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MINING COMPLEX SARCOMA GENOMES: LESSONS FROM OSTEOSARCOMA

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. GENOMIC VIEW OF SARCOMA. A CLEARLY DEFINED ONCOGENIC PATHWAY.

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MINING COMPLEX SARCOMA GENOMES: LESSONS FROM OSTEOSARCOMA

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  1. MINING COMPLEX SARCOMA GENOMES:LESSONS FROM OSTEOSARCOMA

  2. LARGE MARKER CHROMOSOMES IN ADULT SARCOMA

  3. TWO WAYS OF THINKING ABOUT SARCOMA

  4. DEVELOPMENTAL BIOLOGY VIEW OF SARCOMA TEICHER 2012

  5. GENOMIC VIEW OF SARCOMA

  6. GENOMIC VIEW OF SARCOMA A CLEARLY DEFINEDONCOGENIC PATHWAY

  7. GENOMIC VIEW OF SARCOMA NO SINGLE CLEARLY DEFINEDONCOGENIC PATHWAY

  8. APPROACHES TO COMPLEXITY • LARGE INTEGRATED GENOMICS STUDIES • INTEGRATION WITH GWAS STUDIES • COMPARATIVE ONCOLOGY • COMMONALITIES AMONG COMPLEX SARCOMAS • GOAL: A PATH TO CLINICAL RELEVANCE

  9. ENDOCHONDRAL OSSIFICATION MEMBRANOUS OSSIFICATION

  10. NORMAL TUMOR

  11. GLOBAL INCIDENCE International Journal of CancerVolume 125, Issue 1, pages 229-234, 3 FEB 2009 DOI: 10.1002/ijc.24320http://onlinelibrary.wiley.com/doi/10.1002/ijc.24320/full#fig1

  12. EPIDEMIOLOGY CONNECTS BONE GROWTH TO TUMOR RISK Mirabello et al. Cancer Causes Control. 2011 Jun;22(6):899-908.

  13. MINIMAL SURVIVAL IMPROVEMENT IN RECENT DECADES Whelan Ann. Oncol 2011

  14. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  15. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST ENDOCRINE AUTOCRINE PARACRINE MORPHOGENETIC, GROWTH AND DIFFERENTIATION REGULATING SIGNALS CHONDROCYTE

  16. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  17. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA • DERANGED GROWTH • INVASIVE • ABERRANT DIFFERENTIATION • MASSIVE GENOME INSTABILITY • GROSSLY PERTURBED GENE EXPRESSION BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  18. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA • MASSIVE GENOME INSTABILITY • DERANGED GROWTH • INVASIVE • ABERRANT DIFFERENTIATION BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE A SHATTERED GENOME

  19. DISTINCT COPY NUMBER PROFILES EMERGE • MASSIVE GENOME INSTABILITY • DERANGED GROWTH • INVASIVE • ABERRANT DIFFERENTIATION BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  20. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA MASSIVE PERTURBATION OF GENE EXPRESSION BY COPY NUMBER BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  21. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA EVIDENCE BASED CATEGORIES OF GENES ALTERED IN OS OR WHICH CONFER PREDISPOSITION TO OS THAT CAN CONTRIBUTE TO THE TUMOR PHENOTYPE: • CELL CYCLE, DNA REPLICATION AND REPAIR • SIGNAL TRANSDUCTION • BONE DIFFERENTIATION BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  22. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA CELL CYCLE, DNA REPLICATION AND REPAIR GENEEVIDENCE TP53 GERMLINE MUTATION, TUMOR MUTATION, MOUSE MODELS RB1 GERMLINE MUTATION, TUMOR MUTATION, MOUSE MODELS CDKN2A DELETION CCNE1 AMPLIFICATION CDK4 AMPLIFICATION MDM2 AMPLIFICATION CDC5L AMPLIFICATION COPS3 AMPLIFICATION REQL4 GERMLINE MUTATION BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  23. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA BONE DIFFERENTIATION GENES SIGNAL TRANSDUCTION GENE EVIDENCE PTEN DELETION PIK3CA MUTATION RAS MUTATION IGF1R AMPLIFICATION MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  24. TRANSCRIPTION FACTORS IN BONE DIFFERENTIATION BONE DIFFERENTIATION GENES MSC RUNX2 SP7 (OSX) PPARG CEBP’s OSTEOBLAST 2 OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE RUNX2 CHONDROBLAST OTHER TF’S SATB2 TWISTDLX MSX AP1 EGR2 ATF4 SOX 5,6,9 CHONDROCYTE

