Download Life Cycle of a Glioma* From a Molecular Genomic

“Life Cycle of a Glioma”
From a Molecular Genomic
Perspective
Murali Nagarajan1, Ramya Gaddikeri1, Kedar Sharbidre1, Miral Jhaveri1 and Ashok Srinivasan2
Rush University Medical Center, Chicago, IL1 and University of Michigan, Ann Arbor, MI2
Control no. 1232
eEdE no. 49
Disclosures
•
Murali Nagarajan – Nothing to disclose
•
Ramya Gaddikeri - Nothing to disclose
•
Kedar Sharbidre- Nothing to disclose
•
Miral Jhaveri- Nothing to disclose
•
Ashok Srinivasan- Nothing to disclose
Objectives
• To discuss key genomic and epigenetic signatures which
occur during development of a glioma.
• To review specific anatomic and physiologic MRI features
associated various genetic alterations.
• To highlight the clinical impact of the MRI findings in
management of gliomas.
Background
•
Gliomas form the vast majority of primary adult malignant brain tumors
with glioblastoma accounting for more than half of them.
•
Despite significant advances in treatment with multimodal therapy
glioblastoma remains a deadly disease with median overall survival of
12-17 months.
•
One histologic group, but exhibits a wide range of molecular and
genetic heterogeneity.
•
Imaging Genomics links the imaging features to predict and correlate
genomic profiles within the tumor non invasively.
•
Holds promise to aid in more individualized targeted treatment.
Pathogenesis of Glioblastoma
• A glioblastoma typically shows more than 60 genetic alterationsmutations, deletions and amplifications, etc. These work through:

Cell proliferation signaling pathway - Receptor tyrosine
kinase/phosphatase and tensin homolog (PTEN)/phosphatidylinositol
3-kinase (PI3K)

Tumor suppression pathway - p53(TP53) and retinoblastoma
1(Rb1)
Effects of Genetic Alterations
Effects of
Gene
Alterations
Characteristics
Result
Angiogenesis
Hallmark of transition from low grade to high grade. Hypoxia
inducible factor (HIF) 1α and vascular endothelial growth
factor(VEGF) are important molecules. Activated through EGFR,
IDH1 and PTEN mutations
Capillary proliferation and
vascular leakiness
Cellular
proliferation
Lack of cellular inhibition from mutations of tumor suppressors
like p53 and Rb1EGFR/variant III overexpression, increased
PDGF activity
Increased tumor bulk
Cellular invasion
Alterations in cell adhesion, extracellular matrix remodeling, cell
migration and immune modulation
Infiltrative tumor
phenotype
Cell survival and
apoptosis
Enhanced cell survival against apoptosis and other cell death
mechanisms
Resistance to
chemotherapy and
radiation. Major factor in
tumor recurrence
EGFR-epidermal growth factor receptor; PDGF- platelet derived growth factor, IDH – Isocitrate dehydrogenase; PTEN-phosphatase and tensin homolog
Typical Imaging Features of a Glioblastoma
• Thick irregular heterogeneous ring enhancement
• Central necrosis
• Hemorrhage
• Restricted diffusion
• Increase in relative CBV
• Peritumoral T2 Hyperintensity- vasogenic edema+non
enhancing tumor infiltration
Typical Glioblastoma
Enhancement
and Necrosis
Restricted
Diffusion
Edema and
Hemorrhage
Increased rCBV
Typical Glioblastoma on HPE
•
•
•
•
Necrosis
Microvascular proliferation
Invasion
Cellularity, nuclear atypia and mitotic activity
Imaging and Genomic Correlation
• What is Radiogenomics? - A new field that links specific
imaging traits called “radiophenotypes” to genomic
profiles.
• Radiophenotypes are based on conventional imaging
such as T1, T2 and advanced imaging like DWI and PWI.
RadiophenotypesConventional
Contrast Enhancement
Increased expression of angiogenesis and hypoxia related genes in the
enhancing portions of the tumor. Completely enhancing tumors show
increased expression of VEGF as well as several factors related to
angiogenesis when compared to incompletely enhancing tumors
T2/FLAIR Abnormality
Vasogenic Edema
Infiltrative Tumor
Very bright T2 signal with typical
pseudopod appearance- secondary
to increased vascular leakinessassociated with angiogenesis
related factors
Less bright T2 signal- increased
expression of genes associated with
gliogenesis and central nervous
system development
Necrosis
Necrosis is related to abnormal cell survival and resistance to
apoptosis
Contrast-Necrosis Ratio
A high ratio of enhancing tissue volume to necrosis
correlates with EGFR overexpression
EGFR-epidermal growth factor receptor
Mass Effect
Increased expression of genes associated with cellular proliferation
resulting in increase in EGFR and PDGFR
EGFR-epidermal growth factor receptor; PDGF- platelet derived growth factor receptor
Subventricular Zone Involvement
Diminished expression of glioma stem cell
associated genes
RadiophenotypesAdvanced
Restricted Diffusion
Inverse relationship between
ADC value and cellular density
as well as other histological
markers of aggressiveness
Can be used to distinguish nonenhancing tumor from vasogenic
edema.
