HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon.
Data concerning the fine structure of the 12q13-15 amplicon which contains MDM2 and CDK4 in well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS) are scarce. We investigated a series of 38 WDLPS/DDLPS using fluorescence in situ hybridization analysis with 17 probes encompassing the 12q13-15 region. In addition, using quantitative RT-PCR we studied the expression of MDM2, CDK4, DDIT3 (CHOP/GADD153), DYRK2, HMGA2, TSPAN31 and YEATS4 (GAS41) in 11 cases. We showed that CDK4 (12q14.1) belonged to a distinct amplicon than MDM2 (12q15). There was no continuity in the amplified sequences between MDM2 and CDK4. Moreover, while MDM2 was amplified and overexpressed in all cases, CDK4 was not amplified or overexpressed in 13% of cases. The centromeric border of the CDK4 amplicon was located immediately downstream the 5' end of DDIT3, a gene known for being involved in myxoid liposarcoma translocations. DDIT3 was amplified in 3 cases and overexpressed in 9 cases. The overexpression of DDIT3 was correlated to the CDK4 amplification and not to its own amplification status. This suggested that the CDK4 amplicon, as well as the overexpression of DDIT3, might be generated by the disruption of a fragile region in 5' DDIT3. HMGA2 was always amplified and rearranged indicating that it plays a central role in WDLPS/DDLPS. HMGA2 rearrangement frequently resulted in a loss of the 3' end region that is a binding site for let-7. We also found a frequent amplification and overexpression of YEATS4, an oncogene that inactivates P53, suggesting that YEATS4 might play an important role together with MDM2 in WDLPS/DDLPS oncogenesis.
Italiano
Antoine
A
Laboratory of Solid Tumors Genetics, Nice University Hospital, and CNRS, UMR 6543, Faculty of Medicine, Nice, France.
Bianchini
Laurence
L
Keslair
Frédérique
F
Bonnafous
Stéphanie
S
Cardot-Leccia
Nathalie
N
Coindre
Jean-Michel
JM
Dumollard
Jean-Marc
JM
Hofman
Paul
P
Leroux
Agnès
A
Mainguené
Claire
C
Peyrottes
Isabelle
I
Ranchere-Vince
Dominique
D
Terrier
Philippe
P
Tran
Albert
A
Gual
Philippe
P
Pedeutour
Florence
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008067:Lipoma / Q000235:genetics / Q000473:pathology; D008080:Liposarcoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C497249:DDIT3 protein, human; D025743:HMGA2 Protein; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C109446:YEATS4 protein, human; D051742:Transcription Factor CHOP; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4