Transcript bone differentiation gene evidence runx2 amplification satb2 loss

MINING COMPLEX SARCOMA
GENOMES:
LESSONS FROM OSTEOSARCOMA
LARGE MARKER CHROMOSOMES IN ADULT SARCOMA
TWO WAYS OF THINKING ABOUT SARCOMA
DEVELOPMENTAL BIOLOGY VIEW OF SARCOMA
TEICHER 2012
GENOMIC VIEW OF SARCOMA
Karyotypes
SARCOMAS WITH
SPECIFIC FUSION
GENES
Often simple
SARCOMAS
LACKING SPECIFIC
FUSION GENES
Usually complex
Translocations
Reciprocal & specific
Non-reciprocal & nonspecific
<30
>50
Prevalence of P53 pathway
alterations
Relatively low
High
Prognostic impact
of P53 pathway alterations
Strong
Weak to moderate
Incidence in P53-mutant or
knockout mouse models
Rare, if ever
Common
Incidence in
bilateral retinoblastoma and
Li-Fraumeni syndrome
Incidence among radiationinduced sarcomas
Rare
Common
Rare
Common
Average age at diagnosis
GENOMIC VIEW OF SARCOMA
Karyotypes
SARCOMAS WITH
SPECIFIC FUSION
GENES
Often simple
SARCOMAS
LACKING SPECIFIC
FUSION GENES
Usually complex
Translocations
Reciprocal & specific
A
Non-reciprocal & nonspecific
<30
>50
Average age at diagnosis
CLEARLY
Prevalence of P53 pathway
alterations
Prognostic impact
of P53 pathway alterations
Incidence in P53-mutant or
knockout mouse models
Incidence in
bilateral retinoblastoma and
Li-Fraumeni syndrome
Incidence among radiationinduced sarcomas
Relatively low
DEFINED
High
Strong
Weak to moderate
ONCOGENIC
Rare, if ever
Common
PATHWAY
Rare
Common
Rare
Common
GENOMIC VIEW OF SARCOMA
Karyotypes
SARCOMAS WITH
SPECIFIC FUSION
GENES
Often simple
SARCOMAS
LACKING SPECIFIC
FUSION GENES
Usually complex
Translocations
Reciprocal & specific
Non-reciprocal & nonspecific
NO
<30
>50
Average age at diagnosis
SINGLE
Prevalence of P53 pathway
alterations
Relatively low
High
Prognostic impact
of P53 pathway alterations
Strong
Weak to moderate
Incidence in P53-mutant or
knockout mouse models
Rare, if ever
DEFINED
Common
Incidence in
bilateral retinoblastoma and
Li-Fraumeni syndrome
Incidence among radiationinduced sarcomas
Rare
ONCOGENIC
Common
Rare
PATHWAY
Common
CLEARLY
APPROACHES TO COMPLEXITY
• LARGE INTEGRATED GENOMICS STUDIES
• INTEGRATION WITH GWAS STUDIES
• COMPARATIVE ONCOLOGY
• COMMONALITIES AMONG COMPLEX SARCOMAS
• GOAL: A PATH TO CLINICAL RELEVANCE
ENDOCHONDRAL OSSIFICATION
MEMBRANOUS OSSIFICATION
NORMAL
TUMOR
GLOBAL INCIDENCE
International Journal of Cancer
Volume 125, Issue 1, pages 229-234, 3 FEB 2009 DOI: 10.1002/ijc.24320
http://onlinelibrary.wiley.com/doi/10.1002/ijc.24320/full#fig1
EPIDEMIOLOGY CONNECTS BONE GROWTH TO TUMOR RISK
Mirabello et al.
Cancer Causes Control. 2011 Jun;22(6):899-908.
