Diapositive 1

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Genetics of well-differentiated/dedifferentiated
liposarcomas
F. Pedeutour Nice - France
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Well-differentiated liposarcomas Simple
karyotype Supernumerary ring or giant maker
chromosomes
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Dedifferentiated liposarcomas Complex karyotype
Rings or giant marker chromosomes
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The ring and large marker chromosomes of
WDLPS/DDLPS contain 12q14-15 amplification
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Complex genomic composition and centromere
alterations
Consistent amplification of 12q14-15 Consistent
amplification from variable additional regions
Neocentromere
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Detection of MDM2/CDK4 amplification Help for
diagnosis
WDLPS/ lipoma DDLPS/poorly differentiated
malignant tumors
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Immunohistochemistry useful but -false
-false- -some stainings difficult to interpret
Routine molecular detection of MDM2/CDK4
amplification by FISH and/or Q-PCR Fresh, frozen
or formalin-fixed paraffin embedded samples
Sirvent et al., Am J Surg Pathol, 2007
MDM2 CDK4
amplified
not amplified
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Suspicion of adipose tissue tumor Examples of
FISH analyses
MDM2/CDK4
NO AMPLIFICATION
AMPLIFICATION
HMGA2  break-apart 

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Well-differentiated or dedifferentiated
liposarcoma
LIPOMA
Other rearrangements specific for benign or
malignant tumors PLAG1 (8q11) HMGA1
(6p21) del(13)(q 14) FUS-CHOP (t1216)
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Role of low level gains of MDM2 and CK4 in
adipose tissue tumors ?? Rare Gain 3-5 copies
Observed both in cases of ordinary lipomas
and atypical lipomatous tumors
Mandahl et al., Int J Cancer, 67632-5, 1996
Storlazzi et al., Int J Oncol, 2367-71,
2003 Italiano et al., Int J Cancer, 121 308-315,
2007
The missing link between lipomas and liposarcomas
???
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Characterization of the 12q amplicon
in WDLPS/DDLPS Analysis of a large series of
WDLPS/DDLPS by FISH and Q-RT-PCR
MDM2 CDK4 HMGA2 YEATS4 CHOP/DDIT3
Italiano et al., Int J Cancer, 122 2233-2241,
2008
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MDM2 is consistently amplified and
overexpressed in WDLPS/DDLPS
MDM2 target gene of the 12q14-15 amplicon in
WDLPS/DDLPS
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CDK4 is very frequently, but not always amplified
in WDLPS/DDLPS
CDK4 amplification not indispensable
to WDLPS/DDLPS tumorigenesis CDK4 amplification
replaced by other genomic events?? MDM2 and
CDK4 cores of two distinct amplicons
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non amplifié
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HMGA2 exons 1-2 are consistently amplfied,
rearranged and overexpressed in WDLPS
5HMGA2
3HMGA2
Exon 1-2 minimal amplified region
HMGA2 (12q14.3)
HMGA2 Rearranged in lipomas Rearranged and
amplified in WDLPS/DDLPS
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YEATS4 (GAS41) -interferes with P53 pathway
(like MDM2) -amplified in gliomas
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Normal
CHOP/DDIT3 (12q13) rearranged in t(1216) of
myxoid liposarcoma
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DDIT3 is rarely amplified in WDLPS/DDLPS but
often overexpressed, independantly of its
amplification status
DDIT3 a role in myxoid liposarcoma and in
WDLPS/DDLPS ?
DDIT3
DDIT3
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CONCLUSIONS

• -CDK4 and MDM2 cores of two distinct amplicons
• -MDM2 and HMGA2 exons 1-2 amplified in 100
  WDLPS/DDLPS
• -CDK4 not amplified in 10 of WDLPS/DDLPS
• HMGA2 a crucial gene in both malignant and
  benign adipose tissue tumors
• -FISH and Q-PCR detection MDM2/ HMGA2 exon 1-2
  instead of MDM2/CDK4 for WDLPS-DDLPS diagnosis?
• YEATS4 a novel oncogene involved in WDLPS
• DDIT3 a role in WDLPS/DDLPS in addition to its
  role in myxoid liposarcoma?

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Laboratory of Solid Tumors Genetics, University
Hospital and CNRS UMR 6543, Faculty of Medicine,
Nice, France
Antoine Italiano Laurence Bianchini Nicolas
Sirvent Frédérique Keslair Rita Attias Elodie
Basc Thibault Fabas Anne Pierron
Collaboration French Sarcoma Group (GSF-GETO)