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.

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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

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

Profile 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 Profile

Targeted Exome Sequencing (3,769 exons in 236 genes and 47 introns from 19 genes commonly rearranged) 71 patient samples from clinic

Sarcoma SubtypeNumber of Samples Chordoma11 LMS11 STS8 OS7 ES4 Chondrosarcoma3 GIST3 MPNST3 Myxofibrosarcoma3 SFT3 Angiosarcoma2 ASPS2 DDLPS2 myxLPS2 RMS2 Clear Cell Sarcoma1 DSRCT1 LGFMS1 Sarcoma NOS1 Synovial Sarcoma1

Sarcoma SubtypeNumber of SamplesNumber of DNA Alterations Chordoma1121 LMS1139 STS817 OS720 ES47 Chondrosarcoma37 GIST34 MPNST35 Myxofibrosarcoma36 SFT31 Angiosarcoma27 ASPS21 DDLPS211 myxLPS24 RMS24 Clear Cell Sarcoma12 DSRCT10 LGFMS12 Sarcoma NOS11 Synovial Sarcoma DNA alterations 80% with >/= 1 Median = 2 (range 0-8)

162 DNA alterations PI3K/Akt 16 (17%) Cell Cycle 56 (52%) Receptor Tyrosine Kinase (Amplifications) 19 (13%) MAPK 9 (13%) Epigenetic 21 (20%) DNA repair 6 (8%) Other 31 (38%)

Cell Cycle MG1 SG2 p53 MDM2 CDK4/6-Cyclin D CDK2-Cyclin E p15, p16 Rb

Cell Cycle 18 (25%) MG1 SG2 p53 MDM2 CDK4/6-Cyclin D CDK2-Cyclin E p15, p16 Rb 15 (21%) 8 (11%) 31 (44%) 12 (17%)

56 Aberrations (52% samples)

RTK PI3K PDK1 PIP3 AKT TSC1/2 mTOR p70S6K 4EBP1 PTEN RICTOR AMP RAPTOR STK11 Rheb PI3K/AKT

RTK PI3K PDK1 PIP3 AKT TSC1/2 mTOR p70S6K 4EBP1 PTEN RICTOR AMP RAPTOR STK (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