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MOLECULAR CARACTERISATION OFSOFT TISSUE SARCOMAS WITH
COMPLEX GENETICS
Frédéric ChibonPauline Lagarde - Jean-Michel Coindre - Alain Aurias
Tumor GeneticsDépartement 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%)
Analyzed tumors: CGH ARRAY: 203cDNA ARRAY: 170
LPS DD30%
LMS 35%
MFH-PDS 35%
COMPLEX GENETIC PROFIL OF SOFT TISSUE SARCOMAS
MFH 50%MFS 25%PDS 25%
DD LPS
LMS
MFH+
PDS
Two main subgroups of genetic profiles
Amplification Gain Loss
DD LPS: Simple Genetics based on co-amplifications
Amplification Gain Loss
MDM2 is amplified without CDK4 in 10% of the tumorsSimple and specific genetics: 10 /40 were misdiagnosed
DD LPS
LMS
MFH
Two different profils correspond to two different types of LMS
LIMB
TRUNK
Ext
Int
10q23 13q14
10q 13q141q23-qter 17p12
17p13
5p16q12-q227p
Amplification Gain Loss
Average rearrangement number: 37
Average rearrangement number: 26
LIMB
TRUNK
Identification of a target gene
Non Amplified tumors
Amplified tumors
23 Mb
CGH ARRAY cDNA ARRAY
Identification of driver genes in amplifications
Chr 5
PDS / MFH LMS DD LPS
T e m p s e n m o i s1 6 8 , 0 0 01 4 4 , 0 0 01 2 0 , 0 0 09 6 , 0 0 07 2 , 0 0 04 8 , 0 0 02 4 , 0 0 00 , 0 0 0
Pro
bab
ilité
1 , 0
0 , 8
0 , 6
0 , 4
0 , 2
0 , 0
g a in o u a m p l i - c e n s u r ép e r t e o u n o r m - c e n s u r ég a in o u a m p l ip e r t e o u n o r m
c 2 _ t r i o
s u r v i e
5p
p=0,08
Overall Survival
Time in monthspr
obab
ility
Normal or loss
Amplification or gain
T e m p s e n m o i s8 4 , 0 0 07 2 , 0 0 06 0 , 0 0 04 8 , 0 0 03 6 , 0 0 02 4 , 0 0 01 2 , 0 0 00 , 0 0 0
Pro
bab
ilité
1 , 0
0 , 8
0 , 6
0 , 4
0 , 2
0 , 0
g a in o u a m p l i - c e n s u r ép e r t e o u n o r m - c e n s u r ég a in o u a m p l ip e r t e o u n o r m
c 2 _ t r i o
G r o u p e M F H S u r v i e e n f c t d e T r i o
5p
p=0,04
Overall SurvivalMFH
Time in months
prob
abili
ty
Normal or loss
Amplification or gain
5p Amplification : One gene amplified, up-regulated.......Wich effect on the tumor biology ?
Genetic alterations and clinical datas
T e m p s e n m o i s1 6 8 , 0 0 01 4 4 , 0 0 01 2 0 , 0 0 09 6 , 0 0 07 2 , 0 0 04 8 , 0 0 02 4 , 0 0 00 , 0 0 0
Pro
bab
ilité
1 , 0
0 , 8
0 , 6
0 , 4
0 , 2
0 , 0
g a in o u a m p l i - c e n s u r ép e r t e o u n o r m - c e n s u r ég a in o u a m p l ip e r t e o u n o r m
c 2 _ t r i o
M é t a
5p
p=0,08
Metastasis
Time in months
prob
abili
ty
Normal or loss
Amplification or gain
CONCLUSION
Scientific project based on a virtual tumor bank with all clinical, pathological, biological criterias and follow up
Identification of genomic alterations and target genes1q21-q245p7p10q13q17p
CGH: a really helpfull tool in STS diagnosis
At least TWO distinct LMS
Complementarity of CGH and cDNA arrays
DiagnosisPrognosisTherapeutic target
MFH / PDS with « LMS alterations » have to be reviewed by pathologist
MOLECULAR CARACTERISATION OF STS WITH COMPLEX GENETICS
Alain AuriasCaroline Louis
Jean-Michel CoindreBinh Nguyen BuiPauline LagardeVéronique BrousteCécile Garcia
11 CLCCFrench Sarcoma Group Pathologist