An anatomic transcriptional atlas of human glioblastoma

Anatomically correct tumor genomics Glioblastoma is the most lethal form of human brain cancer. The genomic alterations and gene expression profiles characterizing this tumor type have been widely studied. Puchalski et al. created the Ivy Glioblastoma Atlas, a freely available online resource for the research community. The atlas, a collaborative effort between bioinformaticians and pathologists, maps molecular features of glioblastomas, such as transcriptional signatures, to histologically defined anatomical regions of the tumors. The relationships identified in this atlas, in conjunction with associated databases of clinical and genomic information, could provide new insights into the pathogenesis, diagnosis, and treatment of glioblastoma. Science, this issue p. 660 An online resource maps the molecular genetic features of glioblastoma, a lethal brain cancer, to its anatomic features. Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor’s molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.

Fuhui Long | Eric Olson | Nameeta Shah | Allan R. Jones | David Feng | Chinh Dang | Leonard Kuan | Don Marsh | Lydia Ng | Andrew Sodt | Amy Bernard | Shiella Caldejon | Wayne Wakeman | John W. Phillips | Ed Lein | Aaron Szafer | Felix Lee | Allan Jones | Rachel Dalley | Bart Keogh | Guangyu Gu | Michael J Hawrylycz | Antonio Iavarone | Tim Dolbeare | Melissa Reding | Robert Howard | Ali Kriedberg | Kiet Ngo | Patrick J Cimino | C. Lau | Leonard Kuan | C. Slaughterbeck | Wayne Wakeman | David Feng | Kevin Joines | M. Hawrylycz | J. Hohmann | Paul E Wohnoutka | Amy Bernard | Chinh Dang | Kimberly A. Smith | Darren Bertagnolli | J. Goldy | N. Shapovalova | A. Szafer | N. Dee | E. Lein | Fuhui Long | Andrew F. Boe | S. Datta | Tsega Desta | Tim Dolbeare | Amanda J. Ebbert | Tracy A. Lemon | Lydia Ng | R. Puchalski | Z. Riley | Andrew Sodt | A. Iavarone | R. Rostomily | C. Cobbs | J. Barnholtz-Sloan | N. Shah | Mike Chapin | R. Dalley | Benjamin W Gregor | Robert E. Howard | M. Reding | B. Keogh | Krissy Brouner | Stephanie Butler | S. Caldejon | G. Gee | Lindsey Gourley | G. Gu | Felix Lee | Naveed Mastan | E. Olson | D. Sandman | Jae-Geun Yoon | G. Foltz | H. Gittleman | Kris Bickley | N. Dotson | Michael Fisher | Nika Hejazinia | D. Rosen | C. Keene | M. Berens | Ali Kriedberg | E. Mott | Kiet Ngo | J. Lathia | Xu Feng | Farrokh R Farrokhi | Michael E Berens | Jeremy Miller | Steve R Nomura | Michael Lankerovich | P. Hothi | Hwahyung Lee | Chantal Murthy | Graham Stockdale | Steven J White | D. Marsh | J. Barnholtz-Sloan | P. Cimino | M. Uppin | S. Rostad | Tsega Desta | C Dirk Keene | Charles Cobbs | Nick Dee | Chris Lau | Robert C Rostomily | Justin D Lathia | Tracy Lemon | Darren Bertagnolli | Andrew F Boe | Jeff Goldy | Kimberly A Smith | Parvinder Hothi | Haley R Gittleman | Kris Bickley | Krissy Brouner | Nadezhda Dotson | Michael Fisher | David Sandman | John W Phillips | Nadiya Shapovalova | Shiella D. Caldejon | Ralph B Puchalski | Jeremy Miller | Jae-Guen Yoon | Michael Lankerovich | Stephanie Butler | Mike Chapin | Suvro Datta | Amanda Ebbert | Xu Feng | Garrett Gee | Lindsey Gourley | Nika Hejazinia | John Hohmann | Kevin Joines | Hwahyung Lee | Naveed Mastan | Erika Mott | Chantal Murthy | Zack Riley | David Rosen | Clifford R Slaughterbeck | Graham Stockdale | Jill S Barnholtz-Sloan | Megha S Uppin | Steven W Rostad | Greg D Foltz | Garrett Gee | B. Gregor | L. Kuan | Erika Mott | Paul E. Wohnoutka | Farrokh R. Farrokhi | A. Boe

[1]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[2]  Jacob Cohen A Coefficient of Agreement for Nominal Scales , 1960 .

[3]  Emily J. Girard,et al.  Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes , 2014, Genome Biology.

[4]  Raul Rabadan,et al.  The integrated landscape of driver genomic alterations in glioblastoma , 2013, Nature Genetics.

[5]  Antonio Criminisi,et al.  Decision Forests for Computer Vision and Medical Image Analysis , 2013, Advances in Computer Vision and Pattern Recognition.

[6]  E. Chang,et al.  Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse , 2016, Neuron.

[7]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[8]  Andrew Collins,et al.  TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals , 2010, Haematologica.

[9]  Hyunggee Kim,et al.  CD133 Regulates IL-1β Signaling and Neutrophil Recruitment in Glioblastoma , 2017, Molecules and cells.

[10]  Subha Madhavan,et al.  Rembrandt: Helping Personalized Medicine Become a Reality through Integrative Translational Research , 2009, Molecular Cancer Research.

