Department of Radiology and Imaging SciencesDivision of Neuroradiology

University School of Medicine

Associations Between MR Imaging Associations Between MR Imaging and Genomic Features of and Genomic Features of

GlioblastomasGlioblastomas

The Cancer Genome Atlas (TCGA)

Glioma Research Group

MRI Characterization Study

Associations Between MR Imaging Associations Between MR Imaging and Genomic Features of and Genomic Features of

GlioblastomasGlioblastomas

• Emory University In Silico Brain Tumor Research Center (NCI)– Department of Radiology and Imaging Sciences

– Department of Pathology

– Department of Biomedical Informatics

• Thomas Jefferson University, Department of Radiology • University of Virginia, Department of Radiology and Medical Imaging• NCI / NIH• SAIC-Frederick, Inc.

DisclosuresDisclosures

• None

Background – TCGABackground – TCGA

• Joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI)

• Publicly available database for multiple types of tumors from different anatomic sites, including glioblastomas– Pathology specimens– Imaging

• Purpose: to advance the understanding of the molecular basis of cancer through the application of genome analysis technologies, histopathology, and imaging

PurposePurpose

• To identify imaging features of primary glioblastomas that may predict genomic features, including mutation status, gene expression, and DNA copy number variations

MethodsMethods

• Multireader assessment of pre-op MR images – 75 glioblastoma patients– VASARI imaging feature set

• At least 3 CAQ neuroradiologists (from a panel of 6) independently reviewed each MRI data set

MethodsMethods

• VASARI feature set– https://wiki.nci.nih.gov/display/CIP/VASARI– 26 imaging features– For the current analysis, we focused on the following

parameters:• Tumor dimensions (axial plane)

• Percent enhancing tumor

• Percent nonenhancing tumor

• Percent necrosis

• Enhancing pial involvement

• Definition of nonenhancing margin

Other VASARI FeaturesOther VASARI Features

• Tumor location• Side• Eloquent brain• Avidity of enhancement• Cysts• Thickness of enhancing margin• Definition of enhancing margin• Hemorrhage• Diffusion• Pial invasion• Midline crossing

– Enhancing tumor– Nonenhancing tumor

• Distribution– Multifocal– Multicentric– Gliomatosis

• T1/FLAIR ratio– Expansive– Mixed– Infiltrative

• Ependymal invasion• Cortical Involvement• Deep WM invasion• Satellites• Calvarial remodeling

Lesion DimensionsLesion Dimensions

• Maximum and perpendicular dimensions on the basis of the T2w/FLAIR images

Tumor ProportionsTumor Proportions

• Assume the tumor consists of:– Enhancing tumor– Nonenhancing tumor– Necrosis– Edema

• Percent volume of each component rated on an ordinal scale– 0, 1-5%, 6-33%, 34-67%, 68-95%, 95-99%, 100%

Proportion Enhancing TumorProportion Enhancing Tumor

1-5% 68-95%

Proportion Nonenhancing TumorProportion Nonenhancing Tumor

68-95%6-33%

Proportion EdemaProportion Edema

0% 34-67%

Proportion NecrosisProportion Necrosis

34-67%1-5%

MethodsMethods

• Each parameter reduced to a single score– Majority rule– Random selection in case of a tie

• Statistical tests– Linear correlation– Fisher exact test– Student’s t-test

Methods - Genomic FeaturesMethods - Genomic Features

• Genomic data from TCGA’s publicly available information (TCGA, Nature 455:1061, 2008)

• Mutation status (presence versus absence of a gene mutation)– TP53, PTEN, EGFR, NF1, and IDH1

• Quantitative measurements of gene expression– TP53, PTEN, EGFR, NF1, IDH1, and TGFB2

• DNA copy number variations– high-level EGFR gene amplification– high-level PDGFRA amplification– homozygous deletions of CDKN2A– deletions of NF1

ResultsResults• TP53 mutant tumors had a smaller mean tumor

size (p=0.002), measured as the maximum tumor dimension on the T2-weighted and/or FLAIR images

• EGFR mutant tumors were significantly larger than TP53 mutant tumors (p=0.0005)

ResultsResults

• Association between enhancing tumor (>5% proportion) and high-level EGFR amplification (p=0.01)

• Enhancing pial involvement was associated with high-level EGFR amplification (p=0.02)

• Enhancing pial involvement was also associated with the presence of a CDKN2A homozygous deletion (p=0.03)

• Association between the presence of CDKN2A homozygous deletion and an ill-defined nonenhancing tumor margin (p=0.007)

• Having >5% proportion of necrosis may be associated with high-level EGFR amplification (p=0.06)

• No significant associations with PDGRFA amplification or NF1 deletions

• There were trends NF1 deletion was associated with the presence of edema (>5% proportion) (p=0.06) and with the presence of nonenhancing tumor (>5% proportion) (p=0.06)

ResultsResults

• Positive correlation between tumor size and EGFR expression (r=0.30, p=0.02)

• Negative correlation between tumor size and IDH1 expression (r=0.33, p=0.006)

• Mean IDH1 expression in tumors without a significant proportion of enhancement (≤5% of the tumor volume) was less than the mean in tumors with >5% enhancement (p=0.049)

ConclusionsConclusions

• Multiple statistically significant associations between imaging and genomic features in glioblastomas were identified

• In particular, EGFR mutant tumors were significantly larger than TP53 mutant tumors, and were more likely to demonstrate pial involvement

• CDKN2A homozygous deletion was associated with an ill-defined, nonenhancing tumor margin and enhancing pial involvement

Future WorkFuture Work

• Analysis of additional images and genomic data from TCGA

• Quantitative/volumetric image analysis

• Perfusion and DTI data

• Upcoming RTOG study using 5-ALA for resection guidance plans to enroll 600 glioblastomas from 30-40 centers

THANK YOU!THANK YOU!

TCGA Glioma Research GroupTCGA Glioma Research Group• Holder, C.A.1

• Hwang, S.N.1

• Clifford, R.J.2

• Huang, E.2

• Raghavan, P.4

• Nicolasjilwan, M.4

• Wintermark, M.4

• Hammoud, D. 3

• Gutman, D.A1

• Cooper, L.1

• Moreno, C.1

• Freymann, J.5

• Kirby, J.5

• Krishnan, A.1

• Dehkharghani, S.1

• Jaffe, C.C.3

• Saltz, J.H.1

• Brat, D.J.1

• Flanders, A.E. 6

• Buetow, K.H.2

1Emory University2National Cancer Institute3National Institutes of Health4University of Virginia5SAIC-Frederick, Inc.6Thomas Jefferson University