Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

Verhaak, Roel G.W.; Hoadley, Katherine A.; Purdom, Elizabeth; Wang, Victoria; Qi, Yuanyuan; Wilkerson, Matthew D.; Miller, C. Ryan; Li, Ding; Golub, Todd R.; Mesirov, Jill P.; Alexe, Gabriele; Lawrence, Michael S.; O’Kelly, Michael; Tamayo, Pablo; Weir, Barbara A.; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi R.; Feiler, Heidi S.; Hodgson, J. Graeme; James, C. David; Sarkaria, Jann N.; Brennan, Cameron; Kahn, A; Spellman, Paul T.; Wilson, Richard K.; Speed, Terence P.; Gray, Joe W.; Meyerson, Matthew; Getz, Gad; Perou, Charles M.; Hayes, D. Neil

doi:10.1016/j.ccr.2009.12.020

Cited by 6,435 publications

(8,739 citation statements)

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“…Performed in biological triplicate. d , mRNA expression levels of ADAM10 in primary tumor and cultures of DIPG by RNA-seq with values reported as FPKM 12,28 (left; n =8 primary samples, n =7 culture samples) and in 493 individual adult glioblastoma samples from TCGA 29 (right). Values are reported as robust multi-array averages (RMA; right).…”

Section: Extended Datamentioning

confidence: 99%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

402

374

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Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

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Section: Extended Datamentioning

confidence: 99%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

402

374

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“…The present study aims to characterize and monitor treatment response in HPV HNSCC using intra‐ treatment (TX) imaging metrics derived from IVIM DW‐MRI. Inspired by an idea used in many studies that have used clustering approaches for finding sub‐entities in cancer 22, 23, 24. In this study, we will use an unsupervised hierarchical clustering with a distance measure based on the Pearson correlation coefficient to investigate similarities among features and samples.…”

mentioning

confidence: 99%

Intravoxel incoherent motion diffusion‐weighted MRI during chemoradiation therapy to characterize and monitor treatment response in human papillomavirus head and neck squamous cell carcinoma

Paudyal

Riaz

et al. 2016

Magnetic Resonance Imaging

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PurposeCharacterize and monitor treatment response in human papillomavirus (HPV) head and neck squamous cell carcinoma (HNSCC) using intra‐treatment (intra‐TX) imaging metrics derived from intravoxel incoherent motion (IVIM) diffusion‐weighted magnetic resonance imaging (DW‐MRI).Materials and MethodsThirty‐four (30 HPV positive [+] and 4 HPV negative [‐]) HNSCC patients underwent a total of 136 MRI including multi‐b value DW‐MRI (pretreatment [pre‐TX] and intra‐TX weeks 1, 2, and 3) at 3.0 Tesla. All patients were treated with chemo‐radiation therapy. Monoexponential (yielding apparent diffusion coefficient [ADC]) and bi‐exponential (yielding perfusion fraction [f], diffusion [D], and pseudo‐diffusion [D*] coefficients) fits were performed on a region of interest and voxel‐by‐voxel basis, on metastatic neck nodes. Response was assessed using RECISTv1.1. The relative percentage change in D, f, and D* between the pre‐ and intra‐TX weeks were used for hierarchical clustering. A Wilcoxon rank‐sum test was performed to assess the difference in metrics within and between the complete response (CR) and non‐CR groups.ResultsThe delta (Δ) change in volume (V)1wk‐0wk for the CR group differed significantly (P = 0.016) from the non‐CR group, while not for V2wk‐0wk and V3wk‐0wk (P > 0.05). The mean increase in ΔD3wk‐0wk for the CR group was significantly higher (P = 0.017) than the non‐CR group. ADC and D showed an increasing trend at each intra‐TX week when compared with pre‐TX in CR group (P < 0.003). Hierarchical clustering demonstrated the existence of clusters in HPV + patients.ConclusionAfter appropriate validation in a larger population, these IVIM imaging metrics may be useful for individualized treatment in HNSCC patients. Level of Evidence: 2J. Magn. Reson. Imaging 2017;45:1013–1023

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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%

“…Our results encourage investigating the remainder of the tumours in this subgroup for the associated features of Proneural and G-CIMP tumours. The most common molecular subtype in the more lethal subgroup was Mesenchymal [11] ( p <0.02). Additionally, from BRCA pathway aberration profile (Figure S1 in Additional File 4), we discovered a more aggressive subgroup ( p <0.05) (Figure 3c) that was enriched in Her2 positive tumours [14] ( p <1.4e-5).…”

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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Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

Cited by 6,435 publications

References 48 publications

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Intravoxel incoherent motion diffusion‐weighted MRI during chemoradiation therapy to characterize and monitor treatment response in human papillomavirus head and neck squamous cell carcinoma

Characterization of aberrant pathways across human cancers

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