[11]  C. Culling 27 – Cytology technique , 1985 .

[12]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[13]  Todd C. Hollon,et al.  Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy , 2017, Nature Biomedical Engineering.

[14]  Edward F. Chang,et al.  Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. , 2017, Cancer cell.

[15]  S. Horvath,et al.  Development of a Real-time RT-PCR Assay for Detecting EGFRvIII in Glioblastoma Samples , 2008, Clinical Cancer Research.

[16]  Atique U. Ahmed,et al.  Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression , 2017, Proceedings of the National Academy of Sciences.

[17]  Steven J. M. Jones,et al.  Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. , 2015, The New England journal of medicine.

[18]  A. Kriegstein,et al.  Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment , 2017, Genome Biology.

[19]  C. Cobbs,et al.  MGMT methylation in glioblastoma: tale of the tail. , 2015, Neuro-oncology.

[20]  Antonio Criminisi,et al.  Regression forests for efficient anatomy detection and localization in computed tomography scans , 2013, Medical Image Anal..

[21]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[22]  Chibo Hong,et al.  DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors. , 2015, Cancer cell.

[23]  Michael Unser,et al.  Elastic registration of biological images using vector-spline regularization , 2005, IEEE Transactions on Biomedical Engineering.

[24]  J. Akers,et al.  RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas , 2014, Genome research.

[25]  Ash A. Alizadeh,et al.  Robust enumeration of cell subsets from tissue expression profiles , 2015, Nature Methods.

[26]  Lisa C. Wallace,et al.  Targeting Glioma Stem Cells through Combined BMI1 and EZH2 Inhibition , 2017, Nature Medicine.

[27]  Y. Matsumoto,et al.  Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion , 2018, Oncogene.

[28]  D. Lindgren,et al.  CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells. , 2017, Cell reports.

[29]  D. Stanimirovic,et al.  Molecular markers of extracellular matrix remodeling in glioblastoma vessels: Microarray study of laser‐captured glioblastoma vessels , 2007, Glia.

[30]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[31]  Yongmin Kim,et al.  Edge-guided boundary delineation in prostate ultrasound images , 2000, IEEE Transactions on Medical Imaging.

[32]  Gary D Bader,et al.  Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity , 2015, Proceedings of the National Academy of Sciences.

[33]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[34]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Hakho Lee,et al.  MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer , 2017, Stem cell reports.

[36]  V. P. Collins,et al.  Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics , 2013, Proceedings of the National Academy of Sciences.

[37]  L. Hood,et al.  TGFβ‐Responsive HMOX1 Expression Is Associated with Stemness and Invasion in Glioblastoma Multiforme , 2016, Stem cells.

[38]  PDGF Family Expression in Glioblastoma Multiforme: Data Compilation from Ivy Glioblastoma Atlas Project Database , 2017, Scientific Reports.

[39]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[40]  Jing Chen,et al.  ToppGene Suite for gene list enrichment analysis and candidate gene prioritization , 2009, Nucleic Acids Res..

[41]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2013 , 2012, Nucleic Acids Res..

[42]  A. von Deimling,et al.  PCR‐ and Restriction Endonuclease‐Based Detection of IDH1 Mutations , 2010, Brain pathology.

[43]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[44]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[45]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[46]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[47]  J. McCarty,et al.  Neuropilin-1 modulates TGFβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy , 2017, PloS one.

[48]  K. Ligon,et al.  Histology-Based Expression Profiling Yields Novel Prognostic Markers in Human Glioblastoma , 2005, Journal of neuropathology and experimental neurology.

[49]  Alex A. Pollen,et al.  Single‐cell sequencing maps gene expression to mutational phylogenies in PDGF‐ and EGF‐driven gliomas , 2016, Molecular Systems Biology.

[50]  F. Lang,et al.  The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma , 2016, Molecular Cancer Research.

[51]  M. Halterman,et al.  Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche , 2017, Cancer Microenvironment.

[52]  Jae-Geun Yoon,et al.  High-Throughput Chemical Screens Identify Disulfiram as an Inhibitor of Human Glioblastoma Stem Cells , 2012, Oncotarget.

[53]  Koji Kadota,et al.  A normalization strategy for comparing tag count data , 2012, Algorithms for Molecular Biology.

[54]  S. Quake,et al.  A survey of human brain transcriptome diversity at the single cell level , 2015, Proceedings of the National Academy of Sciences.

[55]  Patrick J. Paddison,et al.  Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy , 2017, PloS one.

[56]  Bradley E. Bernstein,et al.  Transcription elongation factors represent in vivo cancer dependencies in glioblastoma , 2017, Nature.

[57]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[58]  Ed S Lein,et al.  Improving reliability and absolute quantification of human brain microarray data by filtering and scaling probes using RNA-Seq , 2014, BMC Genomics.

[59]  In-Hee Lee,et al.  Spatiotemporal genomic architecture informs precision oncology in glioblastoma , 2017, Nature Genetics.

[60]  P. Ivanov,et al.  The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches. , 2016, Cell reports.

[61]  Putting "multiforme" back into glioblastoma: intratumoral transcriptome heterogeneity is a consequence of its complex morphology. , 2017, Neuro-oncology.

[62]  Colin N. Dewey,et al.  RNA-Seq gene expression estimation with read mapping uncertainty , 2009, Bioinform..

[63]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[64]  R. McLendon,et al.  Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth , 2013, Cell.