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Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Brat, Daniel J. and Pachter, Lior (2015) Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. New England Journal of Medicine, 372 (26). pp. 2481-2498. ISSN 0028-4793. PMCID PMC4530011. doi:10.1056/NEJMoa1402121. https://resolver.caltech.edu/CaltechAUTHORS:20170303-132106100

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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.)


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1056/NEJMoa1402121DOIArticle
http://www.nejm.org/doi/full/10.1056/NEJMoa1402121PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530011/PubMed CentralArticle
ORCID:
AuthorORCID
Pachter, Lior0000-0002-9164-6231
Additional Information:© 2015 Massachusetts Medical Society. This article was published on June 10, 2015, at NEJM.org. We thank personnel at the genome sequencing centers and cancer genome characterization centers for data generation and analyses, members of the National Cancer Institute and National Human Genome Research Institute project teams for coordination of project activities, and personnel at the M.D. Anderson Functional Proteomics Core for RPPA data and analysis. The authors are members of the Cancer Genome Atlas Research Network, and their names, affiliations, and roles are listed in Supplementary Appendix 1, available at NEJM.org. Supported by grants (U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, U24CA143731, U24CA143843, and P30CA016672) from the National Institutes of Health. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. The views expressed in this article are those of the authors and do not reflect the official policy of the National Institutes of Health.
Funders:
Funding AgencyGrant Number
NIHU24CA143883
NIHU24CA143858
NIHU24CA143840
NIHU24CA143799
NIHU24CA143835
NIHU24CA143845
NIHU24CA143882
NIHU24CA143867
NIHU24CA143866
NIHU24CA143848
NIHU24CA144025
NIHU54HG003067
NIHU54HG003079
NIHU54HG003273
NIHU24CA126543
NIHU24CA126544
NIHU24CA126546
NIHU24CA126551
NIHU24CA126554
NIHU24CA126561
NIHU24CA126563
NIHU24CA143731
NIHU24CA143843
NIHP30CA016672
Issue or Number:26
PubMed Central ID:PMC4530011
DOI:10.1056/NEJMoa1402121
Record Number:CaltechAUTHORS:20170303-132106100
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170303-132106100
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74706
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:03 Mar 2017 23:48
Last Modified:11 Nov 2021 05:29

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