  25. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA BONE DIFFERENTIATION GENEEVIDENCE RUNX2 AMPLIFICATION SATB2 LOSS RB1 MODELS TP53 MODELS BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  26. A CONCEPTUAL FRAMEWORK FOR OSTEOSARCOMA UNCERTAIN FUNCTION GENEEVIDENCE LSAMP DELETION (REGION?) BONE DIFFERENTIATION GENES MSC OSTEOBLAST 2 OSTEOSARCOMA OSTEOBLAST 1 PREOSTEOBLAST OSTEOCYTE CHONDROBLAST CHONDROCYTE

  27. APPROACHES TO COMPLEXITY • LARGE INTEGRATED GENOMICS STUDIES • INTEGRATION WITH GWAS STUDIES • COMPARATIVE ONCOLOGY • COMMONALITIES AMONG COMPLEX SARCOMAS • GOAL: A PATH TO CLINICAL RELEVANCE

  28. TARGET OSTEOSARCOMA PROJECT

  29. TARGET OSTEOSARCOMA PROJECT • COMPREHENSIVE GENOMIC ANALYSIS • ARRAYS: mRNA,miRNA, DNA Methylation, SNPS •SEQUENCING: EXOME, TRANSCRIPTOME, WHOLE GENOME ON SELECT SAMPLES

  30. THE TURBULENT GENOME OF OSTEOSARCOMA OS NBL

  31. WHOLE GENOME SEQUENCING SOMATIC STRUCTURAL VARIATIONS

  32. WHOLE GENOME SEQUENCING SOMATIC STRUCTURAL VARIATIONS

  33. WHOLE GENOME SEQUENCING STRUCTURAL VARIATIONS: COPY NUMBER LOSS

  34. WHOLE GENOME SEQUENCING COPY NUMBER | | | | | | | | | | | | | | | | |

  35. APPROACHES TO COMPLEXITY • LARGE INTEGRATED GENOMICS STUDIES • INTEGRATION WITH GWAS STUDIES • COMPARATIVE ONCOLOGY • COMMONALITIES AMONG COMPLEX SARCOMAS • GOAL: A PATH TO CLINICAL RELEVANCE

  36. Comparative Oncology Program

  37. Normal Tissues Osteosarcoma Human Dog

  38. APPROACHES TO COMPLEXITY • LARGE INTEGRATED GENOMICS STUDIES • INTEGRATION WITH GWAS STUDIES • COMPARATIVE ONCOLOGY • COMMONALITIES AMONG COMPLEX SARCOMAS • MAPPING A PATH TO CLINICAL RELEVANCE

  39. 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

  40. COMPLEX GENOME OF UPS

  41. RB1 DELETION IN UPS

  42. CHROMOSOME 12 AMPLIFICATION IN A LEIOMYOSARCOMA

  43. TWO MODES OF TELOMERE MAINTENANCE PROGENITOR CELL ALTERNATIVE LENGTHENING OF TELOMERES TELOMERASE ACTIVATION IMMORTALITY

  44. TWO MODES OF TELOMERE MAINTENANCE MESENCHYMAL STEM CELL (LOW TELOMERASE EXPRESSION) ALTERNATIVE LENGTHENING OF TELOMERES TELOMERASE ACTIVATION IMMORTALITY

  45. TELOMERE MAINTENANCE IN SARCOMA Durant, J. Cancer 3:67 2012 Heaphy et al, AJP 179:1609 (2011)

  46. FREQUENCY OF ALT IN SARCOMA % Heaphy et al, AJP 179:1609 (2011)

  47. Osteosarcoma Pancreatic Cell Line Normal DNA Embryonic Kidney w/Adenovirus

  48. RNA SEQ REVEALS A TRUNCATED RNA SEQ TRANSCRIPT IN SAOS2 DIRECTION OF TRANSCRIPTION

  49. ATRX INACTIVATION BY AN INTRACHROMOSOMAL REARRANGEMENT IN SAOS2

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