@article{RN6143,
   author = {Brat, D. J. and Verhaak, R. G. and Aldape, K. D. and Yung, W. K. and Salama, S. R. and Cooper, L. A. and Rheinbay, E. and Miller, C. R. and Vitucci, M. and Morozova, O. and Robertson, A. G. and Noushmehr, H. and Laird, P. W. and Cherniack, A. D. and Akbani, R. and Huse, J. T. and Ciriello, G. and Poisson, L. M. and Barnholtz-Sloan, J. S. and Berger, M. S. and Brennan, C. and Colen, R. R. and Colman, H. and Flanders, A. E. and Giannini, C. and Grifford, M. and Iavarone, A. and Jain, R. and Joseph, I. and Kim, J. and Kasaian, K. and Mikkelsen, T. and Murray, B. A. and O'Neill, B. P. and Pachter, L. and Parsons, D. W. and Sougnez, C. and Sulman, E. P. and Vandenberg, S. R. and Van Meir, E. G. and von Deimling, A. and Zhang, H. and Crain, D. and Lau, K. and Mallery, D. and Morris, S. and Paulauskis, J. and Penny, R. and Shelton, T. and Sherman, M. and Yena, P. and Black, A. and Bowen, J. and Dicostanzo, K. and Gastier-Foster, J. and Leraas, K. M. and Lichtenberg, T. M. and Pierson, C. R. and Ramirez, N. C. and Taylor, C. and Weaver, S. and Wise, L. and Zmuda, E. and Davidsen, T. and Demchok, J. A. and Eley, G. and Ferguson, M. L. and Hutter, C. M. and Mills Shaw, K. R. and Ozenberger, B. A. and Sheth, M. and Sofia, H. J. and Tarnuzzer, R. and Wang, Z. and Yang, L. and Zenklusen, J. C. and Ayala, B. and Baboud, J. and Chudamani, S. and Jensen, M. A. and Liu, J. and Pihl, T. and Raman, R. and Wan, Y. and Wu, Y. and Ally, A. and Auman, J. T. and Balasundaram, M. and Balu, S. and Baylin, S. B. and Beroukhim, R. and Bootwalla, M. S. and Bowlby, R. and Bristow, C. A. and Brooks, D. and Butterfield, Y. and Carlsen, R. and Carter, S. and Chin, L. and Chu, A. and others },
   title = {Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas},
   journal = {N Engl J Med},
   volume = {372},
   number = {26},
   pages = {2481-98},
   note = {1533-4406
Cancer Genome Atlas Research Network
Brat, Daniel J
Verhaak, Roel G W
Aldape, Kenneth D
Yung, W K Alfred
Salama, Sofie R
Cooper, Lee A D
Rheinbay, Esther
Miller, C Ryan
Vitucci, Mark
Morozova, Olena
Robertson, A Gordon
Noushmehr, Houtan
Laird, Peter W
Cherniack, Andrew D
Akbani, Rehan
Huse, Jason T
Ciriello, Giovanni
Poisson, Laila M
Barnholtz-Sloan, Jill S
Berger, Mitchel S
Brennan, Cameron
Colen, Rivka R
Colman, Howard
Flanders, Adam E
Giannini, Caterina
Grifford, Mia
Iavarone, Antonio
Jain, Rajan
Joseph, Isaac
Kim, Jaegil
Kasaian, Katayoon
Mikkelsen, Tom
Murray, Bradley A
O'Neill, Brian Patrick
Pachter, Lior
Parsons, Donald W
Sougnez, Carrie
Sulman, Erik P
Vandenberg, Scott R
Van Meir, Erwin G
von Deimling, Andreas
Zhang, Hailei
Crain, Daniel
Lau, Kevin
Mallery, David
Morris, Scott
Paulauskis, Joseph
Penny, Robert
Shelton, Troy
Sherman, Mark
Yena, Peggy
Black, Aaron
Bowen, Jay
Dicostanzo, Katie
Gastier-Foster, Julie
Leraas, Kristen M
Lichtenberg, Tara M
Pierson, Christopher R
Ramirez, Nilsa C
Taylor, Cynthia
Weaver, Stephanie
Wise, Lisa
Zmuda, Erik
Davidsen, Tanja
Demchok, John A
Eley, Greg
Ferguson, Martin L
Hutter, Carolyn M
Mills Shaw, Kenna R
Ozenberger, Bradley A
Sheth, Margi
Sofia, Heidi J
Tarnuzzer, Roy
Wang, Zhining
Yang, Liming
Zenklusen, Jean Claude
Ayala, Brenda
Baboud, Julien
Chudamani, Sudha
Jensen, Mark A
Liu, Jia
Pihl, Todd
Raman, Rohini
Wan, Yunhu
Wu, Ye
Ally, Adrian
Auman, J Todd
Balasundaram, Miruna
Balu, Saianand
Baylin, Stephen B
Beroukhim, Rameen
Bootwalla, Moiz S
Bowlby, Reanne
Bristow, Christopher A
Brooks, Denise
Butterfield, Yaron
Carlsen, Rebecca
Carter, Scott
Chin, Lynda
Chu, Andy
Chuah, Eric
Cibulskis, Kristian
Clarke, Amanda
Coetzee, Simon G
Dhalla, Noreen
Fennell, Tim
Fisher, Sheila
Gabriel, Stacey
Getz, Gad
Gibbs, Richard
