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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Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma
Adrian Ally,Miruna Balasundaram,Rebecca Carlsen,Eric Chuah,Amanda Clarke,Noreen Dhalla,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Yussanne Ma,Marco A. Marra,Michael Mayo,Richard A. Moore,Andrew J. Mungall,Jacqueline E. Schein,Payal Sipahimalani,Angela Tam,Nina Thiessen,Dorothy Cheung,Tina Wong,Denise Brooks,A. Gordon Robertson,Reanne Bowlby,Karen Mungall,Sara Sadeghi,Liu Xi,Kyle R. Covington,Eve Shinbrot,David A. Wheeler,Richard A. Gibbs,Lawrence A. Donehower,Linghua Wang,Jay Bowen,Julie M. Gastier-Foster,Mark Gerken,Carmen Helsel,Kristen M. Leraas,Tara M. Lichtenberg,Nilsa C. Ramirez,Lisa Wise,Erik Zmuda,Stacey Gabriel,Matthew Meyerson,Carrie Cibulskis,Bradley A. Murray,Juliann Shih,Rameen Beroukhim,Andrew D. Cherniack,Steven E. Schumacher,Gordon Saksena,Chandra Sekhar Pedamallu,Lynda Chin,Gad Getz,Michael S. Noble,Hailei Zhang,David I. Heiman,Juok Cho,Nils Gehlenborg,Douglas Voet,Pei Lin,Scott Frazer,Timothy Defreitas,Sam Meier,Michael S. Lawrence,Jaegil Kim,Chad J. Creighton,Donna M. Muzny,Harshavardhan Doddapaneni,Jianhong Hu,Min Wang,Donna Morton,Viktoriya Korchina,Yi Han,Huyen Dinh,Lora Lewis,Michelle Bellair,Xiuping Liu,Jireh Santibanez,Robert Glenn,Sandra Lee,Walker Hale,Joel S. Parker,Matthew D. Wilkerson,D. Neil Hayes,Sheila Reynolds,Ilya Shmulevich,Wei Zhang,Yuexin Liu,Lisa Iype,Hala Makhlouf,Michael Torbenson,Sanjay Kakar,Matthew M. Yeh,Dhanpat Jain,David E. Kleiner,Renumathy Dhanasekaran,Hashem B. El-Serag,Sun Young Yim,John N. Weinstein,Lopa Mishra,Jianping Zhang,Rehan Akbani,Shiyun Ling,Zhenlin Ju,Xiaoping Su,Apurva M. Hegde,Gordon B. Mills,Yiling Lu,Jian Chen,Ju Seog Lee,Bo Hwa Sohn,Jae-Jun Shim,Pan Tong,Hiroyuki Aburatani,Shogo Yamamoto,Kenji Tatsuno,Wei Li,Zheng Xia,Nicolas Stransky,Eric Seiser,Federico Innocenti,Jianjiong Gao,Ritika Kundra,Hongxin Zhang,Zachary J. Heins,Angelica Ochoa,Chris Sander,Marc Ladanyi,Ronglai Shen,Arshi Arora,Francisco Sanchez-Vega,Nikolaus Schultz,Katayoon Kasaian,Amie Radenbaugh,Karl-Dimiter Bissig,David D. Moore,Yasushi Totoki,Hiromi Nakamura,Tatsuhiro Shibata,Christina Yau,Kiley Graim,Josh Stuart,David Haussler,Betty L. Slagle,Akinyemi I. Ojesina,Panagiotis Katsonis,Amanda Koire,Olivier Lichtarge,Teng-Kuei Hsu,Martin L. Ferguson,John A. Demchok,Ina Felau,Margi Sheth,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jean C. Zenklusen,Jiashan Zhang,Carolyn M. Hutter,Heidi J. Sofia,Roel G.W. Verhaak,Siyuan Zheng,Frederick Lang,Sudha Chudamani,Jia Liu,Laxmi Lolla,Ye Wu,Rashi Naresh,Todd Pihl,Charlie Sun,Yunhu Wan,Christopher C. Benz,Amy H. Perou,Leigh B. Thorne,Lori Boice,Mei Huang,W. Kimryn Rathmell,Houtan Noushmehr,Fabiano Pinto Saggioro,Daniela Pretti da Cunha Tirapelli,Carlos Gilberto Carlotti Junior,Enio David Mente,Orlando de Castro Silva,Felipe Amstalden Trevisan,Koo Jeong Kang,Keun Soo Ahn,Nasra H. Giama,Catherine D. Moser,Thomas J. Giordano,Michelle Vinco,Theodore H. Welling,Daniel Crain,Erin Curley,Johanna Gardner,David Mallery,Scott Morris,Joseph Paulauskis,Robert Penny,Candace Shelton,Troy Shelton,Robin Kate Kelley,Joong-Won Park,Vishal S. Chandan,Lewis R. Roberts,Oliver F. Bathe,Curt H. Hagedorn,J. Todd Auman,Daniel R. O'Brien,Jean-Pierre A. Kocher,Corbin D. Jones,Piotr A. Mieczkowski,Charles M. Perou,Tara Skelly,Donghui Tan,Umadevi Veluvolu,Saianand Balu,Tom Bodenheimer,Alan P. Hoyle,Stuart R. Jefferys,Shaowu Meng,Lisle E. Mose,Yan Shi,Janae V. Simons,Matthew G. Soloway,Jeffrey Roach,Katherine A. Hoadley,Stephen B. Baylin,Hui Shen,Toshinori Hinoue,Moiz S. Bootwalla,David Van Den Berg,Daniel J. Weisenberger,Phillip H. Lai,Andrea Holbrook,Mario Berrios,Peter W. Laird +235 more
TL;DR: Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts and development of a p53 target gene expression signature correlating with poor survival was enabled.
