GENOMIC ANALYSIS OF OVER 400 SARCOMAS – Gregory M. Cote – J. Butrynski, J. Shen, J. Morgan, Z....
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Transcript of GENOMIC ANALYSIS OF OVER 400 SARCOMAS – Gregory M. Cote – J. Butrynski, J. Shen, J. Morgan, Z....
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
No Disclosures
Objective:
To identify the frequency and types of genomic alterations in sarcomas
– Allele-specific mutation analysis
(Profile)
– Targeted exome sequencing (FoundationOne)
Methods
Profile• Mass spectrometry-based
mutation hotspot analysis• 471 mutations in 41
cancer-related genes • Data collected
prospectively• Research study (internal
DFCI funding)
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
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
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
83 mutations in 74 of 377 (20%) patient samples
Profile
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
Targeted Exome Sequencing (3,769 exons in 236 genes and 47 introns from 19 genes
commonly rearranged)
71 patient samples from clinic
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
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)
162 DNA alterations
PI3K/Akt16 (17%)
Cell Cycle56 (52%)
Receptor Tyrosine Kinase(Amplifications)
19 (13%) MAPK9 (13%)
Epigenetic21 (20%)
DNA repair6 (8%)
Other31 (38%)
Cell Cycle
M G1
SG2
p53MDM2
CDK4/6-Cyclin DCDK2-Cyclin E
p15, p16
Rb
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%)
56 Aberrations (52% samples)
RTK
PI3K
PDK1 PIP3
AKT
TSC1/2
mTOR
p70S6K4EBP1
PTEN
RICTOR
AMP
RAPTOR
STK11
Rheb
PI3K/AKT
RTK
PI3K
PDK1 PIP3
AKT
TSC1/2
mTOR
p70S6K4EBP1
PTEN
RICTOR
AMP
RAPTOR
STK11
2
1
1
9 (13%)
2
1
Rheb
PI3K/AKT
16 Aberrations (17% samples)
19 RTK Amplifications, 3 RTK Activating Mutations
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
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