Guin, Ranabir
Hadjipanayis, Angela
Hayes, D Neil
Hinoue, Toshinori
Hoadley, Katherine
Holt, Robert A
Hoyle, Alan P
Jefferys, Stuart R
Jones, Steven
Jones, Corbin D
Kucherlapati, Raju
Lai, Phillip H
Lander, Eric
Lee, Semin
Lichtenstein, Lee
Ma, Yussanne
Maglinte, Dennis T
Mahadeshwar, Harshad S
Marra, Marco A
Mayo, Michael
Meng, Shaowu
Meyerson, Matthew L
Mieczkowski, Piotr A
Moore, Richard A
Mose, Lisle E
Mungall, Andrew J
Pantazi, Angeliki
Parfenov, Michael
Park, Peter J
Parker, Joel S
Perou, Charles M
Protopopov, Alexei
Ren, Xiaojia
Roach, Jeffrey
Sabedot, Thaís S
Schein, Jacqueline
Schumacher, Steven E
Seidman, Jonathan G
Seth, Sahil
Shen, Hui
Simons, Janae V
Sipahimalani, Payal
Soloway, Matthew G
Song, Xingzhi
Sun, Huandong
Tabak, Barbara
Tam, Angela
Tan, Donghui
Tang, Jiabin
Thiessen, Nina
Triche, Timothy Jr
Van Den Berg, David J
Veluvolu, Umadevi
Waring, Scot
Weisenberger, Daniel J
Wilkerson, Matthew D
Wong, Tina
Wu, Junyuan
Xi, Liu
Xu, Andrew W
Yang, Lixing
Zack, Travis I
Zhang, Jianhua
Aksoy, B Arman
Arachchi, Harindra
Benz, Chris
Bernard, Brady
Carlin, Daniel
Cho, Juok
DiCara, Daniel
Frazer, Scott
Fuller, Gregory N
Gao, JianJiong
Gehlenborg, Nils
Haussler, David
Heiman, David I
Iype, Lisa
Jacobsen, Anders
Ju, Zhenlin
Katzman, Sol
Kim, Hoon
Knijnenburg, Theo
Kreisberg, Richard Bailey
Lawrence, Michael S
Lee, William
Leinonen, Kalle
Lin, Pei
Ling, Shiyun
Liu, Wenbin
Liu, Yingchun
Liu, Yuexin
Lu, Yiling
Mills, Gordon
Ng, Sam
Noble, Michael S
Paull, Evan
Rao, Arvind
Reynolds, Sheila
Saksena, Gordon
Sanborn, Zack
Sander, Chris
Schultz, Nikolaus
Senbabaoglu, Yasin
Shen, Ronglai
Shmulevich, Ilya
Sinha, Rileen
Stuart, Josh
Sumer, S Onur
Sun, Yichao
Tasman, Natalie
Taylor, Barry S
Voet, Doug
Weinhold, Nils
Weinstein, John N
Yang, Da
Yoshihara, Kosuke
Zheng, Siyuan
Zhang, Wei
Zou, Lihua
Abel, Ty
Sadeghi, Sara
Cohen, Mark L
Eschbacher, Jenny
Hattab, Eyas M
Raghunathan, Aditya
Schniederjan, Matthew J
Aziz, Dina
Barnett, Gene
Barrett, Wendi
Bigner, Darell D
Boice, Lori
Brewer, Cathy
Calatozzolo, Chiara
Campos, Benito
Carlotti, Carlos Gilberto Jr
Chan, Timothy A
Cuppini, Lucia
Curley, Erin
Cuzzubbo, Stefania
Devine, Karen
DiMeco, Francesco
Duell, Rebecca
Elder, J Bradley
Fehrenbach, Ashley
Finocchiaro, Gaetano
Friedman, William
Fulop, Jordonna
Gardner, Johanna
Hermes, Beth
Herold-Mende, Christel
Jungk, Christine
Kendler, Ady
Lehman, Norman L
Lipp, Eric
Liu, Ouida
Mandt, Randy
McGraw, Mary
Mclendon, Roger
McPherson, Christopher
Neder, Luciano
Nguyen, Phuong
Noss, Ardene
Nunziata, Raffaele
Ostrom, Quinn T
Palmer, Cheryl
Perin, Alessandro
Pollo, Bianca
Potapov, Alexander
Potapova, Olga
Rathmell, W Kimryn
Rotin, Daniil
Scarpace, Lisa
Schilero, Cathy
Senecal, Kelly
Shimmel, Kristen
Shurkhay, Vsevolod
Sifri, Suzanne
Singh, Rosy
Sloan, Andrew E
Smolenski, Kathy
Staugaitis, Susan M
Steele, Ruth
Thorne, Leigh
Tirapelli, Daniela P C
Unterberg, Andreas
Vallurupalli, Mahitha
Wang, Yun
Warnick, Ronald
Williams, Felicia
Wolinsky, Yingli
Bell, Sue
Rosenberg, Mara
Stewart, Chip
Huang, Franklin
Grimsby, Jonna L
Radenbaugh, Amie J
Zhang, Jianan
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Journal Article
Research Support, N.I.H., Extramural
United States
2015/06/11
N Engl J Med. 2015 Jun 25;372(26):2481-98. doi: 10.1056/NEJMoa1402121. Epub 2015 Jun 10.},
   abstract = {BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).},
   keywords = {Adolescent
Adult
Aged
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 19
Cluster Analysis
DNA, Neoplasm/*analysis
Female
*Genes, p53
Glioblastoma/genetics
Glioma/*genetics/metabolism/mortality
Humans
Kaplan-Meier Estimate
Male
Middle Aged
*Mutation
Neoplasm Grading
Proportional Hazards Models
