The integrated landscape of driver genomic alterations in glioblastoma
Veronique Frattini,Vladimir Trifonov,Joseph M. Chan,Angelica Castano,Marie Lia,Francesco Abate,Francesco Abate,Stephen T. Keir,Alan X. Ji,Pietro Zoppoli,Francesco Niola,Francesco Niola,Carla Danussi,Igor Dolgalev,Paola Porrati,Serena Pellegatta,Adriana Heguy,Gaurav Gupta,David J. Pisapia,Peter Canoll,Jeffrey N. Bruce,Roger E. McLendon,Hai Yan,Kenneth Aldape,Gaetano Finocchiaro,Tom Mikkelsen,Gilbert G. Privé,Gilbert G. Privé,Darell D. Bigner,Anna Lasorella,Raul Rabadan,Antonio Iavarone +31 more
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TLDR
A computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma provides insights into the pathogenesis of gliOBlastoma and highlights new targets for therapeutic intervention.Abstract:
Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.read more
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DEMARCATE: Density-based magnetic resonance image clustering for assessing tumor heterogeneity in cancer
Abhijoy Saha,Sayantan Banerjee,Sebastian Kurtek,Shivali Narang,Joonsang Lee,Ganesh Rao,Juan F. Martinez,Karthik Bharath,Arvind Rao,Veerabhadran Baladandayuthapani +9 more
TL;DR: A novel technique, DEMARCATE (DEnsity-based MAgnetic Resonance image Clustering for Assessing Tumor hEterogeneity) is introduced to explore the entire tumor heterogeneity density profiles (THDPs) obtained from the full tumor voxel space.
Journal ArticleDOI
The small molecule SI113 synergizes with mitotic spindle poisons in arresting the growth of human glioblastoma multiforme.
Claudia Abbruzzese,Giada Catalogna,Enzo Gallo,Simona di Martino,Anna Maria Mileo,Mariantonia Carosi,Vincenzo Dattilo,Silvia Schenone,Francesca Musumeci,Patrizia Lavia,Nicola Perrotti,Rosario Amato,Marco G. Paggi +12 more
TL;DR: The outcome of the association between SI113 and selected spindle poisons generated a synergistic cytotoxic effect in GBM cells, drastically reducing their viability and clonogenic capabilities in vitro, as well as inhibiting tumor growth in vivo.
Journal ArticleDOI
Anaplastic glioma: current treatment and management
TL;DR: Maturation of NOA-04 and results of the currently accruing studies, CODEL (for codeleted AG) and CATNON (for uni or non-codeleted AG), will likely refine current up-front treatment recommendations for AG.
Posted ContentDOI
FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses
Andrea Comba,Patrick Dunn,Anna E Argento,Padma Kadiyala,Maria Ventosa,Priti Patel,Daniel Zamler,Felipe J Nunez,Lili Zhao,Maria G. Castro,Pedro R. Lowenstein +10 more
TL;DR: This study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response and suggests that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.
Journal ArticleDOI
Role of Yes-associated protein 1 in gliomas: pathologic and therapeutic aspects.
Yong-Chang Liu,Yan-zhou Wang +1 more
TL;DR: YAP1 can be used as a diagnostic marker for gliomas to monitor the disease status and may help to evaluate its treatment effects, and advances in clinical management based on an improved understanding of the function of YAP1 may help it serve as a molecular target in glioma therapeutics.
References
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Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
Aravind Subramanian,Pablo Tamayo,Vamsi K. Mootha,Sayan Mukherjee,Benjamin L. Ebert,Michael A. Gillette,Amanda G. Paulovich,Scott L. Pomeroy,Todd R. Golub,Eric S. Lander,Jill P. Mesirov +10 more
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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Roger Stupp,Warren P. Mason,Martin J. van den Bent,Michael Weller,Barbara Fisher,Martin J.B. Taphoorn,Karl Belanger,Alba A. Brandes,Christine Marosi,Ulrich Bogdahn,Jürgen Curschmann,Robert C. Janzer,Samuel K. Ludwin,Thierry Gorlia,Anouk Allgeier,Denis Lacombe,J. Gregory Cairncross,Elizabeth Eisenhauer,René O. Mirimanoff +18 more
TL;DR: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.
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The variant call format and VCFtools
Petr Danecek,Adam Auton,Gonçalo R. Abecasis,Cornelis A. Albers,Eric Banks,Mark A. DePristo,Robert E. Handsaker,Gerton Lunter,Gabor T. Marth,Stephen T. Sherry,Gilean McVean,Richard Durbin +11 more
TL;DR: VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API.
