Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

Saratsis, Amanda; Kambhampati, Madhuri; Snyder, Kendall; Yadavilli, Sridevi; Devaney, Joseph M.; Harmon, Brennan; Hall, Jordan; Raabe, Eric H.; An, Ping; Weingart, Melanie; Rood, Brian R.; Magge, Suresh N.; MacDonald, Tobey J.; Packer, Roger J.; Nazarian, Javad

doi:10.1007/s00401-013-1218-2

Cited by 98 publications

(114 citation statements)

References 54 publications

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“…4). For example, a set of three complement related genes -complement C3, α-2 macroglobulin (A2M) and the complement lysis inhibitor SP-40/clusterin (CLU) -that have been implicated in various cancers including gliomas (Reis et al 2018;Saratsis et al 2014;Shinoura et al 1994;Suman et al 2016) were present in this group, and interestingly, these three proteins have been recently shown to form a network of related biomarkers in B-ALL (Cavalcante Mde et al 2016). One tumor contained a cluster of highly .…”

Section: Genes Showing Somatic Mutations In Multiple Tcga Samples Onlmentioning

confidence: 99%

Detection and benchmarking of somatic mutations in cancer genomes using RNA-seq data

Coudray

Battenhouse

Bücher

et al. 2018

Preprint

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To detect functional somatic mutations in tumor samples, whole-exome sequencing (WES) is often used for its reliability and relative low cost. RNA-seq, while generally used to measure gene expression, can potentially also be used for identification of somatic mutations. However there has been little systematic evaluation of the utility of RNA-seq for identifying somatic mutations. Here, we develop and evaluate a pipeline for processing RNA-seq data from glioblastoma multiforme (GBM) tumors in order to identify somatic mutations. The pipeline entails the use of the STAR aligner 2-pass procedure jointly with MuTect2 from GATK to detect somatic variants. Variants identified from RNA-seq data were evaluated by comparison against the COSMIC and dbSNP databases, and also compared to somatic variants identified by exome sequencing. We also estimated the putative functional impact of coding variants in the most frequently mutated genes in GBM. Interestingly, variants identified by RNA-seq alone showed better representation of GBM-related mutations cataloged by COSMIC. RNA-seq-only data substantially outperformed the ability of WES to reveal potentially new somatic mutations in known GBM-related pathways, and allowed us to build a high-quality set of somatic mutations common to exome and RNA-seq calls. Using RNA-seq data in parallel with WES data to detect somatic mutations in cancer genomes can thus broaden the scope of discoveries and lend additional support to somatic variants identified by exome sequencing alone.

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Section: Genes Showing Somatic Mutations In Multiple Tcga Samples Onlmentioning

confidence: 99%

Detection and benchmarking of somatic mutations in cancer genomes using RNA-seq data

Coudray

Battenhouse

Bücher

et al. 2018

Preprint

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“…Although DIPG shares recurrent aberrations in histone 3 genes with supratentorial pediatric gliomas, they are molecularly distinct tumors [42,43,49]. DIPG is characterized by unique hallmarks including a remarkable spatiotemporal specificity (occurring in the ventral pons during mid-childhood) and a diffuse growth pattern.…”

Section: Introductionmentioning

confidence: 99%

Human pontine glioma cells can induce murine tumors

et al. 2014

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Diffuse intrinsic pontine glioma (DIPG), with a median survival of only nine months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy 1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or 2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprised of human cells. Of note, direct injection of cells obtained post mortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.

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“…5 Moreover, genomic analyses have shown that even within a single demographic group or histological entity, multiple molecular subtypes of disease exist. 6,7 Our increased understanding of the molecular characteristics underpinning glioma pathogenesis and increased precision in defining disease subsets will hopefully lead to the development of treatments that target the molecular aberrations driving their genesis. However, to fully achieve the promise of precision medicine, it will be necessary to use preclinical models that match specific disease subsets not only in terms of pathology and demographics, but on genetic mechanisms as well.…”

Section: Human Gliomas Are Genomically Heterogeneousmentioning

confidence: 99%

BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea–Induced Gliomagenesis

McNeill

Irvin

Miller

2016

The American Journal of Pathology

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In this issue of the American Journal of Pathology, Wang et al 1 identified recurrent Braf mutations in N-ethyl-Nnitrosourea (ENU)einduced rat gliomas by DNA sequencing. Their results provide a platform for preclinical development of novel targeted therapies for BRAF-mutant gliomas. Precision oncology promises to revolutionize cancer therapy by stratifying tumors on the basis of their molecular characteristics and using rationally designed treatments in molecularly defined patient populations. 2 Although the field of oncology is transitioning into the precision medicine era, conventional diagnostics, based on tissue type, tumor pathology, and patient demographics, remain essential to quality care. One natural pathological division for gliomas, the most common primary brain tumors in humans, is based on their invasion, with nondiffuse gliomas forming well-circumscribed tumors and diffuse gliomas invading the normal brain. 3 Within these two broad diagnostic categories, gliomas are further subdivided on the basis of patient demographics into pediatric and adult diseases and further into specific diagnostic entities based on their histological appearance.

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Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

Cited by 98 publications

References 54 publications

Detection and benchmarking of somatic mutations in cancer genomes using RNA-seq data

Detection and benchmarking of somatic mutations in cancer genomes using RNA-seq data

Human pontine glioma cells can induce murine tumors

BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea–Induced Gliomagenesis

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