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Comprehensive genomic characterization defines human glioblastoma genes and core pathways
By: Katie Adolphsen, Robin Aldrich, Brandon Hu, Nate Havko
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The Cancer Genome Atlas: TCGA Collaborative effort
$100 million pilot project
Funded by National Cancer Institute and the National Human Genome Research Institute of the National Institutes of Health
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Goals
Standardization of biospecimen collection
Publication of large amount of data in an expedient time frame
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Pilot Project First looked:
squamous carcinoma serous cystadenocarcinoma glioblastoma
DNA copy number
Gene expression
DNA methylation aberrations
Nucleotide sequence aberrations
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Glioblastoma
Most common type of brain cancer 52% of parenchymal brain tumor cases 20% of intracranial tumors
Glioblastoma multiforme (GBM) is most aggressive type of primary brain tumor
Involves glial cells
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Biospecimen Collection
Newly diagnosed glioblastoma
Matched normal tissues
Associated demographic, clinical and pathological data
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Quality Control
Reviewed by Biospecimen Core Resource
Minimum 80% tumor nuclei
Maximum 50% necrosis
Screened for qualification of techniques
206 of the 587 biospecimens screened were qualified
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Methods
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Copy Number Alteration
Microarray platform
Analytical logarithm
Significant copy number alterations
Correlation of copy number
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Genomic and Transcriptional Aberrations
Figure 1
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Nucleotide Alterations
91 matched tumor-normal pairs 72 untreated 19 treated
601 sequences 453 validated non-silent somatic
mutation 223 unique genes
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Treated vs Untreated Background mutation rates
1.4 in untreated 5.8 in treated▪ Caused by temozolomide treatment
TP53 DNA binding domain mutations
Hypermutated Phenotype Prompted MMR investigation MLH1, MSH2, MSH6, PMS2
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Patterns of Somatic Nucleotide Alternations in Glioblastoma
Figure 1
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NF1
Neurofibromin 1
Glioblastoma suppressor gene
47 of 206 inactivating mutations
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NF1
Figure 2 Correlation between gene copy number and gene expression
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EGFR
Epithelia growth factor receptor
Variant III domain mutations Extracellular domain 41 of 91 sequenced samples had some
alteration
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Related Growth Factor Mutations
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PI(3)K complex Phosphoinositide 3-kinase is involved in cellular
functions cell growth, proliferation, differentiation, motility, survival and
intracellular trafficking
Catalytically active protein: p110α
Regulatory protein: p85α
Mutations disrupt interactions Missense Deletions Nucleotide substitution
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PI(3)K PIK3CA
6 detected in 91 samples 4 known 2 novel in-frame
PIK3R1 9 mutations of 91 samples 8 within SH2 domains 4 were 3-bp in-frame deletions
Novel point mutations relieve the inhibitory effect of p85α on p110α
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PI(3)K
p110α p85α
Spatial constraints cause constant PI(3)K activation
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MGMT
Methylation transferase activity
Assay for promotor methylation
Methylated MGMT promotor associated with hypermutator phenotype
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MGMT
Relationship with hypermutator phenotype
Clinical implications Methylation state changes response to
alkylating reagents
C•G A•T
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Figure 4
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Integrative analyses define glioblastoma core pathways Mapped the alterations
Somatic nucleotide substitutions Homozygous deletions Focal amplifications
Analysis found major interconnected network of aberrations
3 major pathways found RTK signaling P53 suppressor pathway RB tumor suppressor pathway
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RTK/RAS/PI(3)K Signaling
Red = activating genetic alterationsBlue = inactivating genetic alterations
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P53 Signaling
Red = activating genetic alterationsBlue = inactivating genetic alterations
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RB Signaling
Red = activating genetic alterationsBlue = inactivating genetic alterations
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Big picture
TCGA Powerful multi-dimensional data Integrative analysis New discoveries Unbiased and systematic analysis Ultimate discoveries
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Questions?