Sequence Analysis, DNA
Signal Transduction},
   ISSN = {0028-4793 (Print)
0028-4793},
   DOI = {10.1056/NEJMoa1402121},
   year = {2015},
   type = {Journal Article}
}

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Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas","journal":"N Engl J Med","volume":"372","number":"26","pages":"2481-98","note":"1533-4406 Cancer Genome Atlas Research Network Brat, Daniel J Verhaak, Roel G W Aldape, Kenneth D Yung, W K Alfred Salama, Sofie R Cooper, Lee A D Rheinbay, Esther Miller, C Ryan Vitucci, Mark Morozova, Olena Robertson, A Gordon Noushmehr, Houtan Laird, Peter W Cherniack, Andrew D Akbani, Rehan Huse, Jason T Ciriello, Giovanni Poisson, Laila M Barnholtz-Sloan, Jill S Berger, Mitchel S Brennan, Cameron Colen, Rivka R Colman, Howard Flanders, Adam E Giannini, Caterina Grifford, Mia Iavarone, Antonio Jain, Rajan Joseph, Isaac Kim, Jaegil Kasaian, Katayoon Mikkelsen, Tom Murray, Bradley A O'Neill, Brian Patrick Pachter, Lior Parsons, Donald W Sougnez, Carrie Sulman, Erik P Vandenberg, Scott R Van Meir, Erwin G von Deimling, Andreas Zhang, Hailei Crain, Daniel Lau, Kevin Mallery, David Morris, Scott Paulauskis, Joseph Penny, Robert Shelton, Troy Sherman, Mark Yena, Peggy Black, Aaron Bowen, Jay Dicostanzo, Katie Gastier-Foster, Julie Leraas, Kristen M Lichtenberg, Tara M Pierson, Christopher R Ramirez, Nilsa C Taylor, Cynthia Weaver, Stephanie Wise, Lisa Zmuda, Erik Davidsen, Tanja Demchok, John A Eley, Greg Ferguson, Martin L Hutter, Carolyn M Mills Shaw, Kenna R Ozenberger, Bradley A Sheth, Margi Sofia, Heidi J Tarnuzzer, Roy Wang, Zhining Yang, Liming Zenklusen, Jean Claude Ayala, Brenda Baboud, Julien Chudamani, Sudha Jensen, Mark A Liu, Jia Pihl, Todd Raman, Rohini Wan, Yunhu Wu, Ye Ally, Adrian Auman, J Todd Balasundaram, Miruna Balu, Saianand Baylin, Stephen B Beroukhim, Rameen Bootwalla, Moiz S Bowlby, Reanne Bristow, Christopher A Brooks, Denise Butterfield, Yaron Carlsen, Rebecca Carter, Scott Chin, Lynda Chu, Andy Chuah, Eric Cibulskis, Kristian Clarke, Amanda Coetzee, Simon G Dhalla, Noreen Fennell, Tim Fisher, Sheila Gabriel, Stacey Getz, Gad Gibbs, Richard Guin, Ranabir Hadjipanayis, Angela Hayes, D Neil Hinoue, Toshinori Hoadley, Katherine Holt, Robert A Hoyle, Alan P Jefferys, Stuart R Jones, Steven Jones, Corbin D Kucherlapati, Raju Lai, Phillip H Lander, Eric Lee, Semin Lichtenstein, Lee Ma, Yussanne Maglinte, Dennis T Mahadeshwar, Harshad S Marra, Marco A Mayo, Michael Meng, Shaowu Meyerson, Matthew L Mieczkowski, Piotr A Moore, Richard A Mose, Lisle E Mungall, Andrew J Pantazi, Angeliki Parfenov, Michael Park, Peter J Parker, Joel S Perou, Charles M Protopopov, Alexei Ren, Xiaojia Roach, Jeffrey Sabedot, Thaís S Schein, Jacqueline Schumacher, Steven E Seidman, Jonathan G Seth, Sahil Shen, Hui Simons, Janae V Sipahimalani, Payal Soloway, Matthew G Song, Xingzhi Sun, Huandong Tabak, Barbara Tam, Angela Tan, Donghui Tang, Jiabin Thiessen, Nina Triche, Timothy Jr Van Den Berg, David J Veluvolu, Umadevi Waring, Scot Weisenberger, Daniel J Wilkerson, Matthew D Wong, Tina Wu, Junyuan Xi, Liu Xu, Andrew W Yang, Lixing Zack, Travis I Zhang, Jianhua Aksoy, B Arman Arachchi, Harindra Benz, Chris Bernard, Brady Carlin, Daniel Cho, Juok DiCara, Daniel Frazer, Scott Fuller, Gregory N Gao, JianJiong Gehlenborg, Nils Haussler, David Heiman, David I Iype, Lisa Jacobsen, Anders Ju, Zhenlin Katzman, Sol Kim, Hoon Knijnenburg, Theo Kreisberg, Richard Bailey Lawrence, Michael S Lee, William Leinonen, Kalle Lin, Pei Ling, Shiyun Liu, Wenbin Liu, Yingchun Liu, Yuexin Lu, Yiling Mills, Gordon Ng, Sam Noble, Michael S Paull, Evan Rao, Arvind Reynolds, Sheila Saksena, Gordon