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MOLECULAR CARACTERISATION OF SOFT TISSUE SARCOMAS WITH COMPLEX GENETICS

MOLECULAR CARACTERISATION OF SOFT TISSUE SARCOMAS WITH COMPLEX GENETICS. Frédéric Chibon Pauline Lagarde - Jean-Michel Coindre - Alain Aurias Tumor Genetics Département of Pathology Insititut Bergonie – Bordeaux - FRANCE. GENETIC CLASSIFICATION OF STS.

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MOLECULAR CARACTERISATION OF SOFT TISSUE SARCOMAS WITH COMPLEX GENETICS

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  1. MOLECULAR CARACTERISATION OF SOFT TISSUE SARCOMAS WITH COMPLEX GENETICS Frédéric Chibon Pauline Lagarde - Jean-Michel Coindre - Alain Aurias Tumor Genetics Département of Pathology Insititut Bergonie – Bordeaux - FRANCE

  2. GENETIC CLASSIFICATION OF STS Sarcomas with recurrent translocations Sarcomas with oncogenic mutations Sarcomas with simple genetics Sarcomas with a complex genetic profile

  3. SARCOMAS WITH A COMPLEX GENETIC PROFILE Leiomyosarcomas Adult Rhabdomyosarcomas Pleomorphic Liposarcomas Myxofibrosarcomas Poorly-differentiated sarcomas / MFH

  4. SARCOMAS WITH A COMPLEX GENETIC PROFILE Different prognosis but…. … Difficult to classify ! share similar morphology Share histological patterns with dedifferentiated liposarcomas Genetic mechanisms still poorly understood

  5. French Sarcoma Group Database 2538 adult STS with untreated primary tumor: (January 2006) Well differentiated and dedifferentiated LPS: 262 (10.3%) LMS, adult RMS, pleomorphic LPS, MFS and Poorly-Differentiated Sarcomas (PDS) / MFH: 1183 (46.6%)

  6. COMPLEX GENETIC PROFIL OF SOFT TISSUE SARCOMAS MFH 50% MFS 25% PDS 25% Analyzed tumors: CGH ARRAY: 203 cDNA ARRAY: 170 LPS DD 30% MFH-PDS 35% LMS 35%

  7. Two main subgroups of genetic profiles DD LPS LMS MFH + PDS Amplification Gain Loss

  8. DD LPS: Simple Genetics based on co-amplifications DDLPS LMS MDM2 is amplified without CDK4 in 10% of the tumors Simple and specific genetics: 10 /40 were misdiagnosed MFH Amplification Gain Loss

  9. Two different profils correspond to two different types of LMS 17p13 16q12 -q22 17p12 7p 1q23-qter 10q 13q14 5p LIMB Average rearrangement number: 37 TRUNK Average rearrangement number: 26 10q23 13q14 LIMB TRUNK Ext Int Amplification Gain Loss

  10. Identification of driver genes in amplifications cDNA ARRAY Amplified tumors Non Amplified tumors Chr 5 23 Mb PDS / MFH LMS DD LPS Identification of a target gene CGH ARRAY

  11. Genetic alterations and clinical datas Overall Survival Metastasis Overall Survival MFH 5p 5p 5p Normal or loss Normal or loss probability Normal or loss probability probability Amplification or gain Amplification or gain p=0,08 Time in months p=0,04 p=0,08 Time in months Amplification or gain Time in months 5p Amplification : One gene amplified, up-regulated.... ...Wich effect on the tumor biology ?

  12. CONCLUSION Scientific project based on a virtual tumor bank with all clinical, pathological, biological criterias and follow up CGH: a really helpfull tool in STS diagnosis At least TWO distinct LMS MFH / PDS with « LMS alterations » have to be reviewed by pathologist Complementarity of CGH and cDNA arrays Identification of genomic alterations and target genes 1q21-q24 5p 7p 10q 13q 17p Diagnosis Prognosis Therapeutic target

  13. MOLECULAR CARACTERISATION OF STS WITH COMPLEX GENETICS Jean-Michel Coindre Binh Nguyen Bui Pauline Lagarde Véronique Brouste Cécile Garcia Alain Aurias Caroline Louis 11 CLCC French Sarcoma Group Pathologist

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