Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma

Noushmehr, Houtan; Weisenberger, Daniel J.; Diefes, Kristin; Phillips, Heidi S.; Pujara, Kanan; Berman, Benjamin P.; Pan, Fei; Pelloski, Christopher E.; Sulman, Erik P.; Bhat, Krishna; Verhaak, Roel G.W.; Hoadley, Katherine A.; Hayes, D. Neil; Perou, Charles M.; Schmidt, Heather; Li, Ding; Wilson, Richard K.; Berg, David Van Den; Shen, Hui; Bengtsson, Henrik; Neuvial, Pierre; Cope, Leslie; Buckley, Jonathan D.; Herman, James G.; Baylin, Stephen B.; Laird, Peter W.; Aldape, Kenneth

doi:10.1016/j.ccr.2010.03.017

Cited by 2,075 publications

(2,186 citation statements)

References 61 publications

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“…Isocitrate dehydrogenase gene mutations, estimated to occur in 70–90% of diffuse lower grade gliomas, are strongly implicated in both tumourigenesis and prognosis 23, 24, 25. Loss of heterozygosity of 1p19q, was occurred in 60–80% of oligodendroglioma and up to 45% of oligoastrocytoma 26.…”

Section: Discussionmentioning

confidence: 99%

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

Zheng

Diao

et al. 2016

J Cellular Molecular Medi

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MicroRNAs are increasingly reported as tumour suppressors that regulate gene expression after transcription. Our results demonstrated that miR‐4295 is overexpression in glioma tissues and its level is significantly correlated with clinical stage. We also found that miR‐4295 inhibited the cell G0/G1 arrest and apoptosis leading to promoted cell proliferation and activity. The murine modelling study revealed that female nude mice injected with U87/anti‐miR‐4295 exhibit subcutaneous tumours in the right groin. Compared with anti‐NC, the tumour volume was significantly decreased in anti‐miR‐4295 treatment group. Furthermore, we confirmed miR‐4295 mediates the expression of RUNX3 by targeting its 3′untranslation region. In addition, N‐myc protein also could bind to the promoter of pri‐miR‐4295 and inhibit the expression of RUNX3 in glioma cells. These results validate a pathogenetic role of a miR‐4295 in gliomas and establish a potentially regulatory and signalling pathway involving N‐myc/miR‐4295/RUNX3 in gliomas.

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Section: Discussionmentioning

confidence: 99%

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

Zheng

Diao

et al. 2016

J Cellular Molecular Medi

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“…27 TET proteins are thought to have a role in tumor development, as inhibition of TET activity, as well as alteration of global DNA methylation, has been demonstrated in multiple tumor types. [28][29][30][31][32] Thus, succinate accumulation in the context of SDH deficiency could potentially drive tumorigenesis via the inhibition of TET family proteins and subsequent changes in DNA methylation and gene expression patterns. Indeed, recent work has shown that siRNA-mediated knockdown of SDHA in cultured cells and in mice leads to an inhibition of TET activity and decreased levels of 5-hmC.…”

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confidence: 99%

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

Mason

Hornick

2013

Modern Pathology

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“…Common molecular subtypes have already been identified in many of the cancers before [11,13,14,17]. To find out how these related to pathway aberrations, and to identify new subgroups based on pathway level changes, we hierarchically clustered the samples into small and homogeneous clusters characterized by a unique set of pathway aberrations (Additional File 3, Figure 2, Figures S1-S7 in Additional File 4,).…”

Section: Resultsmentioning

confidence: 99%

“…Tumours in the less lethal subgroup were enriched of Proneural subtype [11] ( p <4.5e-5), and concordantly with IDH mutations ( p <5.1e-5) and glioma-CpG Island Methylator Phenotype (G-CIMP) [17] ( p <1.7-e6). Since TCGA's GBM cohort currently is considerably larger compared to the one used in the previous studies, not all of tumours were annotated to these groups.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of aberrant pathways across human cancers

et al. 2013

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Background Cancer is a broad group of genetic diseases which account for millions of deaths worldwide each year. Cancers are classified by various clinical, pathological and molecular methods, but even within a well-characterized disease, there is a significant inter-patient variability in survival, response to treatment, and other parameters. Especially in molecular level, tumours of the same category can appear significantly dissimilar due to complex combinations of genetic aberrations leading to a similar malignancy. We extended the current classification methods by studying tumour heterogeneity at pathway level. Methods We computed the rate of alterations in 1994 pathways and 2210 tumours consisting of eight different cancers. Using gene set enrichment analysis, each sample was computed a pathway aberration profile that reflected its molecular state. The profiles were analysed together to infer the characteristic aberration rates for each pathway within each cancer. Subgroups of tumours defined by similar pathway aberrations were identified using clustering analyses. The pathway aberration and gene expression profiles of the subgroups were consecutively compared across all eight cancer types to search for similar tumours crossing the standard classification. Results We identified pathways and processes that were common to all cancers as well as traits that are unique to a cancer type or closely related cancers. Studying the gene expression patterns within the pathway context suggested potential alteration mechanisms. Clustering analysis revealed five clinically relevant subgroups of tumours in four cancers that exhibited significant differences in survival compared to others. The cross-cancer analysis of the subgroups resulted in the identification of tumours that shared potentially significant alterations. Conclusions This study represents the first effort to extend the molecular characterizations towards pathway level descriptions across the family of cancers. In addition to providing a proof-of-concept for single sample pathway aberration analysis in this context, we present a comprehensive pathway aberration dataset that can be used to study pathway aberration patterns within or across cancers. Significant similarities between subgroups of different cancers on pathway and gene expression levels provide interesting hypotheses for understanding variable drug response, or transferring treatments across diseases by identifying common druggable pathways or genes, for example.

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Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma

Cited by 2,075 publications

References 61 publications

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

Characterization of aberrant pathways across human cancers

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