Advances in the molecular genetics of gliomas - implications for classification and therapy.

TLDR: It is illustrated how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

Abstract: Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

Figures

TABLE 2 ǀ 2016 WHO classification of gliomas22

TABLE 3 ǀ Predictive molecular biomarkers relevant to gliomas

TABLE 1 ǀ Common genetic, epigenetic and chromosomal aberrations associated with the major glioma entities40

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Year:2017
Advancesinthemoleculargeneticsofgliomas-implicationsforclassication
andtherapy
Reifenberger,Guido;Wirsching,Hans-Georg;Knobbe-Thomsen,ChristianeB;Weller,Michael
Abstract:Genome-widemolecular-prolingstudieshaverevealedthecharacteristicgeneticalterations
andepigeneticprolesassociatedwithdierenttypesofgliomas.Thesemolecularcharacteristicscanbe
usedtorenegliomaclassication,toimprovepredictionofpatientoutcomes,andtoguideindividualized
treatment.Thus,theWHOClassicationofTumoursoftheCentralNervousSystemwasrevisedin2016
toincorporatemolecularbiomarkers—togetherwithclassichistologicalfeatures—inanintegrated
diagnosis, in orderto denedistinct gliomaentitiesas preciselyas possible.Thisparadigmshiftis
markedlychanginghowgliomaisdiagnosed,andhasimportantimplicationsforfutureclinicaltrialsand
patientmanagementindailypractice.Herein,wehighlightthedevelopmentsinourunderstandingofthe
moleculargeneticsofgliomas,andreviewthecurrentlandscapeofclinicallyrelevantmolecularbiomarkers
foruseinclassicationofthediseasesubtypes.Novelapproachestothegeneticcharacterizationofgliomas
basedonlarge-scaleDNA-methylationprolingandnext-generationsequencingarealsodiscussed.In
addition,weillustratehowadvancesinthemoleculargeneticsofgliomascanpromotethedevelopment
and clinical translation ofnovel pathogenesis-based therapeutic approaches, therebypaving the way
towardsprecisionmedicineinneuro-oncology.
DOI:https://doi.org/10.1038/nrclinonc.2016.204
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-141057
JournalArticle
AcceptedVersion
Originallypublishedat:
Reifenberger,Guido;Wirsching,Hans-Georg;Knobbe-Thomsen,ChristianeB;Weller,Michael(2017).
Advancesinthemoleculargeneticsofgliomas-implicationsforclassicationandtherapy.NatureRe-
views.ClinicalOncology,14(7):434-452.
DOI:https://doi.org/10.1038/nrclinonc.2016.204

Advances in the molecular genetics of gliomas — implications for
classification and therapy
Guido Reifenberger
1,2
, Hans-Georg Wirsching
3*
, Christiane B. Knobbe-Thomsen
1
,
Michael Weller
3
1
Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse. 5, D-
40225 Düsseldorf, Germany.
2
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg,
partner site Essen/Düsseldorf, Moorenstrasse. 5, D-40225 Düsseldorf, Germany.
3
Department of Neurology and Brain Tumour Centre, Cancer Centre Zürich, University
Hospital and University of Zürich, Frauenklinikstrasse 26, CH-8091 Zürich, Switzerland.
*Current address:
Fred Hutchinson Cancer Research Center, Human Biology Division, 1100
Fairview Avenue North, C3-111, P.O. Box 19024, Seattle, Washington 98109-1024, USA.
Correspondence to G.R.
reifenberger@med.uni-duesseldorf.de
Abstract ǀ Genome-wide molecular profiling studies have revealed characteristic genetic
alterations and epigenetic profiles associated with different types of gliomas. These
molecular characteristics can be used to refine glioma classification, to improve prediction of
patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of
Tumours of the Central Nervous System was revised in 2016 to incorporate molecular
biomarkers — together with classic histological features — in an integrated diagnosis, in
order to define distinct glioma entities as precisely as possible. This paradigm shift is
markedly changing glioma diagnostics, and has important implications for future clinical trials
and patient management in daily practice. Herein, we highlight the developments in our

- 2 -
understanding of the molecular genetics of gliomas, and review the current landscape of
clinically relevant molecular biomarkers for use in classification of gliomas. Novel approaches
to the genetic characterization of gliomas based on large-scale DNA-methylation profiling
and next-generation sequencing are also discussed. In addition, we illustrate how advances
in the molecular genetics of gliomas can promote the development and clinical translation of
novel pathogenesis-based therapeutic approaches, thereby paving the way towards
precision medicine in neuro-oncology.