Sanborn, Zack Sander, Chris Schultz, Nikolaus Senbabaoglu, Yasin Shen, Ronglai Shmulevich, Ilya Sinha, Rileen Stuart, Josh Sumer, S Onur Sun, Yichao Tasman, Natalie Taylor, Barry S Voet, Doug Weinhold, Nils Weinstein, John N Yang, Da Yoshihara, Kosuke Zheng, Siyuan Zhang, Wei Zou, Lihua Abel, Ty Sadeghi, Sara Cohen, Mark L Eschbacher, Jenny Hattab, Eyas M Raghunathan, Aditya Schniederjan, Matthew J Aziz, Dina Barnett, Gene Barrett, Wendi Bigner, Darell D Boice, Lori Brewer, Cathy Calatozzolo, Chiara Campos, Benito Carlotti, Carlos Gilberto Jr Chan, Timothy A Cuppini, Lucia Curley, Erin Cuzzubbo, Stefania Devine, Karen DiMeco, Francesco Duell, Rebecca Elder, J Bradley Fehrenbach, Ashley Finocchiaro, Gaetano Friedman, William Fulop, Jordonna Gardner, Johanna Hermes, Beth Herold-Mende, Christel Jungk, Christine Kendler, Ady Lehman, Norman L Lipp, Eric Liu, Ouida Mandt, Randy McGraw, Mary Mclendon, Roger McPherson, Christopher Neder, Luciano Nguyen, Phuong Noss, Ardene Nunziata, Raffaele Ostrom, Quinn T Palmer, Cheryl Perin, Alessandro Pollo, Bianca Potapov, Alexander Potapova, Olga Rathmell, W Kimryn Rotin, Daniil Scarpace, Lisa Schilero, Cathy Senecal, Kelly Shimmel, Kristen Shurkhay, Vsevolod Sifri, Suzanne Singh, Rosy Sloan, Andrew E Smolenski, Kathy Staugaitis, Susan M Steele, Ruth Thorne, Leigh Tirapelli, Daniela P C Unterberg, Andreas Vallurupalli, Mahitha Wang, Yun Warnick, Ronald Williams, Felicia Wolinsky, Yingli Bell, Sue Rosenberg, Mara Stewart, Chip Huang, Franklin Grimsby, Jonna L Radenbaugh, Amie J Zhang, Jianan U24CA143840/CA/NCI NIH HHS/United States U24CA126561/CA/NCI NIH HHS/United States P30 CA016672/CA/NCI NIH HHS/United States U24 CA143882/CA/NCI NIH HHS/United States U54 HG003067/HG/NHGRI NIH HHS/United States U54HG003273/HG/NHGRI NIH HHS/United States U24 CA143835/CA/NCI NIH HHS/United States U24CA143731/CA/NCI NIH HHS/United States U24CA126551/CA/NCI NIH HHS/United States U24CA126543/CA/NCI NIH HHS/United States U24CA126554/CA/NCI NIH HHS/United States U24 CA143866/CA/NCI NIH HHS/United States U24CA143858/CA/NCI NIH HHS/United States U24CA126544/CA/NCI NIH HHS/United States P30CA016672/CA/NCI NIH HHS/United States U24CA143882/CA/NCI NIH HHS/United States U24 CA126551/CA/NCI NIH HHS/United States U24CA144025/CA/NCI NIH HHS/United States U54HG003067/HG/NHGRI NIH HHS/United States U24 CA143845/CA/NCI NIH HHS/United States U24 CA143799/CA/NCI NIH HHS/United States U01 CA168394/CA/NCI NIH HHS/United States U54 HG003273/HG/NHGRI NIH HHS/United States P30 CA008748/CA/NCI NIH HHS/United States U24 CA144025/CA/NCI NIH HHS/United States U24 CA194362/CA/NCI NIH HHS/United States U24CA143883/CA/NCI NIH HHS/United States U54HG003079/HG/NHGRI NIH HHS/United States U24 CA126554/CA/NCI NIH HHS/United States U24 CA180951/CA/NCI NIH HHS/United States U24 CA143840/CA/NCI NIH HHS/United States U24 CA143843/CA/NCI NIH HHS/United States U24CA143867/CA/NCI NIH HHS/United States U24CA143835/CA/NCI NIH HHS/United States U24 CA126561/CA/NCI NIH HHS/United States U24 CA143858/CA/NCI NIH HHS/United States U24CA143843/CA/NCI NIH HHS/United States R01 NS081125/NS/NINDS NIH HHS/United States U24 CA143848/CA/NCI NIH HHS/United States U24 CA126543/CA/NCI NIH HHS/United States U24CA143848/CA/NCI NIH HHS/United States U24CA126563/CA/NCI NIH HHS/United States U24CA126546/CA/NCI NIH HHS/United States U54 HG003079/HG/NHGRI NIH HHS/United States U24CA143799/CA/NCI NIH HHS/United States U54 HG007990/HG/NHGRI NIH HHS/United States U24 CA143883/CA/NCI NIH HHS/United States R01 CA163722/CA/NCI NIH HHS/United States U24CA143866/CA/NCI NIH HHS/United States U24CA143845/CA/NCI NIH HHS/United States U24 CA143867/CA/NCI NIH HHS/United States U24 