The Cancer Genome Atlas TCGA

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The Cancer Genome Atlas (TCGA)
3-year 100 million-dollar pilot project cancer
types brain (glioblastoma multiforme) lung
(squamous carcinoma) ovarian (serous
cystadenocarcinoma) Potentially 1.5 billion
dollars, 50 cancer types
The Cancer Genome Atlas (TCGA) is a comprehensive
and coordinated effort to accelerate our
understanding of the molecular basis of cancer
through the application of genome analysis
technologies, including large-scale genome
sequencing. TCGA is a joint effort of the
National Cancer Institute (NCI) and the National
Human Genome Research Institute (NHGRI), which
are both part of the National Institutes of
Health, U.S. Department of Health and Human
Services. The overarching goal of TCGA is to
improve our ability to diagnose, treat, and
prevent cancer. A pilot project will assess the
feasibility of a full-scale effort to
systematically explore the entire spectrum of
genomic changes involved in human cancer.
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The Cancer Genome Atlas (TCGA)
Clincial annotation
DNA copy number
DNA methylation
DNA sequencingcurrently 1300 genes
Gene expression - mRNA ( exon) - miRNA
Proteomics
Integrative analysis
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Glioblastoma (GBM)
Astrocytoma astrocytic glioma Most common form
Glioblastoma

• Widespread invasion through the brain
• Resistance to therapy
• Destruction of normal brain tissue
• Certain death

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Grade I benign and can be cured if they canbe
surgically resected
Progressive pathway
Grade II Astrocytoma Moderate proliferation and
invasion. 5-10 years survival
Astrocyte
Grade III Anaplastic Astrocytoma Proliferation,
invasion, angiogenesis,treatment responsive. 2-3
years survival
De novo pathway
Grade IV Secondary Glioblastoma Significant
proliferation, invasion, angiogenesis, necrosis.
Treatment refractory.9-14 months survival
Grade IV Primary GlioblastomaSignificant
proliferation, invasion, angiogenesis, necrosis.
Treatment refractory.
9-14 months survival
Typically in older patients (gt45 yrs)
Typically in younger patients (lt45 yrs)
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907 per 100,000 individ. per year, 2 of all
primary tumors
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Data types
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
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GBM clinical data
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data

• Age
• Gender
• Treatment
• Survival
• Tumor pathology

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GBM copy number analysis
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
platforms Agilent CGH 244A (MSKCC
Harvard)Affymetrix SNP 6.0 (Broad)Illumina 550K
SNP (Stanford)
analysis methods GISTICGTSRAE
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GBM copy number analysis
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
RAE on Agilent 244A
platforms Agilent CGH 244A (MSKCC
Harvard)Affymetrix SNP 6.0 (Broad)Illumina 550K
SNP (Stanford)
analysis methods GISTICGTSRAE
Barry Taylor, Nick Socci
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GBM methylation
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
platformarray-based high-throughput
single-site CpG resolution platform (Johns
Hopkins) 1000 genes, 3 probes per gene Probe
selection tricky no correlation between
methylation and mRNA for most genes
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GBM methylation - example MGMT
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
Patients with low MGMT expression levelsare
sensitive to temozolomide MGMT expression
regulated by methylation
Kornel Schuebel, Johns Hopkins
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Clustering of GBM methylation data
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
Jenya Antipin, Boris Reva
Leslie Cope and Kornel Schuebel, Johns Hopkins
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GBM mRNA expression
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
platforms Affymetrix U133 (Broad)Agilent Whole
Genome 4x44k (UNC)Affymetrix Exon 1.0 (LBL)
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GBM mRNA expression - CEO clustering
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
Jenya Antipin, Boris Reva
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GBM miRNA expression
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
platformAgilent 8 x 15k (UNC)
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GBM mutations
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
platformsSanger sequencing at 3 centers
Broad WashU Baylor Next generation
sequencing used for validation genes 1300
genes selected
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GBM mutations
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
The most frequently mutated genes in glioblastoma
Boris Reva, Alexey Stukalov, Jenya Antipin, John
Major
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GBM mutations - example ERBB2
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
ERBB2
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GBM mutations - example ERBB2
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
ERBB2
http//awabi.cbio.mskcc.org/oma/Report.jspx?mutanI
d22
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GBM data integration and visualization
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
signaling pathways
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WeiqingWang
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GBM pathway in Cytoscape
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Cytoscape data mapper pluginmRNA expression
datasingle GBM sample
Benjamin Gross
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(No Transcript)
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Cytoscape data mapper pluginDNA copy
numbersingle GBM sample
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Cytoscape data mapper pluginDNA copy
numbersingle GBM sample
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Cytoscape data mapper pluginHeatmap examples -
constant datatype or constant gene
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Cytoscape data mapper pluginHeatmap examples -
multiple genes and multiple datatypes
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Cytoscape data mapper pluginWebstart
versionPathway Commons supportmissing
linksupply global data files
Ethan Cerami
http//cbio.mskcc.org/tcga/pathways/
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GBM data integration
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
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GBM data integration
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
signaling pathways
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Copy number data only
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Copy number and mutations
deletionor mutation
amplificationor mutation
0
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GBM pathway analysis
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
Larry Donehower, David Wheeler, Baylor
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GBM pathway analysis
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
http//cbio.mskcc.org/cerami/tcga/results_june_2_
2008/
Ethan Cerami