Relative Cerebral Blood Volume
Increased expression of angiogenesis related
factors VEGF and HIF 1α
VEGF- vascular endothelial growth factor, HIF- Hypoxia inducible factor
Spectroscopy
Choline
Choline
Increase in choline and choline to creatine ratio is indicator of cellular
proliferation. Associated with increase in Ki67 labeling index-histological
measure of proliferation
Biomarkers and Associated Imaging Features
• Biomarker- a characteristic that is objectively measured and
evaluated as an indicator of normal biological processes,
pathological processes or pharmacological responses to a
therapeutic intervention.
• Some important Biomarkers-MGMT promoter hypermethylation
-IDH1 mutation
-EGFR
-1p/19q deletion
-TP53 mutation
MGMT Promoter Hypermethylation
• O6-methylguanine-DNA methyltransferase- DNA
repair protein-removes harmful alkyl groupsantagonizes temozolamide(TMZ) and RT.
• If MGMT promoter is hypermethylated  MGMT
decreases, thus favorable.
MGMT Promoter Hypermethylation
Methylated tumors - less edema compared to
unmethylated tumors.
Methylated tumors occur more frequently in the
left temporal lobe.
Methylated tumors with IDH1 mutation - left
frontal lobe.
Unmethylated tumors - right cerebral
hemisphere
Primary methylated glioblastoma –
heterogeneous on T2 and show ring
enhancement
Secondary unmethylated – more
homogeneous on T2 and irregular and
nodular enhancement.
Primary unmethylated glioblastoma show
intermediate characteristics.
IDH Mutation
• Isocitrate dehydrogenase- Tumor suppressor - Normally
protects against oxidative damage.
• IDH mutation oncometabolite 2-hydroxyglutatrate
gliomagenesis via angiogenesis, DNA hypermethylation and
inhibition of cell differentiation.
• IDH1 and IDH2 mutations are seen in gliomas with
IDH1>>IDH2.
• IDH mutations much more common in secondary glioblastoma
than primary.
IDH Mutation
More invasive phenotype. Large nonenhancing tumors. More infiltrative. Can be
mutifocal. Frontal lobe
2-hydroxyglutarate can be detected
on dedicated MR spectroscopy (not
on routine spectroscopy).
EGFR Amplification
• Common molecular event- associated with
invasion, proliferation, apoptosis and
angiogenesis. Activation of EGFR variant III and
PTEN.
• More commonly seen in primary glioblastoma
than secondary.
EGFR Amplification
High ratio of volume of T2 hyperintense component to enhancing
volume. Fuzzier margins. Increased ratio of contrast enhancing
tumor to central necrosis. Restricted diffusion
1p/19q Deletion
• Aka loss of heterozygosity (LOH)- genetic hallmark of
oligodendrogliomas. In glioblastoma, seen in those with
oligodendroglial component.
• Imaging correlate: Indistinct T1 margins indicating invasiveness.
Mixed signal on T1 and T2. Calcification and hemorrhage.
• 1p deletion is associated with high CBV indicating
neovascularization.
• Predilection for frontal lobe. Insular lesions rarely delete 1p/19q.
1p/19q Deletion
Indistinct T1 margins indicating
invasiveness. Mixed signal on T1
and T2. Calcification and
hemorrhage
1p deletion is associated with high
CBV indicating neovascularization.
Predilection for frontal lobe. Insular
lesions rarely delete 1p/19q
TP53
• TP53= mutant tumor p53. Tumor suppressorinactivation leads to cellular proliferation. It indicates
transformation of low grade gliomas to glioblastoma.
• Low TP53- ill-defined margins. High TP53- well defined
margins with typical ring enhancement.
Biomarkers/MRI- Prognostic and Predictive
Features
Biomarker
Radiation
therapy
Chemotherapy
Prognostic value
MGMT promoter
hypermethylation
Respond
Respond
Favorable
IDH Mutation
Respond
Respond
Favorable
EGFR Amplification/
overexpression
Resistant
Respond
Unfavourable
1p/19q deletion
Respond
Respond
Favorable
Primary vs Secondary Glioblastoma
Clinical
Histologic features
Genetic alterations
Primary
glioblastoma
Secondary
glioblastoma
Fraction
95%
5%
Mean age
Older
Younger
Mean Overall Survival
Shorter
Longer
Necrosis
More common
Less common
Oligo component
Infrequent
Common
IDH 1 mutation
Rare
Very common
TP 53 mutation
Infrequent
Very common
EGFR amplification
Common
Rare
1p/19q deletion
Rare
Common
Secondary glioblastomas develop from a known grade II/III glioma. Primary glioblastomas don’t have any
evidence of preexisting glioma. Secondary glioblastomas have better prognosis.