CA126546/CA/NCI NIH HHS/United States U24 CA126563/CA/NCI NIH HHS/United States U24 CA126544/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural United States 2015/06/11 N Engl J Med. 2015 Jun 25;372(26):2481-98. doi: 10.1056/NEJMoa1402121. Epub 2015 Jun 10.","abstract":"BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).","keywords":"Adolescent Adult Aged Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 19 Cluster Analysis DNA, Neoplasm/*analysis Female *Genes, p53 Glioblastoma/genetics Glioma/*genetics/metabolism/mortality Humans Kaplan-Meier Estimate Male Middle Aged *Mutation Neoplasm Grading Proportional Hazards Models Sequence Analysis, DNA Signal Transduction","issn":"0028-4793 (Print) 0028-4793","doi":"10.1056/NEJMoa1402121","year":"2015","bibtex":"@article{RN6143,\n author = {Brat, D. J. and Verhaak, R. G. and Aldape, K. D. and Yung, W. K. and Salama, S. R. and Cooper, L. A. and Rheinbay, E. and Miller, C. R. and Vitucci, M. and Morozova, O. and Robertson, A. G. and Noushmehr, H. and Laird, P. W. and Cherniack, A. D. and Akbani, R. and Huse, J. T. and Ciriello, G. and Poisson, L. M. and Barnholtz-Sloan, J. S. and Berger, M. S. and Brennan, C. and Colen, R. R. and Colman, H. and Flanders, A. E. and Giannini, C. and Grifford, M. and Iavarone, A. and Jain, R. and Joseph, I. and Kim, J. and Kasaian, K. and Mikkelsen, T. and Murray, B. A. and O'Neill, B. P. and Pachter, L. and Parsons, D. W. and Sougnez, C. and Sulman, E. P. and Vandenberg, S. R. and Van Meir, E. G. and von Deimling, A. and Zhang, H. and Crain, D. and Lau, K. and Mallery, D. and Morris, S. and Paulauskis, J. and Penny, R. and Shelton, T. and Sherman, M. and Yena, P. and Black, A. and Bowen, J. and Dicostanzo, K. and Gastier-Foster, J. and Leraas, K. M. and Lichtenberg, T. M. and Pierson, C. R. and Ramirez, N. C. and Taylor, C. and Weaver, S. and Wise, L. and Zmuda, E. and Davidsen, T. and Demchok, J. A. and Eley, G. and Ferguson, M. L. and Hutter, C. M. and Mills Shaw, K. R. and Ozenberger, B. A. and Sheth, M. and Sofia, H. J. and Tarnuzzer, R. and Wang, Z. and Yang, L. and Zenklusen, J. C. and Ayala, B. and Baboud, J. and Chudamani, S. and Jensen, M. A. and Liu, J. and Pihl, T. and Raman, R. and Wan, Y. and Wu, Y. and Ally, A. and Auman, J. T. and Balasundaram, M. and Balu, S. and Baylin, S. B. and Beroukhim, R. and Bootwalla, M. S. and Bowlby, R. and Bristow, C. A. and Brooks, D. and Butterfield, Y. and Carlsen, R. and Carter, S. and Chin, L. and Chu, A. and others },\n title = {Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas},\n journal = {N Engl J Med},\n volume = {372},\n number = {26},\n pages = {2481-98},\n note = {1533-4406\nCancer Genome Atlas Research Network\nBrat, Daniel J\nVerhaak, Roel G W\nAldape, Kenneth D\nYung, W K Alfred\nSalama, Sofie R\nCooper, Lee A D\nRheinbay, Esther\nMiller, C Ryan\nVitucci, Mark\nMorozova, Olena\nRobertson, A Gordon\nNoushmehr, Houtan\nLaird, Peter W\nCherniack, Andrew D\nAkbani, Rehan\nHuse, Jason T\nCiriello, Giovanni\nPoisson, Laila M\nBarnholtz-Sloan, Jill S\nBerger, Mitchel S\nBrennan, Cameron\nColen, Rivka R\nColman, Howard\nFlanders, Adam E\nGiannini, Caterina\nGrifford, Mia\nIavarone, Antonio\nJain, Rajan\nJoseph, Isaac\nKim, Jaegil\nKasaian, Katayoon\nMikkelsen, Tom\nMurray, Bradley A\nO'Neill, Brian Patrick\nPachter, Lior\nParsons, Donald W\nSougnez, Carrie\nSulman, Erik P\nVandenberg, Scott R\nVan Meir, Erwin G\nvon Deimling, Andreas\nZhang, Hailei\nCrain, Daniel\nLau, Kevin\nMallery, David\nMorris, Scott\nPaulauskis, Joseph\nPenny, Robert\nShelton, Troy\nSherman, Mark\nYena, Peggy\nBlack, Aaron\nBowen, Jay\nDicostanzo, Katie\nGastier-Foster, Julie\nLeraas, Kristen M\nLichtenberg, Tara