Molecular pathology/genetics of sarcomas
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1 Molecular pathology/genetics of sarcomas Gunhild Mechtersheimer Institute of Pathology, University of Heidelberg Sarkomkonferenz: Berlin
2 Characterization of soft tissue sarcomas / STS (~ 1% of all malignancies in adulthood, ~ 55 subtypes) - the pathologist s tasks - Tumor classification Tumor grading Tumor staging Further parameters of prognostic relevance Pathogenetic principles Targets for molecular therapy => Stratification of prognosis and therapy Sarkomkonferenz: Berlin
3 Recurrent and tumor-subtype specific balanced chromosomal translocations in soft tissue sarcomas - First description in 1986 in myxoid liosarcomas - Sarkomkonferenz: Berlin
4 Genomic dichotomy of soft tissue sarcomas Simple karyotypes with specific translocations resulting in fusion genes, with amplifications, or with mutations. E.g.: - t(11;22)(q24;q12) - EWS/FLI-1 in Ewing s sarcomas - MDM2-amplification in well-differentiated liposarcomas and in dedifferentiated liposarcomas - KIT or PDGFR- mutations in GIST Complex, unbalanced karyotypes with numerous chromosomal aberrations E.g.: - undifferentiated pleomorphic high-grade sarcomas (MFH) - leiomyosaracomas -MPNST Sarkomkonferenz: Berlin
5 Soft tissue sarcomas with specific chromosomal translocations (approximately 20% of soft tissue sarcomas) Riggi et al.: J Pathol 213: 4-20, 2007 Sarkomkonferenz: Berlin
6 Chromosomal translocations and most important consequences CML t(9;22)(q34;q11) 9 22 der (9) der (22) Burkitt s lymphoma t(8;14)(q24;q32) 8 14 der (8) der (14) BCR BCR ABL ABL MYC IGH IGH MYC C1 C2 C3 5 Fusion gene C1 C2 C3 3 8,5 kb BCR/ABL mrna myc IgH P210 fusion protein Constitutively active tyrosine kinase Upregulated expression of structurally normal MYC protein
7 Recurrent translocations in STS (ca. 20%): Chimeric fusion genes FUS EWS FKHR SYT DDIT3 FLI1 ERG WT1 ATF1 CHN PAX3 PAX7 SSX1 SSX2 SSX4 Myxoid/round cell liposarcoma Ewing s sarcoma/pnet Desmoplastic small, round cell tumor Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Alveolar rhabdomyosarcoma Synovial sarcoma Transkription factor gene Gene with RNA / DNA-binding domain Activated transcription / Deregulated control of proliferation Sarkomkonferenz: Berlin
8 Impact of translocations in soft tssue sarcomas Diagnosis Pathogenesis Prognosis? Therapy?
9 Differential diagnosis of spindele cell sarcomas Leiomyosarcoma / Desmin GIST / CD117 (KIT) SySa mf / CD56 (N-CAM) MPNST / CD56 (N-CAM)
10 Synovial sarcoma versus MPNST Translocation t(x;18)(p11;q11) in synovial sarcoma
11 Molecular detection of translocations Reverse transcriptase-pcr (RT-PCR) Detection of fusion transcripts Fluorescence in situ-hybridization (FISH) Fusion assay: Detection of the fusion of two chromosomal subregions using dual colour FISH Break apart assay: Detection of a chromosomal breakpoint using dual colour FISH Immunhistochemistry Detection of oncogenic fusion proteins
12 Synovial sarcoma versus MPNST -> Translocation t(x;18)(p11;q11) in syonvial sarcoma SS18(SYT)-SSX1/SSX2/SSX4 SSX1/SSX2/SSX4 fusion gene SS18-SSX1/SSX2/SSX4 SSX1/SSX2/SSX4 fusion transcript Chimeric SS18-SSX1/SSX2/SSX4 SSX1/SSX2/SSX4 protein Capillary electrophoretically mediated detection of a SS18(SYT)-SSX1 fusion transcript by RT-multiplex PCR in a case of monophasic synovial sarcoma (FFPE) SS18-SSX1 (147 bp) ß-Aktin (190 bp)
