J. Fernebro, P. Francis, P. Edén, Å. Borg, I. Panagopoulos, F. Mertens, J. Vallon-Christersson, M....
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Transcript of J. Fernebro, P. Francis, P. Edén, Å. Borg, I. Panagopoulos, F. Mertens, J. Vallon-Christersson, M....
J. Fernebro, P. Francis, P. Edén, Å. Borg, I. Panagopoulos,
F. Mertens, J. Vallon-Christersson, M. Åkerman, N. Mandahl,
M. Nilbert
Departments of Oncology, Theoretical Physics, Clinical Genetics, and Pathology
Lund University, Sweden
Gene expression profiles relate to gene fusiontype and metastasis in synovial sarcoma
Aims
Groups of genes discriminating the monophasic from biphasic
have been previously identified
(Allander et al., 2002; Nagayama et al., 2002)
Do gene expression profiles in synovial sarcoma correlate with: Histopathology Cytogenetics Gene fusion type Metastatic potential
23 synovial sarcoma specimens from 21 patientsmean age 46, 12 males, 16 primary tumors, 3 local recurrences, 4 metastases
Histopathology monophasic (17) vs biphasic (4)
Cytogenetics t(X;18) (4) vs complex karyotype (12)
Gene fusion type SS18/SSX1 (12) vs SS18/SSX2 (7)
Metastatic potential metastasis (13) vs metastsis-free (5)
SS18 SSX
Material
Scan
Process Image
Labelled cDNA
18-20 hrs incubation at 42oC
Hybridize to microarray slide
Reference RNA
Tumour RNA
Image and
Data Analysis
cDNA microarray, 27648 IMAGE clones25648 distinct reporters17517 unique UniGene clusters
Hierarchical clusteringbased on ~5800 genes
- Unsupervised
- Supervised Golub scores, random permutation tests
Methods
Expression profiles did not relate to histopathology or karyotype
Significant discriminators for gene fusion type and metastatic potential
Metastasis No Yes
Gene fusion type Type 1 Type 2
Supervised clustering
Up SS18/SSX1 - TCF7 - LEF1 - RTP801 - CKB - NOTCH2 - Metallothioneins
Up SS18/SSX2- BENE - MN1- NEDD4 - FRAG1- MSX2 - TIEG
Gene fusion type
Transcription factors
Signalling molecules
Multiple metallothioneins
Discriminating genes
Up metastasis- TYMS - TOP2A- PTTG1 - IGFBP2- BUB1 - COL18A1
Up without metastasis- ProSAPiP1 - TNNT1- ICAM1 - DDX21- FRAG1 - TCF8
Metastatic potential
Cell proliferation
Cell cycle progression
Transcriptional regulation
45 from top 200 common to both lists Up in metastasis also up in SS18/SSX1
- BSG - FRAG1- NOTCH2- RGS2- TCF7 - TCF8
Common discriminators
Up SS18/SSX1 - TCF7 - LEF1 - RTP801 - CKB - NOTCH2 - Metallothioneins
Up SS18/SSX2- BENE - MN1- NEDD4 - FRAG1- MSX2 - TIEG
Gene fusion type
Up metastasis- TYMS - TOP2A- PTTG1 - IGFBP2- BUB1 - COL18A1
Up without metastasis- ProSAPiP1 - TNNT1- ICAM1 - DDX21- FRAG1 - TCF8
Metastatic potential
Discriminating genes
Targets for chemotherapeutic drugs
Up SS18/SSX1 - TCF7 - LEF1 - RTP801 - CKB - NOTCH2 - Metallothioneins
Up SS18/SSX2- BENE - MN1- NEDD4 - FRAG1- MSX2 - TIEG
Gene fusion type
Up metastasis- TYMS - TOP2A- PTTG1 - IGFBP2- BUB1 - COL18A1
Up without metastasis- ProSAPiP1 - TNNT1- ICAM1 - DDX21- FRAG1 - TCF8
Metastatic potential
Discriminating genes
Previously reported in synovial sarcoma
Up SS18/SSX1 - TCF7 - LEF1 - RTP801 - CKB - NOTCH2 - Metallothioneins
Up SS18/SSX2- BENE - MN1- NEDD4 - FRAG1- MSX2 - TIEG
Gene fusion type
Up metastasis- TYMS - TOP2A- PTTG1 - IGFBP2- BUB1 - COL18A1
Up without metastasis- ProSAPiP1 - TNNT1- ICAM1 - DDX21- FRAG1 - TCF8
Metastatic potential
Discriminating genes
Previously reported in metastasizing tumors
Up SS18/SSX1 - TCF7 - LEF1 - RTP801 - CKB - NOTCH2 - Metallothioneins
Up SS18/SSX2- BENE - MN1- NEDD4 - FRAG1- MSX2 - TIEG
Gene fusion type
Up metastasis- TYMS - TOP2A- PTTG1 - IGFBP2- BUB1 - COL18A1
Up without metastasis- ProSAPiP1 - TNNT1- ICAM1 - DDX21- FRAG1 - TCF8
Metastatic potential
Discriminating genes
Differentially expressed genes relative to gene fusion type and metastatic potential in synovial sarcoma
Signaling molecules, transcription factors and metallothioneins among the fusion type discriminating genes
Known targets for chemotherapy (TYMS and TOP2A) upregulated in metastasizing tumors
Conclusions