Based on the above histological and genetic differences, the respective imaging correlates can potentially
help to differentiate these two tumor types.
Molecular Subtype Classification of Glioblastoma
Tumor type
Gene expression
Classical
EGFR Amplification
Mesenchymal
NF1 deletion
Proneural
PDGFRA/IDH1 mutation
Neural
ERBB2(neural marker)
overexpression
4 subtypes of glioblastoma based on genomic analysis. Different treatment response
despite being the same histopathological type. Proneural type is mostly secondary
glioblastoma and carries best prognosis. Classical and mesenchymal subtypes show
significantly increased survival following aggressive chemoradiation.
Radiophenotypes for corresponding molecular markers can help in treatment selection.
Impact of Imaging
•
Diagnosis and characterization of tumor- extract structural, compositional, physiologic, and
functional information.
•
Non invasively characterize molecular status of tumor – provides insights to molecular
behavior, hypoxia, angiogenesis, etc.
•
Assess spatial and temporal changes in gene expression. Can potentially negate sampling
errors in gene analysis.
•
Surgical planning– Effectively delineate the extent of the tumor including enhancing and
non-enhancing components. Guiding stereotactic biopsy to target more aggressive areas.
•
Potential to classify tumors for personalized targeted treatment such as TMZ, anti VEGF,
anti EGFR etc.
•
Can act as a surrogate for prognostic and predictive biomarkers
•
Monitoring growth or response to therapy- Radiation, chemotherapy and targeted
molecular therapy.
Pseudoprogression
•
Increase in contrast enhancing lesion size after RT + TMZ followed by
improvement without any treatment. No/minimal clinical deterioration.
•
Most prevalent in first 12 weeks after completion of RT.
•
Occurs in >90% methylated tumors due to higher sensitivity to treatment
vs 40% of unmethylated tumors.
•
Pathology- reactive radiation induced changes, increased permeability,
necrosis, edema and gliosis.
•
MRI may help in detection of true progression if contrast enhancement
occurs outside radiation field or if there is increase in rCBV. If not, only
follow-up or pathology can tell the difference.
Pseudoprogression
Before treatment for a
multifocal
glioblastoma. Note the
high CBV
10-29-13
2-10-14
After RT+TMZ –
significant increase in
edema and size of the
enhancing lesion. Only
minimal increase in
CBV
3-25-14
After 6 weeks –
significant decrease in
edema. Decrease in
enhancement. No
increase in CBV
FLAIR
Post T1
rCBV
Pseudoresponse
•
Antiangiogenic agents like bevacizumab (Avastin)  antipermeability,
pseudonormalization of blood brain barrier- rapid decrease in contrast
enhancement and rCBV in hours. Reduction in vasogenic edema.
•
Increase in progression free survival but only modest improvement in
overall survival.
•
Tumor progression under treatment: enlargement of non-enhancing
portion(FLAIR).
•
New areas of restricted diffusion may represent tumor progressionprecede enhancing lesions.
•
Caveat: persistent stable restricted diffusion may represent areas of
chronic ischemia and gelatinous material.
Pseudoresponse
Before
After
Rapid decrease in
contrast enhancement
and rCBV in hours.
Reduction in vasogenic
edema
Persistent Restricted Diffusion on Avastin
2-19-12
Persistent stable restricted
diffusion may represent
areas of chronic ischemia
and gelatinous material and
not tumor
1-23-13
Note the low rCBV
4-24-13
DWI
ADC
rCBV
Summary
• Characteristic genetic alterations occur during
the lifespan of a glioma and many of these are
associated with specific MRI features.
• MRI can act as a surrogate for prognostic and
predictive biomarkers and thus can play a critical
role in management.
References
•
Jamshidi N, Diehn M, Bredel M, et al. Illuminating radiogenomic characteristics of glioblastoma
multiforme through integration of MR imaging, messenger RNA expression, and DNA copy number
variation. Radiology. 2014 Jan;270(1):12. doi: 10.1148/radiol.13130078. Epub 2013 Oct 28.
•
Barajas RF Jr, Hodgson JG, Chang JS, et al. Glioblastoma multiforme regional genetic and cellular
expression patterns: influence on anatomic and physiologic MR imaging. Radiology. 2010 Feb;254(2):564
76. doi: 10.1148/radiol.09090663.
•
Celso Hygino da Cruz L. Jr, Kimura M. Neuroimaging and Genetic Influence in treating Brain Neoplasms.
Neuroimaging Clinics, 2015 Feb, Vol 25, Issue 1, pg 121-140
•
Belden CJ, Valdes PA, Ran C et al. Genetics of glioblastoma: A window into its imaging and
histopathologic variability.Radiographics. 2011 Oct;31(6):1717-40. doi: 10.1148/rg.316115512
•
Bruzzone MG, Eoli M, Cuccarini V, et al. Genetic signature of adult gliomas and correlation with MRI
features. Expert Rev Mol Diagn. 2009 Oct;9(7):70920. doi: 10.1586/erm.09.44. Review.