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.)
| Original language | English |
|---|---|
| Pages (from-to) | 2481-2498 |
| Number of pages | 18 |
| Journal | New England Journal of Medicine |
| Volume | 372 |
| Issue number | 26 |
| DOIs | |
| State | Published - 25 Jun 2015 |
Access to Document
Fingerprint
Dive into the research topics of 'Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: New England Journal of Medicine, Vol. 372, No. 26, 25.06.2015, p. 2481-2498.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas
AU - Brat, Daniel J.
AU - Verhaak, Roel G.W.
AU - Aldape, Kenneth D.
AU - Yung, W. K.Alfred
AU - Salama, Sofie R.
AU - Cooper, Lee A.D.
AU - Rheinbay, Esther
AU - Miller, C. Ryan
AU - Vitucci, Mark
AU - Morozova, Olena
AU - Robertson, A. Gordon
AU - Noushmehr, Houtan
AU - Laird, Peter W.
AU - Cherniack, Andrew D.
AU - Akbani, Rehan
AU - Huse, Jason T.
AU - Ciriello, Giovanni
AU - Poisson, Laila M.
AU - Barnholtz-Sloan, Jill S.
AU - Berger, Mitchel S.
AU - Brennan, Cameron
AU - Colen, Rivka R.
AU - Colman, Howard
AU - Flanders, Adam E.
AU - Giannini, Caterina
AU - Grifford, Mia
AU - Iavarone, Antonio
AU - Jain, Rajan
AU - Joseph, Isaac
AU - Kim, Jaegil
AU - Kasaian, Katayoon
AU - Mikkelsen, Tom
AU - Murray, Bradley A.
AU - O'Neill, Brian Patrick
AU - Pachter, Lior
AU - Parsons, Donald W.
AU - Sougnez, Carrie
AU - Sulman, Erik P.
AU - Vandenberg, Scott R.
AU - Van Meir, Erwin G.
AU - Von Deimling, Andreas
AU - Zhang, Hailei
AU - Crain, Daniel
AU - Lau, Kevin
AU - Mallery, David
AU - Morris, Scott
AU - Paulauskis, Joseph
AU - Penny, Robert
AU - Shelton, Troy
AU - Sherman, Mark
AU - Yena, Peggy
AU - Black, Aaron
AU - Bowen, Jay
AU - Dicostanzo, Katie
AU - Gastier-Foster, Julie
AU - Leraas, Kristen M.
AU - Lichtenberg, Tara M.
AU - Pierson, Christopher R.
AU - Ramirez, Nilsa C.
AU - Taylor, Cynthia
AU - Weaver, Stephanie
AU - Wise, Lisa
AU - Zmuda, Erik
AU - Davidsen, Tanja
AU - Demchok, John A.
AU - Eley, Greg
AU - Ferguson, Martin L.
AU - Hutter, Carolyn M.
AU - Shaw, Kenna R.Mills
AU - Ozenberger, Bradley A.
AU - Sheth, Margi
AU - Sofia, Heidi J.
AU - Tarnuzzer, Roy
AU - Wang, Zhining
AU - Yang, Liming
AU - Zenklusen, Jean Claude
AU - Ayala, Brenda
AU - Baboud, Julien
AU - Chudamani, Sudha
AU - Jensen, Mark A.
AU - Liu, Jia
AU - Pihl, Todd
AU - Raman, Rohini
AU - Wan, Yunhu
AU - Wu, Ye
AU - Ally, Adrian
AU - Auman, J. Todd
AU - Balasundaram, Miruna
AU - Balu, Saianand
AU - Baylin, Stephen B.
AU - Beroukhim, Rameen
AU - Bootwalla, Moiz S.
AU - Bowlby, Reanne
AU - Bristow, Christopher A.
AU - Brooks, Denise
AU - Butterfield, Yaron
AU - Carlsen, Rebecca
AU - Carter, Scott
AU - Chin, Lynda
AU - Chu, Andy
AU - Chuah, Eric
AU - Cibulskis, Kristian
AU - Clarke, Amanda
AU - Coetzee, Simon G.
AU - Dhalla, Noreen
AU - Fennell, Tim
AU - Fisher, Sheila
AU - Gabriel, Stacey
AU - Getz, Gad
AU - Gibbs, Richard
AU - Guin, Ranabir
AU - Hadjipanayis, Angela
AU - Hayes, D. Neil
AU - Hinoue, Toshinori
AU - Hoadley, Katherine
AU - Holt, Robert A.
AU - Hoyle, Alan P.
AU - Jefferys, Stuart R.
AU - Jones, Steven
AU - Jones, Corbin D.
AU - Kucherlapati, Raju
AU - Lai, Phillip H.
AU - Lander, Eric
AU - Lee, Semin
AU - Lichtenstein, Lee
AU - Ma, Yussanne
AU - Maglinte, Dennis T.
AU - Mahadeshwar, Harshad S.
AU - Marra, Marco A.
AU - Mayo, Michael
AU - Meng, Shaowu
AU - Meyerson, Matthew L.
AU - Mieczkowski, Piotr A.
AU - Moore, Richard A.
AU - Mose, Lisle E.
AU - Mungall, Andrew J.
AU - Pantazi, Angeliki
AU - Parfenov, Michael
AU - Park, Peter J.
AU - Parker, Joel S.
AU - Perou, Charles M.
AU - Protopopov, Alexei
AU - Ren, Xiaojia
AU - Roach, Jeffrey
AU - Sabedot, Thaís S.
AU - Schein, Jacqueline
AU - Schumacher, Steven E.
AU - Seidman, Jonathan G.
AU - Seth, Sahil
AU - Shen, Hui
AU - Simons, Janae V.
