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 Sarcomas with recurrent translocations Sarcomas with oncogenic mutations Sarcomas with simple genetics Sarcomas with a complex genetic profile

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

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

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%)

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

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

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

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

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

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

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

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