13 Differential diagnosis of myxoid sarcomas Myxoid liposarcoma: t(12;16)(q13;p11) -> FUS-DDIT3 Myxoid liposarcoma (LS) Myxofibrosarcoma (MFS) Dedifferentiated LS/MFS-like
14 Detection of a DDIT3(CHOP)-translocation in a myxoid liposarcoma using dual colour break apart-fish - Normal signal Break within the DDIT3-locus (12q13)
15 Immunhistochemical detection of oncogenic fusion proteins Inflammatory myofibroblastic tumor, e.g. t(1;2)(q25;p23) ALK Ewing s sarcoma / PNET t(11;22)(q24;q12) FLI1 Alveolar sarcoma of soft parts t(x;17)(p11.2;q25) TFE3 Synovial sarcoma t(x;18)(p11;q11) SYT Desmoplastic small, round cell tumor t(11;22)(q22;q12) WT1
16 Pathogenetic impact of translocations in sarcomas FUS-CHOP (DDIT3) fusion in myxoid liposarxomas (MLS) FUS-CHOP protein expression in MPC und MLS Tumor growth in SCID mice T1-2 T1-2 Human MRLS grams T1-1 MPC-FUS-CHOP FUS-CHOP expression -> initiating event in the pathogenesis of Mesenchymal progentitor cells (MPC) -> precursors of MLS
17 High-grade STS with complex karyotypes - Differential diagnoses - Myxofibrosarcoma Leiomyosarcoma Pleomorphic rhabdomyosarcoma Pleomorphic liposarcoma MPNST UPHGS/MFH AJSP 1992 Dedifferentaiated liposarcoma Melanoma Carcinoma Lymphoma
18 Karyotype of a leiomyosarcoma Nilbert et al.: Cancer Genet Cytogenet 1990
19 High-grade STS with complex karyotypes - Molecular characterization - Comparative genomic hybrodization (CGH) Array-CGH (cdna-arrays) Expression profiling (oligonucleotid-arrays) Proteomics UPHGS/MFH Pleomorphic LS
20 CGH-profile: Undifferentiated pleomorpgic high-grade sarcoma (MFH)
21 Chromosomal imbalances detected by CGH in 158 high grade STS - unsupervised hierarchical cluster analysis - MFH LMS MFH LMS MFH LMS MFH MFH MPNST LS-DD MFH LS-PL MPNST LS-PL LS-DD are genetically different from other subtypes of high-grade STS Subgroups of MFH are genetically similar to either LMS or LS-PL or MPNST => MFH are not a distinct entity + 12q p q22-q24-11q22-q24-10q23-q25
22 Chromosome 5p array-cgh Control-DNA Tumor-DNA Contig comprising 416 5p-BACs, 100 control-bacs (resolution approx. 50 kb) Matrix of genomic fragments (BAC- or PAC-clonees = Gain in tumor genome = Loss in tumor genome = Balanced status Adamovics et al., Genes Chromosom Cancer 2006
23 Chromosome 5p-DNA array: Analysed sarcomas Chromsomal status of 5p Balanced (n = 18) Low level gain (n = 9) Distinct amplification (n = 7) Sarcoma subtype MFH (n = 4) MPNST (n = 7) LS-PL (n = 4) LS-DD (n = 3) MFH (n = 1) MPNST (n = 1) LS-PL (n = 6) LS-DD (n = 1) MFH (n = 1) MPNST (n = 2) LS-PL (n = 2) LS-DD (n = 2) Adamowicz et al.: Genes Chrosmosomes Cancer, 2006
24 Distinct chromosome 5p-amplifications in STS (7/34) and candidate genes => 4 highly amplified consensus regions 5,0 4,0 3,0 2,0 1, Candidate genes involved in proliferation or differenetiation: (1): NKD2, htert, SLC6A3, IRX2; (2): POLS (3): TRIO (4): SKP2, FYB, FGF10, PTGER4, FBOX32 Strict correlation between gene copy number and mrna-expression (critical target genes) ->TRIO, NKD2 und IRX2 5pter 5pcen (1) (2) (3) (4) Adamovics et al., Genes Chromosom Cancer 2006
25 Expression Profiling Unsupervised clustering Marcus Renner, Heidelberg (KO.SAR)
26 Morphological liposarcoma subtypes Well-differentiated Myxoid Round cell Dedifferentuated Dedifferentiated Pleomorphic
