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The Cancer Genome Atlas TCGA

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The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to ... De novo pathway. Progressive pathway. Typically in younger patients ( 45 yrs) ... – PowerPoint PPT presentation

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Title: The Cancer Genome Atlas TCGA


1
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.
2
The Cancer Genome Atlas (TCGA)
Clincial annotation
DNA copy number
DNA methylation
DNA sequencingcurrently 1300 genes
Gene expression - mRNA ( exon) - miRNA
Proteomics
Integrative analysis
3
Glioblastoma (GBM)
Astrocytoma astrocytic glioma Most common form
Glioblastoma
  • Widespread invasion through the brain
  • Resistance to therapy
  • Destruction of normal brain tissue
  • Certain death

4
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)
10
907 per 100,000 individ. per year, 2 of all
primary tumors
5
Data types
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
6
GBM clinical data
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
  • Age
  • Gender
  • Treatment
  • Survival
  • Tumor pathology

7
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
8
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
9
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
10
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
11
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
12
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)
13
GBM mRNA expression - CEO clustering
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
Jenya Antipin, Boris Reva
14
GBM miRNA expression
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
platformAgilent 8 x 15k (UNC)
15
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
16
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
17
GBM mutations - example ERBB2
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
ERBB2
18
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
19
GBM data integration and visualization
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
signaling pathways
20
WeiqingWang
21
GBM pathway in Cytoscape
22
Cytoscape data mapper pluginmRNA expression
datasingle GBM sample
Benjamin Gross
23
(No Transcript)
24
Cytoscape data mapper pluginDNA copy
numbersingle GBM sample
25
Cytoscape data mapper pluginDNA copy
numbersingle GBM sample
26
Cytoscape data mapper pluginHeatmap examples -
constant datatype or constant gene
27
Cytoscape data mapper pluginHeatmap examples -
multiple genes and multiple datatypes
28
Cytoscape data mapper pluginWebstart
versionPathway Commons supportmissing
linksupply global data files
Ethan Cerami
http//cbio.mskcc.org/tcga/pathways/
29
GBM data integration
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
30
GBM data integration
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
signaling pathways
31
Copy number data only
32
Copy number and mutations
deletionor mutation
amplificationor mutation
0
25
25
33
GBM pathway analysis
DNA copy number
DNA methylation
mRNA expression
miRNA expression
mutations
Clinical data
Larry Donehower, David Wheeler, Baylor
34
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
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