reconstructing genomic architectures of tumor genomes pavel pevzner and ben raphael department of...
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Reconstructing Genomic Architectures of Tumor Genomes
Pavel Pevzner and Ben Raphael
Department of Computer Science & Engineering University of California, San Diego
(joint work with Colin Collins lab at UCSF Cancer Center)
Chromosome Painting: Normal Cells
Chromosome Painting: Tumor Cells
Rearrangements in Tumors
• GleevecTM (Novartis 2001) targets BCR-ABL oncogene.
• Change gene structure and regulatory “wiring” of the genome.
• Create “bad” novel fusion genes and break “good” old genes.
• Example: translocation in leukemia.
promoter
promoter ABL gene
BCR genepromoter
Chromosome 9
Chromosome 22
BCR-ABL oncogene
Complex Tumor Genomes
1) What are detailed architectures of tumor genomes?
2) What rearrangements/duplications produce these architectures and what is the order of these events?
3) What are the novel fusion genes and old “broken” genes?
• What are the the “architectural blocks” forming the existing genomes and how to find them?
• What is the architecture of the ancestral genome?• What is the evolutionary scenario for transforming
one genome into the other?
Unknown ancestor~ 80 million yearsago
Mouse (X chrom.)
Human (X chrom.)
Genome rearrangements
History of Chromosome X
Rat Consortium, Nature, 2004
Inversions
• Blocks represent conserved genes.• In the course of evolution or in a clinical context,
blocks 1,2,…,10 could be misread as:
1, 2, 3, -8, -7, -6, -5, -4, 9, 10.
1 32
4
10
56
8
9
7
1, 2, 3, 4, 5, 6, 7, 8, 9, 10
Inversions1 32
4
10
56
8
9
7
1, 2, 3, -8, -7, -6, -5, -4, 9, 10
Blocks represent conserved genes. In the course of evolution or in a clinical context, blocks
1,…,10 could be misread as 1, 2, 3, -8, -7, -6, -5, -4, 9, 10.
Evolution: occurred one-two times every million years. Cancer: may occur every month.
End Sequence Profiling (ESP)C. Collins et al. (UCSF Cancer Center)
1) Pieces of tumor genome: clones (100-250kb).
Human DNA
2) Sequence ends of clones (500bp).
3) Map end sequences to human genome.
Tumor DNA
Each clone corresponds to pair of end sequences (ES pair) (x,y).
yx
Human genome(known)
Tumor genome(unknown)
Unknown sequence of rearrangements
Location of ES pairsin human genome.(known)
Map ES pairs tohuman genome.
-C -D EA B
B C EA D
x2 y2x3 x4 y1 x5 y5 y4 y3x1
Tumor Genome Reconstruction Puzzle
Reconstruct tumor genome
B C EA D
-C
-D
E
A
B
Tumor
Human
Tumor Genome Reconstruction
B C EA D
-C
-D
E
A
B
Tumor
Human
Tumor Genome Reconstruction
B C EA D
-C
-D
E
A
B
Tumor (x2,y2)
(x3,y3)
(x4,y4)
(x1,y1)
y4 y3x1 x2 x3 x4 y1 y2
Tumor Genome Reconstruction
B
C
E
A
D
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
(x2,y2)
(x3,y3)
(x4,y4)
(x1,y1)
ESP Plot
Human
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B C EA D
2D Representation of ESP Data
• Each point is ES pair.• Can we reconstruct the tumor genome from the positions of the ES pairs?
B
C
E
A
D
Human
Human
B
-D
E
A
DA C
E
-C
B
-C -D EA B
ReconstructedTumor Genome
Real data noisy and incomplete!
Breast Cancer MCF7 Cell Line
Human chromosomes MCF7 chromosomes5 inversions
15 translocations
Raphael et al. 2003.
33/70 clustersTotal length: 31Mb
Complications with MCF7: Chromosomes 1,3,17, 20
sA
tC-B
sA
tCB inversion
Human
uA B
uA
wDB C D
vE
wC D
vE
duplication/transposition
uA B
wC
vE ????
Rearrangement Signatures Tumor
sA
t
-Bs
At
-CB DC D translocation
Complex Tumor Genomes
Tumor Amplisomes
33 clustersTotal length: 31Mb
17 201 3
Reconstructed MCF7 amplisome
Chromosomecolors
Explains 24/33 invalid clusters.
Raphael and Pevzner, 2004.
Sequencing Tumor Clones Confirms Complex Mosaic Structure
What’s Next?
• Human Genome Project, 2001• Mouse Genome Project, 2002• Rat Genome Project, 2003• Chicken Genome Project, 2004• Chimp Genome Project, 2005• ???
Tumor Genomes Projects
Tumor genomeHuman genome
1) Identify recurrent aberrations2) Identify temporal sequence of aberrations3) Use these data for tumor diagnostics and therapeutics
Mutation, selection
Tumor genome 2
Tumor genome 4
Tumor genome 3