AU - Sipahimalani, Payal
AU - Soloway, Matthew G.
AU - Song, Xingzhi
AU - Sun, Huandong
AU - Tabak, Barbara
AU - Tam, Angela
AU - Tan, Donghui
AU - Tang, Jiabin
AU - Thiessen, Nina
AU - Triche, Timothy
AU - Van Den Berg, David J.
AU - Veluvolu, Umadevi
AU - Waring, Scot
AU - Weisenberger, Daniel J.
AU - Wilkerson, Matthew D.
AU - Wong, Tina
AU - Wu, Junyuan
AU - Xi, Liu
AU - Xu, Andrew W.
AU - Yang, Lixing
AU - Zack, Travis I.
AU - Zhang, Jianhua
AU - Aksoy, B. Arman
AU - Arachchi, Harindra
AU - Benz, Chris
AU - Bernard, Brady
AU - Carlin, Daniel
AU - Cho, Juok
AU - DiCara, Daniel
AU - Frazer, Scott
AU - Fuller, Gregory N.
AU - Gao, Jian Jiong
AU - Gehlenborg, Nils
AU - Haussler, David
AU - Heiman, David I.
AU - Iype, Lisa
AU - Jacobsen, Anders
AU - Ju, Zhenlin
AU - Katzman, Sol
AU - Kim, Hoon
AU - Knijnenburg, Theo
AU - Kreisberg, Richard Bailey
AU - Lawrence, Michael S.
AU - Lee, William
AU - Leinonen, Kalle
AU - Lin, Pei
AU - Ling, Shiyun
AU - Liu, Wenbin
AU - Liu, Yingchun
AU - Liu, Yuexin
AU - Lu, Yiling
AU - Mills, Gordon
AU - Ng, Sam
AU - Noble, Michael S.
AU - Paull, Evan
AU - Rao, Arvind
AU - Reynolds, Sheila
AU - Saksena, Gordon
AU - Sanborn, Zack
AU - Sander, Chris
AU - Schultz, Nikolaus
AU - Senbabaoglu, Yasin
AU - Shen, Ronglai
AU - Shmulevich, Ilya
AU - Sinha, Rileen
AU - Stuart, Josh
AU - Sumer, S. Onur
AU - Sun, Yichao
AU - Tasman, Natalie
AU - Taylor, Barry S.
AU - Voet, Doug
AU - Weinhold, Nils
AU - Weinstein, John N.
AU - Yang, Da
AU - Yoshihara, Kosuke
AU - Zheng, Siyuan
AU - Zhang, Wei
AU - Zou, Lihua
AU - Abel, Ty
AU - Sadeghi, Sara
AU - Cohen, Mark L.
AU - Eschbacher, Jenny
AU - Hattab, Eyas M.
AU - Raghunathan, Aditya
AU - Schniederjan, Matthew J.
AU - Aziz, Dina
AU - Barnett, Gene
AU - Barrett, Wendi
AU - Bigner, Darell D.
AU - Boice, Lori
AU - Brewer, Cathy
AU - Calatozzolo, Chiara
AU - Campos, Benito
AU - Carlotti, Carlos Gilberto
AU - Chan, Timothy A.
AU - Cuppini, Lucia
AU - Curley, Erin
AU - Cuzzubbo, Stefania
AU - Devine, Karen
AU - DiMeco, Francesco
AU - Duell, Rebecca
AU - Elder, J. Bradley
AU - Fehrenbach, Ashley
AU - Finocchiaro, Gaetano
AU - Friedman, William
AU - Fulop, Jordonna
AU - Gardner, Johanna
AU - Hermes, Beth
AU - Herold-Mende, Christel
AU - Jungk, Christine
AU - Kendler, Ady
AU - Lehman, Norman L.
AU - Lipp, Eric
AU - Liu, Ouida
AU - Mandt, Randy
AU - McGraw, Mary
AU - Mclendon, Roger
AU - McPherson, Christopher
AU - Neder, Luciano
AU - Nguyen, Phuong
AU - Noss, Ardene
AU - Nunziata, Raffaele
AU - Ostrom, Quinn T.
AU - Palmer, Cheryl
AU - Perin, Alessandro
AU - Pollo, Bianca
AU - Potapov, Alexander
AU - Potapova, Olga
AU - Rathmell, W. Kimryn
AU - Rotin, Daniil
AU - Scarpace, Lisa
AU - Schilero, Cathy
AU - Senecal, Kelly
AU - Shimmel, Kristen
AU - Shurkhay, Vsevolod
AU - Sifri, Suzanne
AU - Singh, Rosy
AU - Sloan, Andrew E.
AU - Smolenski, Kathy
AU - Staugaitis, Susan M.
AU - Steele, Ruth
AU - Thorne, Leigh
AU - Tirapelli, Daniela P.C.
AU - Unterberg, Andreas
AU - Vallurupalli, Mahitha
AU - Wang, Yun
AU - Warnick, Ronald
AU - Williams, Felicia
AU - Wolinsky, Yingli
AU - Bell, Sue
AU - Rosenberg, Mara
AU - Stewart, Chip
AU - Huang, Franklin
AU - Grimsby, Jonna L.
AU - Radenbaugh, Amie J.
AU - Zhang, Jianan
N1 - Publisher Copyright: Copyright © 2015 Massachusetts Medical Society.
PY - 2015/6/25
Y1 - 2015/6/25
N2 - 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.)
AB - 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.)
UR - http://www.scopus.com/inward/record.url?scp=84932628860&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1402121
DO - 10.1056/NEJMoa1402121
M3 - Article
C2 - 26061751
AN - SCOPUS:84932628860
SN - 0028-4793
VL - 372
SP - 2481
EP - 2498
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 26
ER -