Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas.
HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma. We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas. We correlated their amplification status with clinicopathological features and outcomes. Histologically, both CDK4 (P=0.007) and JUN (P=0.005) amplifications were associated with dedifferentiated liposarcoma, whereas amplification of the proximal parts of HMGA2 (5'-untranslated region (UTR) and exons 1-3) was associated with atypical lipomatous tumor/well-differentiated liposarcoma (P=0.01). CDK4 amplification was associated with axial tumors. Amplification of 5'-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1. Shorter overall survival was correlated with: age >64 years (P=0.03), chemotherapy used in first intent (P<0.001), no surgery (P=0.003), grade 3 (P<0.001), distant metastasis (P<0.001), node involvement (P=0.006), and CDK4 amplification (P=0.07). In multivariate analysis, distant metastasis (HR=8.8) and grade 3 (HR=18.2) were associated with shorter overall survival. A shorter recurrence-free survival was associated with dedifferentiated liposarcoma (P<0.001), grade 3 (P<0.001), node involvement (P<0.001), distant metastasis (P=0.02), recurrent status (P=0.009), axial location (P=0.001), and with molecular features such as CDK4 (P=0.05) and JUN amplification (P=0.07). Amplification of 5'-UTR and exons 1-3 (P=0.08) and 3'-UTR (P=0.01) of HMGA2 were associated with longer recurrence-free survival. Distant metastasis was associated with shorter recurrence-free survival (HR=5.8) in multivariate analysis. Dedifferentiated liposarcoma type was associated with axial location, grade 3 and recurrent status. In conclusion, we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis. In addition, we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses, which was consistent with our general observations.
Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.|Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, University of Nice-Sophia Antipolis, Nice, France.|Medical Oncology Department, Centre Antoine-Lacassagne, Nice, France.
Esma
E
Saâda-Bouzid
Central Laboratory of Pathology, Nice University Hospital, Nice, France.
Fanny
F
Burel-Vandenbos
Biopathology Department, Centre Léon-Bérard, Lyon, France.
Dominique
D
Ranchère-Vince
Laboratory of Cytology and Pathology, Centre Antoine-Lacassagne, Nice, France.
Isabelle
I
Birtwisle-Peyrottes
Biopathology Department, Institut Paoli-Calmettes, Marseille, France.
Bruno
B
Chetaille
Pathology Department, Marseille University Hospital La Timone, Marseille, France.
Corinne
C
Bouvier
Laboratory of Cytology and Pathology, Centre Val d'Aurelle, Montpellier, France.
Marie-Christine
MC
Château
Laboratory of Pathology, University Hospital of Saint-Etienne, Saint-Etienne, France.
Michel
M
Peoc'h
Laboratory of Pathology, Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Paris, France.
Maxime
M
Battistella
Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.
Audrey
A
Bazin
Department of Biostatistics, Centre Antoine-Lacassagne, Nice, France.
Jocelyn
J
Gal
Central Laboratory of Pathology, Nice University Hospital, Nice, France.
Jean-François
JF
Michiels
Laboratory of Pathology, Bergonie Institute, Bordeaux, France.
Jean-Michel
JM
Coindre
Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.|Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, University of Nice-Sophia Antipolis, Nice, France.
Florence
F
Pedeutour
Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.|Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, University of Nice-Sophia Antipolis, Nice, France.
Laurence
L
Bianchini
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D055028:Comparative Genomic Hybridization; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D016758:Genes, jun / Q000235:genetics*; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008080:Liposarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016759:Oncogene Protein p65(gag-jun) / Q000235:genetics; D011379:Prognosis; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; D016759:Oncogene Protein p65(gag-jun); C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4