Multidimensional scaling of diffuse gliomas: application to the 2016 World Health Organization classification system with prognostically relevant molecular subtype discovery

Patrick J Cimino,Michael Zager,Andreas Von Deimling,Michael Weller,Bettina Hentschel,Guido Reifenberger,David Jones,Lisa Mcferrin,Hamid Bolouri,Hans-Georg Wirsching,Eric C Holland

doi:10.1186/s40478-017-0443-7

Abstract

Recent updating of the World Health Organization (WHO) classification of central nervous system (CNS) tumors in 2016 demonstrates the first organized effort to restructure brain tumor classification by incorporating histomorphologic features with recurrent molecular alterations. Revised CNS tumor diagnostic criteria also attempt to reduce interobserver variability of histological interpretation and provide more accurate stratification related to clinical outcome. As an example, diffuse gliomas (WHO grades II–IV) are now molecularly stratified based upon isocitrate dehydrogenase 1 or 2 (IDH) mutational status, with gliomas of WHO grades II and III being substratified according to 1p/19q codeletion status. For now, grading of diffuse gliomas is still dependent upon histological parameters. Independent of WHO classification criteria, multidimensional scaling analysis of molecular signatures for diffuse gliomas from The Cancer Genome Atlas (TCGA) has identified distinct molecular subgroups, and allows for their visualization in 2-dimensional (2D) space. Using the web-based platform Oncoscape as a tool, we applied multidimensional scaling-derived molecular groups to the 2D visualization of the 2016 WHO classification of diffuse gliomas. Here we show that molecular multidimensional scaling of TCGA data provides 2D clustering that represents the 2016 WHO classification of diffuse gliomas. Additionally, we used this platform to successfully identify and define novel copy-number alteration-based molecular subtypes, which are independent of WHO grading, as well as predictive of clinical outcome. The prognostic utility of these molecular subtypes was further validated using an independent data set of the German Glioma Network prospective glioblastoma patient cohort.

Highlights

For nearly a century, classification of primary brain tumors has been based solely upon histomorphologic characteristics and presumed histogenesis of neoplastic cell types [2, 3]
Visualizing World Health Organization (WHO) diffuse glioma classification Initially, the diffuse glioma The Cancer Genome Atlas (TCGA) data were visualized in relation to 2007 WHO classification criteria, including histopathology and WHO grade (Fig. 1)
Histopathologic diagnoses as defined by the outdated 2007 WHO classification of primary brain tumors are not molecular cluster-specific, as each cluster contains a variable amount of histopathologic heterogeneity (Fig. 1b)

Summary

Introduction

Classification of primary brain tumors has been based solely upon histomorphologic characteristics and presumed histogenesis of neoplastic cell types [2, 3]. Special attention has been made in this new version to conceptually restructure glioma classification to consider all diffuse gliomas (astrocytomas and oligodendrogliomas) under the common header of “diffuse astrocytic and oligodendroglial tumors” [23] Within this category, molecular alterations help to drive WHO grade II and III diagnoses, and diagnostic entities include diffuse astrocytoma designated as IDH-mutant or IDHwildtype; anaplastic astrocytoma designated as IDH-mutant or IDH-wildtype; Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted; and anaplastic oligodendroglioma, IDHmutant, and 1p/19q-codeleted [23]. A NOS designation can be applied in cases of insufficient molecular information concerning the IDH mutation status

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Discussion

Conclusion