Download Detecting Chromosomal Rearrangements

Genomic DNA Variation
Computer-Aided Discovery Methods
Baylor College of Medicine course 311-405
Term 3, 2010/2011
Lecture on Wednesday, February 2nd, 2011
Aleksandar Milosavljevic, PhD
http://www.brl.bcm.tmc.edu
Cancer Genome Variation: Methods
Cancer Genome Variation:
Sequencing Provides Comprehensive
Tumor Characterization
Chromosome Aberrations: References
1 of 2
Background reviews
[Balmain 2001]
Balmain, A., Cancer genetics: from Boveri and
Mendel to microarrays. Nat Rev Cancer, 2001. 1(1): p. 77-82.
[Albertson et al. 2003] Albertson, D.G., et al., Chromosome aberrations
in solid tumors. Nat Genet, 2003. 34(4): p. 369-76.
[Rabbitts et al. 2003]
Rabbitts, T.H. and M.R. Stocks, Chromosomal
translocation products engender new intracellular therapeutic
technologies. Nat Med, 2003. 9(4): p. 383-6.
[Kumar-Sinha et al. 2008] Kumar-Sinha, C., S. A. Tomlins, et al. (2008).
"Recurrent gene fusions in prostate cancer." Nat Rev Cancer 8(7):
497-511.
•
Chromosome Aberrations References
2 of 2
Research articles
[Chin et al. 2006] Chin K. et al. Genomic and transcriptional aberrations
linked to breast cancer pathophysiologies, Cancer Cell 10:529541 2006
[Tomlins et al. 2005] Tomlins SA et al., Recurrent fusion of TMPRSS2
and ETS transcription factor genes in prostate cancer. Science,
2005. 310(5748): p. 644-8.
[TCGA 2008] The Cancer Genome Atlas Network "Comprehensive
genomic characterization defines human glioblastoma genes and
core pathways." Nature 455(7216): 1061-1068.
[Miller et al.] Miller C.A. et al. Discovering functional modules by
identifyingrecurrent and mutually exclusive mutational patterns in
tumors [in review].
Cancer Genome Variation
object of discovery
pathway /
module /
gene set
[Miller et al.]
[TCGA 2008]
[Chin et al. 2006]
single
gene
[Tomlins et al. 2005]
none
expression
and other
attributes of
individual
genes
[Kumar-Sinha et al.
2008]
networks /
modules /
gene sets
background
knowledge
employed in
discovery
Boveri, one century ago …
Multiple cell poles cause unequal
segregation of chromosomes.
a | Fertilization of sea-urchin eggs by
two sperm results in multiple cell poles.
b | Chromosomes are aberrantly
segregated
[Balmain 2001]
Chromosomal aberrations
[Albertson et al.]
Chromosomal aberrations
[Albertson et al.]
Cancer Genome Variation: Methods
(Array) Comparative Genome Hybridization
(array CGH)
Cancer Genome Variation
object of discovery
pathway /
module /
gene set
[Miller et al.]
[TCGA 2008]
[Chin et al. 2006]
single
gene
[Tomlins et al. 2005]
none
expression
and other
attributes of
individual
genes
[Kumar-Sinha et al.
2008]
networks /
modules /
gene sets
background
knowledge
employed in
discovery
Genomic and transcriptional aberrations linked to breast
cancer pathophysiologies [Chin et al. 2006]
• 100+ aggressively treated early stage breast tumors
1989-1997, before ERBB2 antagonist Trastuzumab
(Herceptin) was approved for treating ERBB2+ breast
cancer
ERBB2 heuristic (“paradigm”)
formulated in last sentence of Chin K. et al.
“Taking ERBB2 as the paradigm
(recurrently amplified, overexpressed,
associated with outcome and with
demonstrated functional importance in
cancer) suggests FGFR1, TACC1,
ADAM9, IKBKB, PNMT, and GRB7 as
high-priority therapeutic targets in these
regions of amplification.”
“Taking ERBB2 as the paradigm
(recurrently amplified, overexpressed…
Array CGH (~3K BAC array)
Gene expression (Affymetrix U133A array)
“Taking ERBB2
as the paradigm
(recurrently
amplified…
“Taking ERBB2
as the
paradigm (…
associated with
outcome…)
“Taking ERBB2 as the paradigm (…
associated with outcome…)
Going beyond copy-number changes
Deletions, amplifications induce aberrant
fusions
…but…
Some aberrant fusion-producing
rearrangements ( reciprocal
translocations, inversions ) may not affect
copy number
Cancer Genome Variation
object of discovery
pathway /
module /
gene set
[Miller et al.]