Journal ArticleDOI
Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.
Michele Ceccarelli,Floris P. Barthel,Tathiane M. Malta,Thais S. Sabedot,Sofie R. Salama,Bradley A. Murray,Olena Morozova,Yulia Newton,Amie Radenbaugh,Stefano Maria Pagnotta,Samreen Anjum,Jiguang Wang,Ganiraju C. Manyam,Pietro Zoppoli,Shiyun Ling,Arjun A. Rao,Mia Grifford,Andrew D. Cherniack,Hailei Zhang,Laila M. Poisson,Carlos Gilberto Carlotti,Daniela Pretti da Cunha Tirapelli,Arvind Rao,Tom Mikkelsen,Ching C. Lau,W. K. Alfred Yung,Raul Rabadan,Jason T. Huse,Daniel J. Brat,Norman L. Lehman,Jill S. Barnholtz-Sloan,Siyuan Zheng,Kenneth R. Hess,Ganesh Rao,Matthew Meyerson,Rameen Beroukhim,Lee Cooper,Rehan Akbani,Margaret Wrensch,David Haussler,Kenneth Aldape,Peter W. Laird,David H. Gutmann,Houtan Noushmehr,Antonio Iavarone,Roel G.W. Verhaak +45 more
TL;DR: The complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas were defined from The Cancer Genome Atlas and molecular profiles were used to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease.
Journal ArticleDOI
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma
Gang Wu,Alexander K. Diaz,Alexander K. Diaz,Barbara S. Paugh,Sherri Rankin,Bensheng Ju,Yongjin Li,Xiaoyan Zhu,Chunxu Qu,Xiang Chen,Junyuan Zhang,John Easton,Michael N. Edmonson,Xiaotu Ma,Charles Lu,Panduka Nagahawatte,Erin Hedlund,Michael Rusch,Stanley Pounds,Tong Lin,Arzu Onar-Thomas,Robert Huether,Richard W. Kriwacki,Matthew Parker,Pankaj Gupta,Jared Becksfort,Lei Wei,Heather L. Mulder,Kristy Boggs,Bhavin Vadodaria,Donald Yergeau,Jake C. Russell,Kerri Ochoa,Robert S. Fulton,Lucinda Fulton,Chris Jones,Frederick A. Boop,Alberto Broniscer,Cynthia Wetmore,Amar Gajjar,Li Ding,Elaine R. Mardis,Richard K. Wilson,Michael R. Taylor,James R. Downing,David W. Ellison,Jinghui Zhang,Suzanne J. Baker,Suzanne J. Baker +48 more
TL;DR: In this article, the authors analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGG (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing.
Journal ArticleDOI
Mutational landscape and clonal architecture in grade II and III gliomas
Hiromichi Suzuki,Kosuke Aoki,Kenichi Chiba,Yusuke Sato,Yusuke Shiozawa,Yuichi Shiraishi,Teppei Shimamura,Atsushi Niida,Kazuya Motomura,Fumiharu Ohka,Takashi Yamamoto,Kuniaki Tanahashi,Melissa Ranjit,Toshihiko Wakabayashi,Tetsuichi Yoshizato,Keisuke Kataoka,Kenichi Yoshida,Yasunobu Nagata,Aiko Sato-Otsubo,Hiroko Tanaka,Masashi Sanada,Yutaka Kondo,Hideo Nakamura,Masahiro Mizoguchi,Tatsuya Abe,Yoshihiro Muragaki,Reiko Watanabe,Ichiro Ito,Satoru Miyano,Atsushi Natsume,Seishi Ogawa +30 more
TL;DR: In this article, the authors delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors, suggesting that there is functional interplay between the mutations that drive clonal selection.
Reference EntryDOI
National Institute of Neurological Disorders and Stroke
Milton Budoff,Tamara J. Martin +1 more
TL;DR: Marmosets are poised to be a central player to advance the core mission of the NINDS, as their brains retain the typical anatomical and functional organization of the primate brain and the species exhibits the breadth of cognitive sophistication that distinguishes primates from other taxonomic groups.
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