genomic analysis of over 400 sarcomas – gregory m. cote – j. butrynski, j. shen, j. morgan, z....
TRANSCRIPT
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GENOMIC ANALYSIS OF OVER 400 SARCOMAS
– Gregory M. Cote –
J. Butrynski, J. Shen, J. Morgan, Z. Duan, D. D’Adamo, G. Nielsen, S. George, F. Hornicek, G. Demetri, D. Harmon, C.
Raut, J. Hornick, E. Choy, A. Wagner
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No Disclosures
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Objective:
To identify the frequency and types of genomic alterations in sarcomas
– Allele-specific mutation analysis
(Profile)
– Targeted exome sequencing (FoundationOne)
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Methods
Profile• Mass spectrometry-based
mutation hotspot analysis• 471 mutations in 41
cancer-related genes • Data collected
prospectively• Research study (internal
DFCI funding)
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Methods
Profile• Mass spectrometry-based
mutation hotspot analysis• 471 mutations in 41
cancer-related genes • Data collected
prospectively• Research study (internal
DFCI funding)
FoundationOne• Next-generation
sequencing platform• 3,769 exons in 236 genes
and 47 introns from 19 genes commonly rearranged
• Data collected retrospectively
• Clinical study billed to insurance/patients
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ProfileSarcoma Subtype Number of Samples
GIST 84 LMS 68
Unclassified STS 27 DDLPS 26
Angiosarcoma 15 Myxofibrosarcoma 15
Solitary fibrous tumor 15 Desmoid 10
Synovial sarcoma 10 myxLPS 9 PEComa 9 WDLPS 9 DFSP 7
Ewing Sarcoma 7 Endometrial Stromal Sarcoma 6
MPNST 6 Osteosarcoma 6
Pleomorphic liposarcoma 6 Chondrosarcoma 5
ASPS 4 DSRCT 4
IMT 4 PVNS 4
Epithelioid sarcoma 3 Low grade sarcoma 3 Clear cell sarcoma 2
EHE 2 FDCS 2
Phylloides 2 Undifferentiated uterine STS 2
extraskeletal myxoid chondrosarcoma
1
Intimal sarcoma 1 Myofibroblastic 1
Rhabdomyosarcoma 1 Unclassified liposarcoma 1
377 Patient Samples
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Sarcoma Subtype Number of Samples Number of DNA Alterations
GIST 84 41 LMS 68 5
Unclassified STS 27 3 DDLPS 26 2
Angiosarcoma 15 3 Myxofibrosarcoma 15 0
Solitary fibrous tumor 15 0 Desmoid 10 6
Synovial sarcoma 10 1 myxLPS 9 5 PEComa 9 0 WDLPS 9 0 DFSP 7 0
Ewing Sarcoma 7 0 Endometrial Stromal Sarcoma 6 0
MPNST 6 1 Osteosarcoma 6 1
Pleomorphic liposarcoma 6 1 Chondrosarcoma 5 2
ASPS 4 0 DSRCT 4 0
IMT 4 0 PVNS 4 0
Epithelioid sarcoma 3 1 Low grade sarcoma 3 0 Clear cell sarcoma 2 0
EHE 2 0 FDCS 2 0
Phylloides 2 1 Undifferentiated uterine STS 2 0
extraskeletal myxoid chondrosarcoma
1 0
Intimal sarcoma 1 0 Myofibroblastic 1 1
Rhabdomyosarcoma 1 0 Unclassified liposarcoma 1 0
377 Patient Samples
- 74 mutations - 20% - 9% (excluding GIST and Desmoid)
Profile
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83 mutations in 74 of 377 (20%) patient samples
Profile
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83 mutations in 74 of 377 (20%) patient samples
Gene Mutation Sarcoma c-KIT 42/84 GIST
CTNNB1 6/10 Desmoid 1/26 LPS* 1/6 MPNST 1/3 Epithelioid 1/1 Myofibroblastic 1/27 STS NOS
RAS 3/15 Angiosarcoma 1/84 GIST 1/27 STS NOS
IDH1 1/5 Chondrosarcoma VHL 1/5 Chondrosarcoma
MLH1 1/26 LPS 1/84 GIST
PIK3CA 4/9 myxLPS 1/84 GIST 1/6 Osteosarcoma
AKT1 1/9 myxLPS
Profile
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Targeted Exome Sequencing (3,769 exons in 236 genes and 47 introns from 19 genes
commonly rearranged)
71 patient samples from clinic
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Sarcoma Subtype Number of Samples
Chordoma 11
LMS 11
STS 8
OS 7
ES 4
Chondrosarcoma 3
GIST 3
MPNST 3
Myxofibrosarcoma 3
SFT 3
Angiosarcoma 2
ASPS 2
DDLPS 2
myxLPS 2
RMS 2
Clear Cell Sarcoma 1
DSRCT 1
LGFMS 1
Sarcoma NOS 1
Synovial Sarcoma 1
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Sarcoma Subtype Number of Samples Number of DNA Alterations
Chordoma 11 21
LMS 11 39
STS 8 17
OS 7 20
ES 4 7
Chondrosarcoma 3 7
GIST 3 4
MPNST 3 5
Myxofibrosarcoma 3 6
SFT 3 1
Angiosarcoma 2 7
ASPS 2 1
DDLPS 2 11
myxLPS 2 4
RMS 2 4
Clear Cell Sarcoma 1 2
DSRCT 1 0
LGFMS 1 2
Sarcoma NOS 1 1
Synovial Sarcoma 1 0
162 DNA alterations80% with >/= 1Median = 2 (range 0-8)
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162 DNA alterations
PI3K/Akt16 (17%)
Cell Cycle56 (52%)
Receptor Tyrosine Kinase(Amplifications)
19 (13%) MAPK9 (13%)
Epigenetic21 (20%)
DNA repair6 (8%)
Other31 (38%)
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Cell Cycle
M G1
SG2
p53MDM2
CDK4/6-Cyclin DCDK2-Cyclin E
p15, p16
Rb
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Cell Cycle
18 (25%)
M G1
SG2
p53MDM2
CDK4/6-Cyclin DCDK2-Cyclin E
p15, p16
Rb
15 (21%)
8 (11%)
8 (11%)31 (44%)
12 (17%)
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56 Aberrations (52% samples)
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RTK
PI3K
PDK1 PIP3
AKT
TSC1/2
mTOR
p70S6K4EBP1
PTEN
RICTOR
AMP
RAPTOR
STK11
Rheb
PI3K/AKT
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RTK
PI3K
PDK1 PIP3
AKT
TSC1/2
mTOR
p70S6K4EBP1
PTEN
RICTOR
AMP
RAPTOR
STK11
2
1
1
9 (13%)
2
1
Rheb
PI3K/AKT
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16 Aberrations (17% samples)
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19 RTK Amplifications, 3 RTK Activating Mutations
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Summary
• Exome sequencing identified more alterations v. allele-specific analysis
• Alterations in sarcomas are heterogeneous
• Therapeutic/prognostic relevance unclear (I.e. EGFR amplification pathway addiction)
• Potential to guide clinical studies
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Acknowledgements
MGH• J. Shen • Z. Duan• G. Nielsen• F. Hornicek• D. Harmon• E. Choy
Profile• Neal Lindeman
DFCI• J. Butrynski • J. Morgan• D. D’Adamo• S. George• G. Demetri• C. Raut• A. Wagner
BWH• J. Hornick