M\nPierson, Christopher R\nRamirez, Nilsa C\nTaylor, Cynthia\nWeaver, Stephanie\nWise, Lisa\nZmuda, Erik\nDavidsen, Tanja\nDemchok, John A\nEley, Greg\nFerguson, Martin L\nHutter, Carolyn M\nMills Shaw, Kenna R\nOzenberger, Bradley A\nSheth, Margi\nSofia, Heidi J\nTarnuzzer, Roy\nWang, Zhining\nYang, Liming\nZenklusen, Jean Claude\nAyala, Brenda\nBaboud, Julien\nChudamani, Sudha\nJensen, Mark A\nLiu, Jia\nPihl, Todd\nRaman, Rohini\nWan, Yunhu\nWu, Ye\nAlly, Adrian\nAuman, J Todd\nBalasundaram, Miruna\nBalu, Saianand\nBaylin, Stephen B\nBeroukhim, Rameen\nBootwalla, Moiz S\nBowlby, Reanne\nBristow, Christopher A\nBrooks, Denise\nButterfield, Yaron\nCarlsen, Rebecca\nCarter, Scott\nChin, Lynda\nChu, Andy\nChuah, Eric\nCibulskis, Kristian\nClarke, Amanda\nCoetzee, Simon G\nDhalla, Noreen\nFennell, Tim\nFisher, Sheila\nGabriel, Stacey\nGetz, Gad\nGibbs, Richard\nGuin, Ranabir\nHadjipanayis, Angela\nHayes, D Neil\nHinoue, Toshinori\nHoadley, Katherine\nHolt, Robert A\nHoyle, Alan P\nJefferys, Stuart R\nJones, Steven\nJones, Corbin D\nKucherlapati, Raju\nLai, Phillip H\nLander, Eric\nLee, Semin\nLichtenstein, Lee\nMa, Yussanne\nMaglinte, Dennis T\nMahadeshwar, Harshad S\nMarra, Marco A\nMayo, Michael\nMeng, Shaowu\nMeyerson, Matthew L\nMieczkowski, Piotr A\nMoore, Richard A\nMose, Lisle E\nMungall, Andrew J\nPantazi, Angeliki\nParfenov, Michael\nPark, Peter J\nParker, Joel S\nPerou, Charles M\nProtopopov, Alexei\nRen, Xiaojia\nRoach, Jeffrey\nSabedot, Thaís S\nSchein, Jacqueline\nSchumacher, Steven E\nSeidman, Jonathan G\nSeth, Sahil\nShen, Hui\nSimons, Janae V\nSipahimalani, Payal\nSoloway, Matthew G\nSong, Xingzhi\nSun, Huandong\nTabak, Barbara\nTam, Angela\nTan, Donghui\nTang, Jiabin\nThiessen, Nina\nTriche, Timothy Jr\nVan Den Berg, David J\nVeluvolu, Umadevi\nWaring, Scot\nWeisenberger, Daniel J\nWilkerson, Matthew D\nWong, Tina\nWu, Junyuan\nXi, Liu\nXu, Andrew W\nYang, Lixing\nZack, Travis I\nZhang, Jianhua\nAksoy, B Arman\nArachchi, Harindra\nBenz, Chris\nBernard, Brady\nCarlin, Daniel\nCho, Juok\nDiCara, Daniel\nFrazer, Scott\nFuller, Gregory N\nGao, JianJiong\nGehlenborg, Nils\nHaussler, David\nHeiman, David I\nIype, Lisa\nJacobsen, Anders\nJu, Zhenlin\nKatzman, Sol\nKim, Hoon\nKnijnenburg, Theo\nKreisberg, Richard Bailey\nLawrence, Michael S\nLee, William\nLeinonen, Kalle\nLin, Pei\nLing, Shiyun\nLiu, Wenbin\nLiu, Yingchun\nLiu, Yuexin\nLu, Yiling\nMills, Gordon\nNg, Sam\nNoble, Michael S\nPaull, Evan\nRao, Arvind\nReynolds, Sheila\nSaksena, Gordon\nSanborn, Zack\nSander, Chris\nSchultz, Nikolaus\nSenbabaoglu, Yasin\nShen, Ronglai\nShmulevich, Ilya\nSinha, Rileen\nStuart, Josh\nSumer, S Onur\nSun, Yichao\nTasman, Natalie\nTaylor, Barry S\nVoet, Doug\nWeinhold, Nils\nWeinstein, John N\nYang, Da\nYoshihara, Kosuke\nZheng, Siyuan\nZhang, Wei\nZou, Lihua\nAbel, Ty\nSadeghi, Sara\nCohen, Mark L\nEschbacher, Jenny\nHattab, Eyas M\nRaghunathan, Aditya\nSchniederjan, Matthew J\nAziz, Dina\nBarnett, Gene\nBarrett, Wendi\nBigner, Darell D\nBoice, Lori\nBrewer, Cathy\nCalatozzolo, Chiara\nCampos, Benito\nCarlotti, Carlos Gilberto Jr\nChan, Timothy A\nCuppini, Lucia\nCurley, Erin\nCuzzubbo, Stefania\nDevine, Karen\nDiMeco, Francesco\nDuell, Rebecca\nElder, J Bradley\nFehrenbach, Ashley\nFinocchiaro, Gaetano\nFriedman, William\nFulop, Jordonna\nGardner, Johanna\nHermes, Beth\nHerold-Mende, Christel\nJungk, Christine\nKendler, Ady\nLehman, Norman L\nLipp, Eric\nLiu, Ouida\nMandt, Randy\nMcGraw, Mary\nMclendon, Roger\nMcPherson, Christopher\nNeder, Luciano\nNguyen, Phuong\nNoss, Ardene\nNunziata, Raffaele\nOstrom, Quinn T\nPalmer, Cheryl\nPerin, Alessandro\nPollo, Bianca\nPotapov, Alexander\nPotapova, Olga\nRathmell, W