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
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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Book ChapterDOI
Computational and Systems Cancer Biology
TL;DR: The goal is to improve the ability to leverage full repertoires of tumor specific molecular interactions to elucidate drivers and mechanisms of tumor initiation, progression, and drug sensitivity, with application to therapy.
Fluorescence in situ Hybridization in Surgical Pathology: Principles and Applications
TL;DR: A review of FISH detected translocations with a focus on strategies for clinical application in surgical pathology practice can be found in this paper, where the authors provide a theoretical and practical survey of translocations detected by FISH.
Journal ArticleDOI
The genomic landscape of familial glioma
Dong-Joo Choi,Georgina Armstrong,Brittney Lozzi,Prashanth Vijayaraghavan,Sharon E. Plon,Terence Wong,Eric Boerwinkle,Donna M. Muzny,Hsiao-Chi Chen,Richard A. Gibbs,Quinn T. Ostrom,Beatrice Melin,Benjamin Deneen,Melissa L. Bondy,Matthew N. Bainbridge,Christopher I. Amos,Jill S. Barnholtz-Sloan,Jonine L. Bernstein,Elizabeth B. Claus,Richard S. Houlston,Dora Il'yasova,Robert B. Jenkins,Christoffer Johansen,Daniel H. Lachance,Rose Lai,Ryan Merrell,Sara H. Olson,Siegal Sadetzki,Joellen M. Schildkraut,Sanjay Shete,J. Ambrose,Prabhu Arumugam,Roel P. J. Bevers,Marta Bleda,Freya Boardman-Pretty,Chris Boustred,Hank Brittain,M. A. Brown,Margaret Caulfield,G. Chan,Adriane Giess,John M. Griffin,A Hamblin,Seth Henderson,Tim Hubbard,R. Jackson,L. J. Jones,Dalia Kasperaviciute,Mehmet Suat Kayikci,Athanasios Kousathanas,L. Lahnstein,Antony Lakey,Sarah Leigh,I. Leong,F. J. López,Fiona Maleady-Crowe,M. McEntagart,Fabiana Minneci,Jonathan S. Mitchell,Loukas Moutsianas,M. Mueller,Nirupa Murugaesu,Anna C. Need,Peter O'Donovan,Christopher A. Odhams,Clyde L. Patch,Daniel Perez-Gil,M. Pereira,John Pullinger,T. Rahim,Augusto Rendon,Tim Rogers,K Savage,K. Sawant,Robt. H. Scott,Afshan Siddiq,A. Sieghart,S.C. Smith,Alona Sosinsky,Alexander Stuckey,Maël Tanguy,Ana Lisa Taylor Tavares,Era Thomas,Sue Thompson,Arianna Tucci,M. Welland,Eleanor Williams,K. Witkowska,S. Wood,Magdalena Zarowiecki +89 more
TL;DR: This paper performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families.
Posted ContentDOI
A Novel And Efficient Algorithm For De Novo Discovery Of Mutated Driver Pathways In Cancer
TL;DR: A new algorithm based on a novel formulation of the problem as non-convex programming and nonconveX regularization is developed, which is computationally more efficient, effective and scalable than existing Monte Carlo searching and several other algorithms, which have been applied to The Cancer Genome Atlas project.
Journal ArticleDOI
Gene-Tailored Treatments for Brain Disorders: Challenges and Opportunities
Giovanni Esposito,Jean Marc Burgunder,John Dunlop,Philip Gorwood,Amir Inamdar,Stefan M. Pfister,Roland Pochet,Martin J. van den Bent,Nancy Van Hoylandt,Michael Weller,Manfred Westphal,Wolfgang Wick,David Nutt +12 more
TL;DR: Genetic analyses show that for major common disorders such as schizophrenia and depression there are no single gene alterations which offer options for targeted therapy development, and new approaches are being developed to leverage genetic information to predict patients' responses to treatment.
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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
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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.
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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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