Journal ArticleDOI
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
Roger E. McLendon,Allan H. Friedman,Darrell D. Bigner,Erwin G. Van Meir,Daniel J. Brat,Gena M. Mastrogianakis,Jeffrey J. Olson,Tom Mikkelsen,Norman L. Lehman,Kenneth Aldape,W. K. Alfred Yung,Oliver Bogler,John N. Weinstein,Scott R. VandenBerg,Mitchel S. Berger,Michael D. Prados,Donna M. Muzny,Margaret Morgan,Steve Scherer,Aniko Sabo,Lynn Nazareth,Lora Lewis,Otis Hall,Yiming Zhu,Yanru Ren,Omar Alvi,Jiqiang Yao,Alicia Hawes,Shalini N. Jhangiani,Gerald R. Fowler,Anthony San Lucas,Christie Kovar,Andrew Cree,Huyen Dinh,Jireh Santibanez,Vandita Joshi,Manuel L. Gonzalez-Garay,Christopher A. Miller,Aleksandar Milosavljevic,Lawrence A. Donehower,David A. Wheeler,Richard A. Gibbs,Kristian Cibulskis,Carrie Sougnez,Timothy Fennell,Scott Mahan,Jane Wilkinson,Liuda Ziaugra,Robert C. Onofrio,Toby Bloom,Rob Nicol,Kristin G. Ardlie,Jennifer Baldwin,Stacey Gabriel,Eric S. Lander,Eric S. Lander,Li Ding,Robert S. Fulton,Michael D. McLellan,John W. Wallis,David E. Larson,Xiaoqi Shi,Rachel Abbott,Lucinda Fulton,Ken Chen,Daniel C. Koboldt,Michael C. Wendl,Rick Meyer,Yuzhu Tang,Ling Lin,John R. Osborne,Brian H. Dunford-Shore,Tracie L. Miner,Kim D. Delehaunty,Chris Markovic,Gary W. Swift,William Courtney,Craig Pohl,Scott Abbott,Amy Hawkins,Shin Leong,Carrie A. Haipek,Heather Schmidt,Maddy Wiechert,Tammi L. Vickery,Sacha Scott,David J. Dooling,Asif T. Chinwalla,George M. Weinstock,Elaine R. Mardis,Richard K. Wilson,Gad Getz,Wendy Winckler,Roel G.W. Verhaak,Michael S. Lawrence,Michael J. T. O’Kelly,James A. Robinson,Gabriele Alexe,Rameen Beroukhim,Scott L. Carter,Derek Y. Chiang,Josh Gould,Supriya Gupta,Josh Korn,Craig H. Mermel,Jill P. Mesirov,Stefano Monti,Huy V. Nguyen,Melissa Parkin,Michael R. Reich,Nicolas Stransky,Barbara A. Weir,Levi A. Garraway,Todd R. Golub,Matthew Meyerson,Lynda Chin,Alexei Protopopov,Jianhua Zhang,Ilana Perna,Sandy Aronson,Narayanan Sathiamoorthy,Georgia Ren,Jun Yao,W. Ruprecht Wiedemeyer,Hyun Soo Kim,Won Kong Sek,Yonghong Xiao,Isaac S. Kohane,Jon G. Seidman,Peter J. Park,Raju Kucherlapati,Peter W. Laird,Leslie Cope,James G. Herman,Daniel J. Weisenberger,Fei Pan,David Van Den Berg,Leander Van Neste,Mi Yi Joo,Kornel E. Schuebel,Stephen B. Baylin,Devin Absher,Jun Li,Audrey Southwick,Shannon T. Brady,Amita Aggarwal,Tisha Chung,Gavin Sherlock,James D. Brooks,Richard M. Myers,Paul T. Spellman,Elizabeth Purdom,Lakshmi Jakkula,Anna Lapuk,Henry Marr,Shannon Dorton,Gi Choi Yoon,Ju Han,Amrita Ray,Victoria Wang,Steffen Durinck,Mark D. Robinson,Nicholas J. Wang,Karen Vranizan,Vivian Peng,Eric Van Name,Gerald V. Fontenay,John Ngai,John G. Conboy,Bahram Parvin,Heidi S. Feiler,Terence P. Speed,Terence P. Speed,Joe W. Gray,Cameron Brennan,Nicholas D. Socci,Adam B. Olshen,Barry S. Taylor,Barry S. Taylor,Alex E. Lash,Nikolaus Schultz,Boris Reva,Yevgeniy Antipin,Alexey Stukalov,Benjamin Gross,Ethan Cerami,Qing Wang Wei,Li-Xuan Qin,Venkatraman E. Seshan,Liliana Villafania,Magali Cavatore,Laetitia Borsu,Agnes Viale,William L. Gerald,Chris Sander,Marc Ladanyi,Charles M. Perou,D. Neil Hayes,Michael D. Topal,Katherine A. Hoadley,Yuan Qi,Sai Balu,Yan Shi,Junyuan Wu,Robert Penny,Michael L. Bittner,Troy Shelton,Elizabeth Lenkiewicz,Scott Morris,Debbie Beasley,Sheri Sanders,Ari B. Kahn,Robert Sfeir,Jessica Chen,David Nassau,Larry Feng,Erin Hickey,Anna D. Barker,Daniela S. Gerhard,Joseph G. Vockley,Carolyn C. Compton,Jim Vaught,Peter Fielding,Martin L. Ferguson,Carl F. Schaefer,Jinghui Zhang,Subhashree Madhavan,Kenneth H. Buetow,Francis S. Collins,Peter J. Good,Mark S. Guyer,Brad Ozenberger,Jane Peterson,Elizabeth J. Thomson +233 more
TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Journal ArticleDOI
I-TASSER: a unified platform for automated protein structure and function prediction
TL;DR: The iterative threading assembly refinement (I-TASSER) server is an integrated platform for automated protein structure and function prediction based on the sequence- to-structure-to-function paradigm.
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