MINIMAL SURVIVAL IMPROVEMENT IN RECENT DECADES
Whelan Ann. Oncol 2011
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION GENES
MSC
PREOSTEOBLAST
CHONDROBLAST
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION GENES
MSC
PREOSTEOBLAST
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
CHONDROBLAST
CHONDROCYTE
MORPHOGENETIC,
GROWTH
AND
DIFFERENTIATION
REGULATING SIGNALS
ENDOCRINE
AUTOCRINE
PARACRINE
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION GENES
MSC
PREOSTEOBLAST
CHONDROBLAST
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
MSC
• DERANGED GROWTH
BONE DIFFERENTIATION GENES
• INVASIVE
• ABERRANT DIFFERENTIATION
• MASSIVE GENOME INSTABILITY
• GROSSLY PERTURBED GENE EXPRESSION
PREOSTEOBLAST
CHONDROBLAST
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
MSC
• MASSIVE GENOME INSTABILITY
• DERANGED GROWTH
• INVASIVE
• ABERRANT DIFFERENTIATION
PREOSTEOBLAST
OSTEOBLAST 1
BONE DIFFERENTIATION GENES
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
CHONDROBLAST
CHONDROCYTE
A SHATTERED GENOME
DISTINCT COPY NUMBER PROFILES EMERGE
MSC
• MASSIVE GENOME INSTABILITY BONE DIFFERENTIATION GENES
• DERANGED GROWTH
• INVASIVE
• ABERRANT DIFFERENTIATION
PREOSTEOBLAST
CHONDROBLAST
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION GENES
MSC
PREOSTEOBLAST
CHONDROBLAST
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
EVIDENCE BASED CATEGORIES OF GENES ALTERED IN
BONE DIFFERENTIATION
GENES
OS OR WHICH CONFER PREDISPOSITION
TO OS THAT
CAN CONTRIBUTE TO THE TUMOR PHENOTYPE:
MSC
• CELL CYCLE, DNA REPLICATION AND REPAIR
OSTEOBLAST 1
PREOSTEOBLAST
• SIGNAL
TRANSDUCTION
CHONDROBLAST
• BONE DIFFERENTIATION
CHONDROCYTE
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
CELL CYCLE, DNA REPLICATION AND REPAIR
MSC
BONE DIFFERENTIATION GENES
GENE
EVIDENCE
TP53
GERMLINE MUTATION, TUMOR MUTATION,
MOUSE MODELS
RB1
GERMLINE MUTATION,
MUTATION,
OSTEOBLAST
2
OSTEOBLAST 1 TUMOR
PREOSTEOBLAST
OSTEOCYTE
OSTEOSARCOMA
MOUSE MODELS
CHONDROBLAST
CDKN2A
DELETION
CCNE1
AMPLIFICATION
CDK4
AMPLIFICATION
MDM2
AMPLIFICATION
CDC5L
AMPLIFICATION
CHONDROCYTE
COPS3
AMPLIFICATION
REQL4
GERMLINE MUTATION
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION GENES
SIGNAL TRANSDUCTION
MSC
GENE
EVIDENCE
PTEN
DELETION
PREOSTEOBLAST
PIK3CA
CHONDROBLAST
RAS
IGF1R
CHONDROCYTE
OSTEOBLAST 1
MUTATION
MUTATION
AMPLIFICATION
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
TRANSCRIPTION FACTORS IN BONE DIFFERENTIATION
BONE DIFFERENTIATION GENES
MSC
RUNX2
PPARG
CEBP’s
SP7 (OSX)
PREOSTEOBLAST
CHONDROBLAST
SOX 5,6,9
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
RUNX2
OTHER TF’S
SATB2
TWIST
DLX
MSX
AP1
EGR2
ATF4
OSTEOCYTE
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION
MSC
GENE
EVIDENCE
RUNX2
AMPLIFICATION
SATB2
LOSS
RB1
MODELS
PREOSTEOBLAST
OSTEOBLAST 1
CHONDROBLAST
TP53
CHONDROCYTE
MODELS
BONE DIFFERENTIATION GENES
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA
BONE DIFFERENTIATION GENES
UNCERTAIN FUNCTION
MSC
GENE
EVIDENCE
LSAMP
PREOSTEOBLAST
(REGION?)
DELETION
CHONDROBLAST
CHONDROCYTE
OSTEOBLAST 1
OSTEOBLAST 2
OSTEOCYTE
OSTEOSARCOMA
APPROACHES TO COMPLEXITY
• LARGE INTEGRATED GENOMICS STUDIES
• INTEGRATION WITH GWAS STUDIES
• COMPARATIVE ONCOLOGY
• COMMONALITIES AMONG COMPLEX SARCOMAS
• GOAL: A PATH TO CLINICAL RELEVANCE
TARGET OSTEOSARCOMA PROJECT
TARGET OSTEOSARCOMA PROJECT
• COMPREHENSIVE GENOMIC ANALYSIS
