Comprehensive genomic characterization defines human glioblastoma genes and core pathways

  title={Comprehensive genomic characterization defines human glioblastoma genes and core pathways},
  author={Roger E. McLendon and Allan H. Friedman and Darrell D. Bigner and Erwin G. Van Meir and Daniel J. Brat and Gena M Mastrogianakis and Jeffrey J. Olson and Tom Mikkelsen and Norman L. Lehman and Kenneth D. Aldape and Wai Kwan Alfred Yung and Oliver Bogler and John N. Weinstein and Scott R. Vandenberg and Mitchel S. Berger and M. Prados and Donna M. Muzny and Margaret B. Morgan and Steven E. Scherer and Aniko Sabo and Lynne V. Nazareth and Lora L Lewis and Otis Hall and Yiming Zhu and Yanru Ren and Omar Alvi and Jiqiang Yao and Alicia C. Hawes and Shalini N. Jhangiani and Gerald R. Fowler and Anthony San Lucas and Christie L. Kovar and Andrew Cree and Huyen Dinh and Jireh Santibanez and Vandita Joshi and M L Gonzalez-Garay and Christopher A. Miller and Aleksandar Milosavljevic and Lawrence A. Donehower and David A. Wheeler and Richard A. Gibbs and Kristian Cibulskis and Carrie Sougnez and Tim Fennell and Scott Mahan and Jane Wilkinson and Liuda Ziaugra and Roberto Onofrio and Toby Bloom and Robert Nicol and Kristin G. Ardlie and Jennifer Baldwin and S. Gabriel and Eric S. Lander and Li Ding and Robert S. Fulton and Michael D. McLellan and John W. Wallis and David E. Larson and Xiaoqi Shi and Rachel M. Abbott and Lucinda A. Fulton and Ken Chen and Daniel C. Koboldt and Michael C. Wendl and Rick Meyer and Yuzhu Tang and Ling Lin and John R. Osborne and Brian H. Dunford-Shore and Tracie L. Miner and Kimberly D. Delehaunty and Chris Markovic and Gary W. Swift and William Courtney and Craig S. Pohl and Scott Abbott and Amy E. Hawkins and Shin Leong and Carrie A. Haipek and Heather K. Schmidt and M. Wiechert and Tammi L. Vickery and Sacha Scott and David J. Dooling and Asif T. Chinwalla and George M. Weinstock and Elaine R. Mardis and Richard K. Wilson and Gad Getz and Wendy Winckler and Roel G. W. Verhaak and Michael S. Lawrence and Michael J. T. O’Kelly and James Robinson and Gabriele Alexe and Rameen Beroukhim and Scott L. Carter and Derek Y. Chiang and Josh Gould and Supriya Gupta and Joshua M. Korn and Craig H. Mermel and Jill P. Mesirov and Stefano Monti and Huy Nguyen and Melissa Parkin and Michael Reich and Nicolas Stransky and Barbara A. Weir and Levi A. Garraway and Todd R. Golub and Matthew L Meyerson and Lynda Chin and Alexei Protopopov and Jianhua Zhang and Ilana Perna and S. J. Aronson and Narayanan Sathiamoorthy and Georgi Ren and Jun Yao and Wolf Ruprecht Wiedemeyer and Hyun Soo Kim and Won Kong Sek and Yonghong Xiao and Isaac S. Kohane and Jonathan G. Seidman and Peter J. Park and Raju Kucherlapati and Peter W. Laird and Leslie M. Cope and James Gordon Herman and Daniel J. Weisenberger and Fei Pan and David J. Van Den Berg and Leander Van Neste and Mingyu Joo and Kornel E. Schuebel and Stephen B. Baylin and Devin M Absher and Jun Z. Li and Audrey M. Southwick and Shannon T. Brady and Amita Aggarwal and Tisha Chung and Gavin Sherlock and James D. Brooks and Richard M. Myers and Paul T. Spellman and Elizabeth Purdom and Lakshmi R. Jakkula and A. V. Lapuk and Henry Marr and Shannon Dorton and Gi Choi Yoon and Ju Han and Amrita Ray and Victoria E. H. Wang and Steffen Durinck and Mark D. Robinson and Nicholas J. Wang and Karen Vranizan and Vivian Peng and Eric Van Name and Gerald V. Fontenay and John Ngai and John G Conboy and Bahram Parvin and Heidi S. Feiler and Terence P. Speed and Joe W. Gray and Cameron W. Brennan and Nicholas D. Socci and Adam B. Olshen and Barry S. Taylor and Alex E. Lash and Nikolaus D. Schultz and Boris Reva and Yevgeniy Antipin and Alexey Stukalov and Benjamin E. Gross and Ethan G. Cerami and Qingqing Wei and Li-Xuan Qin and Venkatraman E. Seshan and Liliana Villafania and Magali Cavatore and Laetitia Borsu and Agnes J. Viale and William L. Gerald and Chris Sander and Marc Ladanyi and Charles M. Perou and David Neil Hayes and Michael D. Topal and Katherine A. Hoadley and Yuan Qi and Saianand Balu and Yan Shi and Junyuan Wu and Robert J. Penny and Michael L. Bittner and Troy Shelton and Elizabeth Lenkiewicz and Scott Morris and D. Beasley and Sheri Sanders and Ari B. Kahn and Robert Sfeir and Jessica Chen and David Eduardo Nassau and L. D. Feng and Erin Hickey and Anna D Barker and Daniela S. Gerhard and Joseph G Vockley and Carolyn C. Compton and Jimmie B. Vaught and Peter Fielding and Martin L Ferguson and Carl F. Schaefer and Jinghui Zhang and Subha Madhavan and Kenneth H. Buetow and Francis S. Collins and Peter J. Good and Mark Guyer and Bradley A Ozenberger and Jane Peterson and Elizabeth J. Thomson},
  pages={1061 - 1068}
Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations… 
An integrative characterization of recurrent molecular aberrations in glioblastoma genomes
An algorithm to build ‘association modules’ linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets justified the utility of an integrative analysis on cancer genomes and provide testable characterizations of driver aberration events in GBM.
In silico Analysis of Transcription Factors Associated to Differentially Expressed Genes in Irradiated Glioblastoma Cell Lines
The majority of GBM tumors present genetic alterations in all three pathways, which helps to stimulate cell proliferation and enhance cell survival while allowing tumor cells to escaping from cell-cycle checkpoints, senescence, and apoptosis.
Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes
A multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a possible oncogene, and provides insight on targets for oncogenic pathway-based therapy.
A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival.
A previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM is uncovered.
Comprehensive molecular characterization of human colon and rectal cancer
Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
The integrated landscape of driver genomic alterations in glioblastoma
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.
Comprehensive molecular portraits of human breast tumors
The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.
Integrated Genomic Analyses of Ovarian Carcinoma
It is reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1,BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes.
The Promoter Hypermethylation Status of GATA6, MGMT, and FHIT in Glioblastoma
Investigation of methylation status at the promoter regions of GATA6, MGMT, and FHIT using the methylation-specific polymerase chain reaction shows that promoter hypermethylation of MGMT is a common event in GBM, whereas GATA 6 is epigenetically affected in GBMs.
One step forward toward identification of the genetic signature of glioblastomas.
Two articles in this issue of JAMA take this global genomic approach a step further by identifying and validating networks of altered genes that may play a crucial role in the development and progression of GBM, providing additional potential targets for novel therapies.


Functional Copy-Number Alterations in Cancer
A comprehensive computational approach to robustly map chromosomal alterations in tumor samples and assess their functional importance in cancer is presented, applicable to high-resolution genomic data.
Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma
A systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer, is used to study gliomas and the results support the feasibility and utility of systematic characterization of the cancer genome.
A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.
The evidence suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression, and the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers is highlighted.
PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme
It is confirmed that PIK3CA mutations occur in a significant number of human glioblastomas, further indicating that therapeutic targeting of this pathway in gliOBlastomas is of value and providing a molecular target in this important pediatric malignancy.
Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme.
  • Yu Liang, M. Diehn, M. Israel
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
It is found that the gene expression patterns in paired specimens from the same GBM invariably were more closely related to each other than to any other tumor, even when the paired specimens had strikingly divergent histologies.
Genetic Alterations of Phosphoinositide 3‐kinase Subunit Genes in Human Glioblastomas
The results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating thePI3K‐AKT signaling pathway independently of PTEN mutation.
Molecular Analysis of Glioblastoma: Pathway Profiling and Its Implications for Patient Therapy
Identifying biologically relevant molecular subsets of glioblastoma and detecting pathway profiles that can be used to guide patient therapy are likely to result in significant improvement in the survival of gloOBlastoma patients.
Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment
Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozlomide treatment, mirroring the alkylator resistance conferred by MSH 6 inactivation in vitro.
Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.
Loss of MSH6 occurs in a subset of post-XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozlomide treatment, mirroring the alkylator resistance conferred by MSH 6 inactivation in vitro.