Emerging insights into the molecular and cellular basis of glioblastoma

Dunn, Gavin P.; Rinne, Mikael L.; Wykosky, Jill; Genovese, Giannicola; Quayle, Steven N.; Dunn, Ian F.; Agarwalla, Pankaj K.; Chheda, Milan G.; Campos, Benito; Wang, Alan; Brennan, Cameron; Ligon, Keith L.; Furnari, Frank B.; Cavenee, Webster K.; DePinho, Ronald A.; Chin, Lynda; Hahn, William C.

doi:10.1101/gad.187922.112

Cited by 499 publications

(505 citation statements)

References 349 publications

(402 reference statements)

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“…Previous studies demonstrated frequent IDH1 mutation in the subset of the high-grade gliomas with better prognosis (28), and losses of heterozygosity (LOH) at Chr 1p/19q as a genomic hallmark in oligodendrogliomas (22); whereas other genomic alterations were not unambiguously specific to glioma subtypes (29). We found that IDH1 mutation was enriched in both PM and EM low PM low gliomas, LOH at 1p/19q in PM gliomas, whereas EGFR amplifications were enriched in EM gliomas (P < 0.0001, two-sided Fisher's exact test, Tiantan and GSE16011 data sets; SI Appendix, Table S3).…”

Section: Resultsmentioning

confidence: 99%

A glioma classification scheme based on coexpression modules of EGFR and PDGFRA

Sun

Zhang

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM low PM low gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM low PM low gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM low PM low gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtypespecific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

A glioma classification scheme based on coexpression modules of EGFR and PDGFRA

Sun

Zhang

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…2 are the most common and lethal of all primary brain neoplasms (1). Current treatment regimens encompass radiation and concomitant chemotherapy, yet progress to increase median survival has not been forthcoming and currently remains ϳ12 months (2).…”

Section: Glioblastomas (Gbm)mentioning

confidence: 99%

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

Artinian

Cloninger

Holmes

et al. 2015

Journal of Biological Chemistry

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“…The lower methylation percentage detected in GC cases compared to H. pylori positive-IM cases may be explained with the absence of heterozygosity of RB1 gene in several cases of GC group [19]. The fact that RB1 methylation level is 40% in the control group suggests that clinically, radiologically, and pathologically normal individuals may not be normal at molecular level, and monitoring the methylation levels may increase the efficiency of tumor screening procedures.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of RB1 function by loss of heterozygosity has been reported in GC, glioblastomas, breast cancer, renal carcinoma, and laryngeal cancer [19]. However methylation studies on the promoter region of RB1 gene in relation to the GC and its pathogenesis are limited.…”

Section: Discussionmentioning

confidence: 99%