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