27 Chromosomal imbalances detected by CGH in 73/79 liposarcomas - unsupervised hierarchical cluster analysis (Eisen et al., 1998) - WD-LS DD-LS MR-LS PL-LS + 5p13-p15 + 1q21-q q13-q15-13q14-q21
28 Dedifferentiated liposarcomas are genetically different from pleomorphic and myxoid/round cell liposarcomas Cluster 1: + 12q13-q15* Cluster 2: + 1p12-p21*. + 1q21-q24*, + 5p13-p15*, + 17p11.2-p12*, - 2q33-q36* *p < Cluster 1 Cluster 2 Liposarcomas of cluster 2 show significant associations with higher numbers of chromosomal gains and losses high grade malignancy (G2/G3 vs. G1) tumor site (lower extremity vs. retroperitoneum)
29 Array-CGH of a dedifferentiated liposarcoma 6q Oncogene-Array (188 BAC/PAC Clones) 12q Chrom. 12q Array (112 BAC Clones) 3,75 3,5 3,25 3 2,75 2,5 2,25 2 1,75 1,5 1,25 1 0,75 0,5 0,25 0-0,25-0,5 MDM2 MDM2 Distinct amplifications: Cyclin D2 (12q13), MDM2 (12q14.3-q15), CDK4 (12q14), GLI (12q13.2-q13.3), DLK (12q13), MYB (6q22), Cyclin D1 (11q13) Fritz et al.: Cancer Res, 2002
30 Dedifferentiated (DDLS) and pleomorphic LS (PLLS) - Differentially expressed genes - PLLS DDLS CDK4 (12q14) MDM2 (12q14.3-q15) Marcus Renner, Heidelberg (KO.SAR)
31 MDM2 as a target for the MDM2 antagonist nutlin-3a in dedifferentiated liposarcoma (LS) cells with MDM2 overexpression Nutlin-3a (5 mol/l) induces considerable inhibition of proliferation, apoptosis, and G2 cell cycle arrest in dedifferentiated LS cells compared with normal adipocytes. Nutlin-3a induces activation of the p53 pathway in dedifferentiated LS cells. Proliferation following Nutlin-3a treatment Proliferation (% control) Increased p53, p21 and MDM2 protein expression following nutlin-3a treatment % Apoptosis / Annexin Aopotosis following Nutlin3a treatment NADIP DDLS LS141 Singer et al.: Cancer Res 2007
32 Molecular pathology/genetics of soft tissue sarcomas - perspectives - Definition of biological tumor entities Identification of pathogenetically and biologically relevant genes Detection of molecular targets Basis for new therapeutic strategies
33 Dedifferentiated liposarcomas: Genetically separate subgroups Subgroup 1: + 12q13-q15 Subgroup 2: + 12q13-q15, + 1q21-q24* Subgroup 3: + 12q13-q15, + 6q22-q24*, + 12q24*, + 20q13*, - 11q22-q23*, - 13q14-q21* *p < Subgroup 1 Subgroup 2 Subgroup 3 SG 2 vs. SG 1: Trend to more chromosomal gains (p = ) SG 3 vs. SG 1: Significantly more chromosomal gains (p = ) and chromosomal losses (p = ) No correlation with tumor s grade, stage (primary vs. recurrent) or site
34 Potential therapeutic target: MAP3K5 (6q22.33) CGH: Frequent 6q22-q24 amplifications in high-grade liposarcomas (PLLS, DDLS) and MFHs Array-CGH: Chromosome 6q22.33 MAP3K5 Mitogen-activated proteinkinase kinase kinase 5 (ASK1, MEKK5) Thioredoxin TNFR1 MAP3K5 MAP2K 4/7 + JUNK - PPAR + Loss of adipogenic differentiation Chibon et al.: Genes Chromosomes Cancer 2004
35 Differentiation of the MFH cell line TSL Lipid accumulation under Thioredoxin und N-Acetyl-Cystein (NAC) Untreated NAC Thioredoxin Troglitazon (PPAR- L) Chibon et al.: Genes Chromosomes Cancer 2004
36 Molecular pathology/genetics of soft tissue sarcomas - perspectives - Definition of biological tumor entities Identification of pathogenetically and biologically relevant genes Detection of molecular targets Basis for new therapeutic strategies
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