Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

By D. Brat, R. Verhaak, Kenneth D. Aldape, W. Yung, S. Salama, Lee A. D. Cooper, Esther Rheinbay, C. Miller, M. Vitucci, Olena Morozova and 297 more. New England Journal of Medicine, 2015

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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.)

Subfields: Cancer Research, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/e76642c7e25784cd3bfe6c3c7d4d48d43ed94ace

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Citations in the corpus

Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging (2017, background): “Conversely, most lower grade gliomaswithwild-type IDHweremolecularly and clinically similar to glioblastoma with equally dismal survival outcomes (1).”
The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary (2016, background): “It is important to recognize, however, that diffuse astrocytoma, IDH-wildtype is an uncommon diagnosis and that such cases need to be carefully evaluated to avoid misdiagnosis of lower grade lesions such as gangliogliomas; moreover, anaplastic astrocytoma, IDH-wildtype is also rare, and most such tu”
Predicting cancer outcomes from histology and genomics using convolutional networks (2017, background): “Infiltrating gliomas with the combination of IDH mutations and codeletion of chromosomes 1p/19q are classified as oligodendrogliomas in the current WHO schema, and these have the lowest overall predicted risks consistent with overall survivals of 10 + y (37, 39).”
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics (2018, methodology): “Two did not meet the assumptions because of causes that remain to be studied with time-dependent or multivariable models.”
Harnessing multimodal data integration to advance precision oncology (2021, background): “Multimodal patient stratification using complementary multi-omics cancer data is well developed 64–69 .”