Kimryn\nRotin, Daniil\nScarpace, Lisa\nSchilero, Cathy\nSenecal, Kelly\nShimmel, Kristen\nShurkhay, Vsevolod\nSifri, Suzanne\nSingh, Rosy\nSloan, Andrew E\nSmolenski, Kathy\nStaugaitis, Susan M\nSteele, Ruth\nThorne, Leigh\nTirapelli, Daniela P C\nUnterberg, Andreas\nVallurupalli, Mahitha\nWang, Yun\nWarnick, Ronald\nWilliams, Felicia\nWolinsky, Yingli\nBell, Sue\nRosenberg, Mara\nStewart, Chip\nHuang, Franklin\nGrimsby, Jonna L\nRadenbaugh, Amie J\nZhang, Jianan\nU24CA143840/CA/NCI NIH HHS/United States\nU24CA126561/CA/NCI NIH HHS/United States\nP30 CA016672/CA/NCI NIH HHS/United States\nU24 CA143882/CA/NCI NIH HHS/United States\nU54 HG003067/HG/NHGRI NIH HHS/United States\nU54HG003273/HG/NHGRI NIH HHS/United States\nU24 CA143835/CA/NCI NIH HHS/United States\nU24CA143731/CA/NCI NIH HHS/United States\nU24CA126551/CA/NCI NIH HHS/United States\nU24CA126543/CA/NCI NIH HHS/United States\nU24CA126554/CA/NCI NIH HHS/United States\nU24 CA143866/CA/NCI NIH HHS/United States\nU24CA143858/CA/NCI NIH HHS/United States\nU24CA126544/CA/NCI NIH HHS/United States\nP30CA016672/CA/NCI NIH HHS/United States\nU24CA143882/CA/NCI NIH HHS/United States\nU24 CA126551/CA/NCI NIH HHS/United States\nU24CA144025/CA/NCI NIH HHS/United States\nU54HG003067/HG/NHGRI NIH HHS/United States\nU24 CA143845/CA/NCI NIH HHS/United States\nU24 CA143799/CA/NCI NIH HHS/United States\nU01 CA168394/CA/NCI NIH HHS/United States\nU54 HG003273/HG/NHGRI NIH HHS/United States\nP30 CA008748/CA/NCI NIH HHS/United States\nU24 CA144025/CA/NCI NIH HHS/United States\nU24 CA194362/CA/NCI NIH HHS/United States\nU24CA143883/CA/NCI NIH HHS/United States\nU54HG003079/HG/NHGRI NIH HHS/United States\nU24 CA126554/CA/NCI NIH HHS/United States\nU24 CA180951/CA/NCI NIH HHS/United States\nU24 CA143840/CA/NCI NIH HHS/United States\nU24 CA143843/CA/NCI NIH HHS/United States\nU24CA143867/CA/NCI NIH HHS/United States\nU24CA143835/CA/NCI NIH HHS/United States\nU24 CA126561/CA/NCI NIH HHS/United States\nU24 CA143858/CA/NCI NIH HHS/United States\nU24CA143843/CA/NCI NIH HHS/United States\nR01 NS081125/NS/NINDS NIH HHS/United States\nU24 CA143848/CA/NCI NIH HHS/United States\nU24 CA126543/CA/NCI NIH HHS/United States\nU24CA143848/CA/NCI NIH HHS/United States\nU24CA126563/CA/NCI NIH HHS/United States\nU24CA126546/CA/NCI NIH HHS/United States\nU54 HG003079/HG/NHGRI NIH HHS/United States\nU24CA143799/CA/NCI NIH HHS/United States\nU54 HG007990/HG/NHGRI NIH HHS/United States\nU24 CA143883/CA/NCI NIH HHS/United States\nR01 CA163722/CA/NCI NIH HHS/United States\nU24CA143866/CA/NCI NIH HHS/United States\nU24CA143845/CA/NCI NIH HHS/United States\nU24 CA143867/CA/NCI NIH HHS/United States\nU24 CA126546/CA/NCI NIH HHS/United States\nU24 CA126563/CA/NCI NIH HHS/United States\nU24 CA126544/CA/NCI NIH HHS/United States\nJournal Article\nResearch Support, N.I.H., Extramural\nUnited States\n2015/06/11\nN Engl J Med. 2015 Jun 25;372(26):2481-98. doi: 10.1056/NEJMoa1402121. Epub 2015 Jun 10.},\n abstract = {BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).},\n keywords = {Adolescent\nAdult\nAged\nChromosomes, Human, Pair 1\nChromosomes, Human, Pair 19\nCluster Analysis\nDNA, Neoplasm/*analysis\nFemale\n*Genes, p53\nGlioblastoma/genetics\nGlioma/*genetics/metabolism/mortality\nHumans\nKaplan-Meier Estimate\nMale\nMiddle Aged\n*Mutation\nNeoplasm Grading\nProportional Hazards Models\nSequence Analysis, DNA\nSignal Transduction},\n ISSN = {0028-4793 (Print)\n0028-4793},\n DOI = {10.1056/NEJMoa1402121},\n year = {2015},\n type = {Journal