Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas

Daniel J. Brat, Roel G.W. Verhaak, Kenneth D. Aldape, W. K.Alfred Yung, Sofie R. Salama, Lee A.D. Cooper, Esther Rheinbay, C. Ryan Miller, Mark Vitucci, Olena Morozova, A. Gordon Robertson, Houtan Noushmehr, Peter W. Laird, Andrew D. Cherniack, Rehan Akbani, Jason T. Huse, Giovanni Ciriello, Laila M. Poisson, Jill S. Barnholtz-Sloan, Mitchel S. Berger & 30 others Cameron Brennan, Rivka R. Colen, Howard Colman, Adam E. Flanders, Caterina Giannini, Mia Grifford, Antonio Iavarone, Rajan Jain, Isaac Joseph, Jaegil Kim, Katayoon Kasaian, Tom Mikkelsen, Bradley A. Murray, Brian Patrick O'Neill, Lior Pachter, Donald W. Parsons, Carrie Sougnez, Erik P. Sulman, Scott R. Vandenberg, Erwin G. Van Meir, Andreas Von Deimling, Hailei Zhang, Daniel Crain, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Troy Shelton, Mark Sherman

Research output: Contribution to journalArticle

  • 501 Citations

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.)

LanguageEnglish (US)
Pages2481-2498
Number of pages18
JournalNew England Journal of Medicine
Volume372
Issue number26
DOIs
StatePublished - Jun 25 2015

Fingerprint

Glioma
Mutation
Glioblastoma
DNA Methylation
Exome
Observer Variation
National Institutes of Health (U.S.)
MicroRNAs
Uncertainty
Cluster Analysis
Chromosomes
RNA
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brat, D. J., Verhaak, R. G. W., Aldape, K. D., Yung, W. K. A., Salama, S. R., Cooper, L. A. D., ... Sherman, M. (2015). Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. New England Journal of Medicine, 372(26), 2481-2498. DOI: 10.1056/NEJMoa1402121

Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. / 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.

In: New England Journal of Medicine, Vol. 372, No. 26, 25.06.2015, p. 2481-2498.

Research output: Contribution to journalArticle

Brat, DJ, Verhaak, RGW, Aldape, KD, Yung, WKA, Salama, SR, Cooper, LAD, Rheinbay, E, Miller, CR, Vitucci, M, Morozova, O, Robertson, AG, Noushmehr, H, Laird, PW, Cherniack, AD, Akbani, R, Huse, JT, Ciriello, G, Poisson, LM, Barnholtz-Sloan, JS, Berger, MS, Brennan, C, Colen, RR, Colman, H, Flanders, AE, Giannini, C, Grifford, M, Iavarone, A, Jain, R, Joseph, I, Kim, J, Kasaian, K, Mikkelsen, T, Murray, BA, O'Neill, BP, Pachter, L, Parsons, DW, Sougnez, C, Sulman, EP, Vandenberg, SR, Van Meir, EG, Von Deimling, A, Zhang, H, Crain, D, Lau, K, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, T & Sherman, M 2015, 'Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas' New England Journal of Medicine, vol 372, no. 26, pp. 2481-2498. DOI: 10.1056/NEJMoa1402121
Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, Cooper LAD et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. New England Journal of Medicine. 2015 Jun 25;372(26):2481-2498. Available from, DOI: 10.1056/NEJMoa1402121
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. / Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. In: New England Journal of Medicine. 2015 ; Vol. 372, No. 26. pp. 2481-2498
@article{0c4c3df03fd0486587d690b8297526bd,
title = "Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas",
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.)",
author = "Brat, {Daniel J.} and Verhaak, {Roel G.W.} and Aldape, {Kenneth D.} and Yung, {W. K.Alfred} and Salama, {Sofie R.} and Cooper, {Lee A.D.} and Esther Rheinbay and Miller, {C. Ryan} and Mark Vitucci and Olena Morozova and Robertson, {A. Gordon} and Houtan Noushmehr and Laird, {Peter W.} and Cherniack, {Andrew D.} and Rehan Akbani and Huse, {Jason T.} and Giovanni Ciriello and Poisson, {Laila M.} and Barnholtz-Sloan, {Jill S.} and Berger, {Mitchel S.} and Cameron Brennan and Colen, {Rivka R.} and Howard Colman and Flanders, {Adam E.} and Caterina Giannini and Mia Grifford and Antonio Iavarone and Rajan Jain and Isaac Joseph and Jaegil Kim and Katayoon Kasaian and Tom Mikkelsen and Murray, {Bradley A.} and O'Neill, {Brian Patrick} and Lior Pachter and Parsons, {Donald W.} and Carrie Sougnez and Sulman, {Erik P.} and Vandenberg, {Scott R.} and {Van Meir}, {Erwin G.} and {Von Deimling}, Andreas and Hailei Zhang and Daniel Crain and Kevin Lau and David Mallery and Scott Morris and Joseph Paulauskis and Robert Penny and Troy Shelton and Mark Sherman",
year = "2015",
month = "6",
day = "25",
doi = "10.1056/NEJMoa1402121",
language = "English (US)",
volume = "372",
pages = "2481--2498",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "26",

}

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

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

UR - http://www.scopus.com/inward/citedby.url?scp=84932628860&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1402121

DO - 10.1056/NEJMoa1402121

M3 - Article

VL - 372

SP - 2481

EP - 2498

JO - New England Journal of Medicine

T2 - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 26

ER -