation or temozolomide in vitro. Taken together, our findings indicate that epigenetic silencing of PRDX1 is frequent in 1p/19q-deleted oligodendroglial tumours and likely contributes to radioand chemosensitivity of these tumours.

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“…Recent data indicate that these combined 1p and 19q losses are mediated by an unbalanced t(1;19)(q10;p10) translocation (Griffin et al, 2006;Jenkins et al, 2006). Importantly, 1p/19q deletion is associated with favourable response to radioand chemotherapy as well as prolonged survival (Cairncross et al, 1998(Cairncross et al, , 2006van den Bent et al, 2006).…”

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confidence: 99%

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

et al. 2007

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Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio-and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2 0 -deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.

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Identification of der(1;19)(q10;p10) in Five Oligodendrogliomas Suggests Mechanism of Concurrent 1p and 19q Loss

Cited by 267 publications

References 30 publications

Segregation of non-p.R132H mutations inIDH1in distinct molecular subtypes of glioma

Segregation of non-p.R132H mutations inIDH1in distinct molecular subtypes of glioma

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

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