Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

N Engl J Med
Authors
Keywords
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.).

Year of Publication
2015
Journal
N Engl J Med
Volume
372
Issue
26
Pages
2481-98
Date Published
2015 Jun 25
ISSN
1533-4406
URL
DOI
10.1056/NEJMoa1402121
PubMed ID
26061751
PubMed Central ID
PMC4530011
Links
Grant list
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
U24 CA144025 / 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
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
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