[TCGA 2008]
[Chin et al. 2006]
[Kumar-Sinha et al.
2008]
[Tomlins et al. 2005]
single
gene
none
expression
and other
attributes of
individual
genes
networks /
modules /
gene sets
background
knowledge
employed in
discovery
Two significant types of aberrant
fusions
aberrantly
amplified
expression
aberrant
activation
of signaling
protein
[Rabbitts et al.]
BCR-ABL fusion in Chronic Myeloid Leukaemia: four
decades from lesion discovery
to Imatinib ( Gleevec)
1960: Philadelphia chromosome discovered
1973: Chromosome translocation t(9;22)
identified
1983: Activated oncogene ABL identified
2001: Drug inhibiting BCR-ABL fusion
identified
Fourfold significance of recurrent
chromosomal aberrations
Prognostic Marker
Drug target
Pointing to biological pathway
Early diagnostic marker
Case Study: Prostate Cancer [Tomlins et al. 2005]
Recurrent ( > 50% cases) chromosomal aberrations discovered in
leukaemias, lymphomas, and sarcomas
Carcinomas more complex:
-- more rearrangements
-- submicroscopic structure
Gene overexpression  recurrent chromosomal aberration
present in > 50% prostate carcinomas [Tomlins et al. 2005]
Cancer Outlier Profile Analysis (COPA) using
Oncomine database reveals overexpression of
ETV1 and ERG
[Tomlins et al.]
Frequent gene amplifications and losses in
receptor tyrosine kinase-mediated signaling
ETV1
ERG
Recurrent TMPRSS2:ETV1 and
TMPRSS2:ERG fusions
revealed by the study of rearrangements
involving ETV1 and ERG
Expression of
TMPRSS2
is regulated
by androgen
[Tomlins et al. 2005]
Exclusivity of rearrangement:
either ETV1 or ERG
[Tomlins et al. 2005]
TMPRSS2 translocation associated with:
• Aggressive disease
Cancer Res 66:8347-51, 2006
• Reduced disease free survival
Cancer Biol Ther 6, 2007
• Higher rate of prostate cancer specific death
TMPRSS2:ERG gene fusion associated with
lethal
prostate cancer in a watchful waiting
cohort. Oncogene, 2007
Expanding gamut of fusions in prostate cancer
[Kumar-Sinha et al. 2009]
Cancer Genome Variation
object of discovery
pathway /
module /
gene set
[Miller et al.]
[TCGA 2008]
[Chin et al. 2006]
single
gene
[Tomlins et al. 2005]
none
expression
and other
attributes of
individual
genes
[Kumar-Sinha et al.
2008]
networks /
modules /
gene sets
background
knowledge
employed in
discovery
Study: aberrations in the context of interaction
networks [Kumar-Sinha et al. 2008]
Cancer Genome Variation
object of discovery
pathway /
module /
gene set
[Miller et al.]
[TCGA 2008]
[Chin et al. 2006]
single
gene
[Tomlins et al. 2005]
none
expression
and other
attributes of
individual
genes
[Kumar-Sinha et al.
2008]
networks /
modules /
gene sets
background
knowledge
employed in
discovery
Integrating basepair-level and copy number
alterations in study of 206 glioblastoma tumors
[TCGA 2008]
Recurrent mutually exclusive mutational
patterns identified in pathways [TCGA 2008]
Cancer Genome Variation
object of discovery
pathway /
module /
gene set
[Miller et al.]
[TCGA 2008]
[Chin et al. 2006]
single
gene
[Tomlins et al. 2005]
none
expression
and other
attributes of
individual
genes
[Kumar-Sinha et al.
2008]
networks /
modules /
gene sets
background
knowledge
employed in
discovery
Hallmarks of cancer (“acquired capabilities”)
are acquired by positive selection
Hallmarks of cancer (“acquired capabilities”)
cause
recurrent mutually exclusive mutational patterns
RME (“recurrent mutually exclusive”) pattern
discovery algorithm
RME algorithm
Sensitivity and Specificity of the RME
algorithm
Applying RME algorithm to glioblastoma
Effect of EP300 expression on survival in
glioblastoma
Laboratory exercise this week: array CGH
( Chia-Chin Wu)
Analysis of array CGH data from a set of tumor
samples using Genboree
– Upload array CGH data
– Perform segmentation (invoke Bioconductor
tool)
– Subtract polymorphisms (databases, current
literature)
– Identify recurrent amplifications or deletions
– Study correlation with gene expression