Article}\n}\n\n","author_short":["Brat, D. J.","Verhaak, R. G.","Aldape, K. D.","Yung, W. K.","Salama, S. R.","Cooper, L. A.","Rheinbay, E.","Miller, C. R.","Vitucci, M.","Morozova, O.","Robertson, A. G.","Noushmehr, H.","Laird, P. W.","Cherniack, A. D.","Akbani, R.","Huse, J. T.","Ciriello, G.","Poisson, L. M.","Barnholtz-Sloan, J. S.","Berger, M. S.","Brennan, C.","Colen, R. R.","Colman, H.","Flanders, A. E.","Giannini, C.","Grifford, M.","Iavarone, A.","Jain, R.","Joseph, I.","Kim, J.","Kasaian, K.","Mikkelsen, T.","Murray, B. A.","O'Neill, B. P.","Pachter, L.","Parsons, D. W.","Sougnez, C.","Sulman, E. P.","Vandenberg, S. R.","Van Meir, E. G.","von Deimling, A.","Zhang, H.","Crain, D.","Lau, K.","Mallery, D.","Morris, S.","Paulauskis, J.","Penny, R.","Shelton, T.","Sherman, M.","Yena, P.","Black, A.","Bowen, J.","Dicostanzo, K.","Gastier-Foster, J.","Leraas, K. M.","Lichtenberg, T. M.","Pierson, C. R.","Ramirez, N. C.","Taylor, C.","Weaver, S.","Wise, L.","Zmuda, E.","Davidsen, T.","Demchok, J. A.","Eley, G.","Ferguson, M. L.","Hutter, C. M.","Mills Shaw, K. R.","Ozenberger, B. A.","Sheth, M.","Sofia, H. J.","Tarnuzzer, R.","Wang, Z.","Yang, L.","Zenklusen, J. C.","Ayala, B.","Baboud, J.","Chudamani, S.","Jensen, M. A.","Liu, J.","Pihl, T.","Raman, R.","Wan, Y.","Wu, Y.","Ally, A.","Auman, J. T.","Balasundaram, M.","Balu, S.","Baylin, S. B.","Beroukhim, R.","Bootwalla, M. S.","Bowlby, R.","Bristow, C. A.","Brooks, D.","Butterfield, Y.","Carlsen, R.","Carter, S.","Chin, L.","Chu, A.","others"],"key":"RN6143","id":"RN6143","bibbaseid":"brat-verhaak-aldape-yung-salama-cooper-rheinbay-miller-etal-comprehensiveintegrativegenomicanalysisofdiffuselowergradegliomas-2015","role":"author","urls":{},"keyword":["Adolescent Adult Aged Chromosomes","Human","Pair 1 Chromosomes","Human","Pair 19 Cluster Analysis DNA","Neoplasm/*analysis Female *Genes","p53 Glioblastoma/genetics Glioma/*genetics/metabolism/mortality Humans Kaplan-Meier Estimate Male Middle Aged *Mutation Neoplasm Grading Proportional Hazards Models Sequence Analysis","DNA Signal Transduction"],"metadata":{"authorlinks":{"verhaak, r":"https://verhaaklab.com/publications/bib/"}},"downloads":0},"bibtype":"article","biburl":"https://verhaaklab.com/files/verhaak.bib","creationDate":"2019-11-15T05:44:04.128Z","downloads":0,"keywords":["adolescent adult aged chromosomes","human","pair 1 chromosomes","human","pair 19 cluster analysis dna","neoplasm/*analysis female *genes","p53 glioblastoma/genetics glioma/*genetics/metabolism/mortality humans kaplan-meier estimate male middle aged *mutation neoplasm grading proportional hazards models sequence analysis","dna signal transduction"],"search_terms":["comprehensive","integrative","genomic","analysis","diffuse","lower","grade","gliomas","brat","verhaak","aldape","yung","salama","cooper","rheinbay","miller","vitucci","morozova","robertson","noushmehr","laird","cherniack","akbani","huse","ciriello","poisson","barnholtz-sloan","berger","brennan","colen","colman","flanders","giannini","grifford","iavarone","jain","joseph","kim","kasaian","mikkelsen","murray","o'neill","pachter","parsons","sougnez","sulman","vandenberg","van meir","von deimling","zhang","crain","lau","mallery","morris","paulauskis","penny","shelton","sherman","yena","black","bowen","dicostanzo","gastier-foster","leraas","lichtenberg","pierson","ramirez","taylor","weaver","wise","zmuda","davidsen","demchok","eley","ferguson","hutter","mills shaw","ozenberger","sheth","sofia","tarnuzzer","wang","yang","zenklusen","ayala","baboud","chudamani","jensen","liu","pihl","raman","wan","wu","ally","auman","balasundaram","balu","baylin","beroukhim","bootwalla","bowlby","bristow","brooks","butterfield","carlsen","carter","chin","chu","others"],"title":"Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas","year":2015,"dataSources":["iFXeF2qjAL2y5TeTz"]}