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ASNR 2012
ASNR 2012
Imaging Genomic mapping of Edema/Cellular
Invasion MRI-Phenotypes in Glioblastoma
Multiforme
PO Zinn1, B Mahajan2, P Sathyan1, S Singh1, S Majumdar1, A Flanders3, E Huang4, R
Jain5, D Gutman6, S Hwang6, J Kirby7, J Freyman7, TCGA Glioma Phenotype Research
Group, , F Jolesz2, RR Colen2,
1
M.D. Anderson Cancer Center, Houston, TX, USA.
2 Brigham and Women's Hospital, Boston, MA, USA.
3 Thomas Jefferson University Hospital, Philadelphia, PA, USA.
4 National Cancer Institute, Bethesda, MD, USA.
5 Henry Ford, Detroit, MI, USA.
6 Emory University, Atlanta, GA, USA.
7 SAIC-Frederick, Bethesda, MD, USA.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Disclosure
 No Disclosures.
R25 CA089017(RRC)
P41 RR019703 (FAJ)
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Glioblastoma Multiforme
• Cellular invasion is one of the major reasons for therapy failure of modern
multimodal GBM treatment
• The discovery of targetable genes responsible for cell spread and
invasion can be expected to impact modern therapy and patient survival.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Imaging genomics
• Imaging genomics has emerged as a new field which links the specific
imaging traits (radiophenotypes) with gene-expression profiles.
• We present our paper on the first comprehensive imaging genomic
analysis using quantitative MRI volumetrics and large scale gene- and
micro-RNA expression profiling in GBM.
•
This was first described by our group (Zinn et al PLOSOne 2011) in
2011 where an invasive gene and microRNA was uncovered using the
FLAIR volume as an MRI biomarker (radiophenotype).
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Purpose
In this presentation, we seek to demonstrate the imaging-genomic mapping
of an invasive MRI radiophenotype, linking MR imaging traits with geneand miRNA expression profiles, in GBM patients to determine genomic
correlates of an edema/invasion MRI radiophenotype
In order to:
- Discover new genomic targets for GBM treatment (decreasing
edema/invasion)
- Predict key genetic events by MRI
- Identify patients who are candidates for the targeted treatment
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Methods and Materials
•
We retrospective identified 78 treatment naïve GBM patients whom
had:
• Pre-treatment MRI neuroimaging from The Cancer Imaging
Archive (TCIA)
• Gene- and miRNA- expression profiles The Cancer Genome
Atlas (TCGA)
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Methods and Materials
•
All Image Analysis was performed on Slicer 3.6
(slicer.org)
-
-
The Segmentation module was used to obtain
volumes of the peritumoral non-enhancing FLAIR
hyperintensity reflecting tumor invasion/edema
T2/FLAIR was registered to the post- contrast T1WI.
Volumetric segmentation was performed in a
simple hierarchical model of anatomy, proceeding
from peripheral to central.
3 distinct structures were segmented:
• edema/invasion
• enhancing tumor
• necrosis
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Methods and Materials
Tumor Segmentation. 65 year old male patient with a right temporal GBM. Segmentation of tumor edema (blue),
enhancement (yellow) and necrosis (red) was performed and edema volume was obtained.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Methods and Materials
• Image- Genomic Biostatistics analysis
12, 674 genes(22,267 hybridization probes) and 555 microRNAs (1,510
hybridization probes) were analyzed (Affymetrix/Agilent chip technology) in
each patient
• Quantitative edema volumes for each patient (N=78) were obtained
High and low groups corresponding to volumes of high and low peritumoral
edema/invasion were analyzed/compared for differential genomic expression
profiles
• Comparative Marker Selection (Broad Institute)
Statistical method to identify preferentially upregulated genomic events in one
vs. another predefined patient group (high_low)
•
Ingenuity Pathway Analysis (IPA) was used to determine gene ontology
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Methods and Materials
Example of a patient with high edema/tumor infiltration
High FLAIR Radiophenotype
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Methods and Materials
Example of a patient with low edema/tumor infiltration
Low FLAIR Radiophenotype
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Results
Genes associated with
invasion were seen in
the high FLAIR
discovery and validation
sets.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Results
Top concordant genes across discovery and validation sets
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Results
Top Cellular function migration/invasion
TOP CONCORDANT MICRORNAS ACROSS DISCOVERY AND VALIDATION SETS
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Results
BIOINFORMATICALLY PREDICTED GENE-MICRORNA REGULATORY NETWORKS IN HIGH
FLAIR SIGNAL GBMS.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Results
Our genes and microRNAs were more predictive of patient survival than the current
subclassification schema used in GBM today.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Conclusion
• In this presentation, we present the first comprehensive image- genomic
analysis using quantitative MRI volumetrics and large-scale gene- and
microRNA expression profiling in GBM
• We identified MRI as a possible screening tool and imaging surrogate for
genes and microRNAs involved in GBM cellular migration and invasion
• Specifically, we identified miR-219 and Periostin as a potential therapeutic
target against GBM invasion.
© NlH National Center for Image Guided Therapy, 2012
ASNR 2012
Acknowledgements
Helping make cancer history using imaging
Thank you!
[email protected]
This work is supported R25
CA089017(RRC), P41 RR019703
(FAJ).
A collaborative project between
BWH and M.D. Anderson.
© NlH National Center for Image Guided Therapy, 2012