• ARRAYS: mRNA,miRNA, DNA Methylation,
SNPS
•SEQUENCING: EXOME,
TRANSCRIPTOME,
WHOLE GENOME ON SELECT SAMPLES
THE TURBULENT GENOME OF OSTEOSARCOMA
OS
NBL
WHOLE GENOME SEQUENCING
SOMATIC STRUCTURAL VARIATIONS
WHOLE GENOME SEQUENCING
SOMATIC STRUCTURAL VARIATIONS
WHOLE GENOME SEQUENCING
STRUCTURAL VARIATIONS: COPY NUMBER LOSS
WHOLE GENOME SEQUENCING
COPY NUMBER
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APPROACHES TO COMPLEXITY
• LARGE INTEGRATED GENOMICS STUDIES
• INTEGRATION WITH GWAS STUDIES
• COMPARATIVE ONCOLOGY
• COMMONALITIES AMONG COMPLEX SARCOMAS
• GOAL: A PATH TO CLINICAL RELEVANCE
Normal Tissues
Osteosarcoma
Human
Dog
APPROACHES TO COMPLEXITY
• LARGE INTEGRATED GENOMICS STUDIES
• INTEGRATION WITH GWAS STUDIES
• COMPARATIVE ONCOLOGY
• COMMONALITIES AMONG COMPLEX SARCOMAS
• MAPPING A PATH TO CLINICAL RELEVANCE
PROFILING ADULT PLEOMORPHIC SARCOMAS
• HIGH DENSITY SNP ARRAYS
• TARGETED SEQUENCING OF 1300 GENES
MANY COMMONALITIES WITH OSTEOSARCOMA
•FEW TARGETABLE POINT MUTATIONS
• STRUCTURAL COMPLEXITY
• SHARED REGIONS OF CNA
• SHARED SNV’S (TP53, RB1)
• TELOMERE MAINTENANCE MECHANISMS
COMPLEX GENOME OF UPS
RB1 DELETION IN UPS
CHROMOSOME 12 AMPLIFICATION IN A LEIOMYOSARCOMA
TWO MODES OF TELOMERE MAINTENANCE
PROGENITOR CELL
TELOMERASE
ACTIVATION
ALTERNATIVE
LENGTHENING
OF TELOMERES
IMMORTALITY
TWO MODES OF TELOMERE MAINTENANCE
MESENCHYMAL STEM CELL
(LOW TELOMERASE EXPRESSION)
TELOMERASE
ACTIVATION
ALTERNATIVE
LENGTHENING
OF TELOMERES
IMMORTALITY
TELOMERE MAINTENANCE IN SARCOMA
Durant, J. Cancer
3:67 2012
Heaphy et al,
AJP 179:1609 (2011)
FREQUENCY OF ALT IN SARCOMA
%
Heaphy et al,
AJP 179:1609 (2011)
Osteosarcoma
Pancreatic Cell Line
Embryonic Kidney w/Adenovirus
Normal DNA
RNA SEQ REVEALS A TRUNCATED RNA SEQ TRANSCRIPT IN SAOS2
DIRECTION OF TRANSCRIPTION
ATRX INACTIVATION BY AN INTRACHROMOSOMAL REARRANGEMENT
IN SAOS2
ATRX INACTIVATION BY A DELETION IN LEIOMYOSARCOMA
WORKING MODEL OF COMPLEX SARCOMA GENESIS
PROGENITOR
• LOW BASELINE TERT
RECOMBINATION PRONE PROGENITOR
•DEFECTIVE TELOMERE MAINTENANCE
PROLIFERATING
TUMOR CELL
• ALT ACTIVATION
• MASSIVE CNA
• DYSREGULATED GENE
EXPRESSION
• ACCUMULATION OF POINT
MUTATIONS
RECOMBINATION COMPETENT PROGENITOR
•DEFECTIVE TELOMERE MAINTENANCE
• CELL CYCLE CHECKPOINT DEFECTS
APPROACHES TO COMPLEXITY
• LARGE INTEGRATED GENOMICS STUDIES
• INTEGRATION WITH GWAS STUDIES
• COMPARATIVE ONCOLOGY
• COMMONALITIES AMONG COMPLEX SARCOMAS
• MAPPING A PATH TO CLINICAL RELEVANCE
• HIGH COMPLEXITY = NEED FOR TUMOR SAMPLING.
• PROGNOSTIC SIGNATURES (OF ANY TYPE).
• EXPLORE SYNTHETIC LETHALITY WITH TSG DEFICIENCY.
• DOES ALT CREATE A THERAPEUTIC OPPORTUNITY?
• IDENTIFY SUBSETS WITH GAIN OF FUNCTION
ALTERATIONS WHICH MAY BE TARGETED (e.g. MDM2).
• IDENTIFY VULNERABILITIES WHICH ARE RELATED TO
THE DIFFERENTIATION STATE OF A GIVEN SARCOMA.
• WEAK LINKS IN THE METASTATIC CHAIN.
COLLABORATORS
NCI Genetics Branch
Sean Davis
Sven Bilke
Jack Zhu
Josh Waterfall
Yevgeniy Gindin
Robert Walker
Marbin Pineda
Mark Mackiewicz
Yuan Jiang
So Young Moon
Princy Francis
Rizzoli Institute
NCI DCEG
Luca Sangiorgi
Piero Picci
Sharon Savage
Lisa Mirabello
TARGET PROJECT
Ching Lau
Mark Krailo
Don Barkauskas
Lisa Teot
Laura Monovich
Julie Gestier-Foster
Chand Khanna
Richard Gorlick
Tim Triche
Greg Reaman
Neyssa Marina
Lee Helman
Irene Andrulis
Jay Wunder
Jaime Guidry-Auvil
Daniela Gerhard
Malcolm Smith