- 3 -
Malignant tumours of the central nervous system (CNS) are among the cancers with the
poorest prognosis, as indicated by the association of brain tumours with the highest
estimated number of years (mean: ~20 years) of potential life lost owing to any cancer
1
.
Gliomas are the most common primary CNS tumours, with an estimated annual incidence of
6.6 per 100,000 individuals in the USA
2
. About half of all newly diagnosed gliomas
correspond to glioblastoma, which is the most malignant type of brain cancer — with median
patient survival durations of approximately 14–17 months in contemporary clinical trials
3-5
and
~12 months in population-based studies
2,6
.
Studies in transgenic mice indicate that gliomas can arise from a range of cell types,
including neural stem cells, astrocytes, or oligodendroglial progenitor cells
7
. Genome-wide
molecular-profiling studies have revealed comprehensive mutational landscapes for all major
types of human gliomas occurring in adults
8-12
and children
13-21
. These developments have
markedly advanced our mechanistic understanding of glioma tumorigenesis, and have
identified novel biomarkers for improved tumour classification, as well as promising new
therapeutic targets.
Before publication of the revised WHO Classification of Tumours of the CNS in 2016
22
,
gliomas were exclusively classified using light microscopy according to histological criteria
defined in the 2007 WHO Classification
23
. In addition to histological tumour typing, each
tumour is assigned to a histological grade based on the degree of anaplasia, from WHO
grade I to IV. This WHO grading system reflects tumour malignancy and presumed natural
disease course, with WHO grade I indicating a slow-growing lesion usually associated with
favourable prognosis, whereas WHO grade IV is assigned to highly malignant tumours.
Histological classification has for many decades served as the ‘gold-standard’ for glioma
diagnostics, but is associated with considerable interobserver variability, particularly in the
context of diffusely infiltrating gliomas
24
. Studies have revealed that molecular classifications
of gliomas correlate better with clinical outcome than histological classification
10,11,25,26
.
Moreover, certain histological entities, such as glioblastoma, encompass a spectrum of
biologically distinct tumour groups associated with differences in age at onset, tumour

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location, and prognosis
8,9,12,21
. In addition, some traditional glioma categories, including
oligoastrocytoma and gliomatosis cerebri, lack disease-specific genetic profiles, and consist
of diverse astrocytic and oligodendroglial entities
27,28
. In the revised 2016 WHO Classification
of Tumours of the CNS
22
, the advances in our molecular understanding of gliomas are
leveraged in a novel, multilayered approach to disease categorization incorporating both
histological and molecular information in an ‘integrated diagnosis’ (BOX 1).
29-30
In this Review, we highlight advances in the molecular genetics of gliomas, with a
particular focus on diagnostically relevant alterations. In addition, we address the role of
predictive biomarkers and novel high-throughput molecular testing in glioma diagnostics, and
discuss the implications of these advances on the clinical management of patients with
glioma, as well as the design of future clinical trials.
[H1] Molecular genetics of adult gliomas
A major improvement in the 2016 WHO classification of gliomas, compared with the
preceding 2007 classification, is the distinction of different glioma entities according to
isocitrate dehydrogenase 1 or 2 (IDH) mutation status (TABLE 1). The discovery of IDH
mutations in most WHO grade II and III gliomas constituted a key breakthrough in
understanding the disease
31-33
. Numerous studies have revealed that the presence of IDH
mutations distinguishes gliomas with distinct biologies and clinical behaviours
34
.
Mechanistically, mutant IDH proteins acquire a neomorphic enzymatic activity that results in
conversion of α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D-2-HG), which in turn inhibits
α-KG-dependent dioxygenases, such as ten-eleven translocation (TET) family
5-methylcytosine hydroxylases and the Jumonji-C-domain-containing histone lysine
demethylases
35
. Thereby, IDH mutation causes aberrant DNA and histone methylation,
eventually leading to widespread hypermethylation of CpG islands, a phenomenon termed
the ‘glioma CpG-island methylator phenotype’ (G-CIMP)
36
. Diagnostic testing for IDH
mutations usually involves immunostaining with an antibody to IDH1 R132H protein
37
, which
detects the most common missense mutation in gliomas present in approximately 90% of the