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).
A study of HMGA2 expression in a variety of adipocytic tumors showed aberrant expression in lipomas with 12q13-15 aberrations and ring chromosomes as well as in ALTs and well-differentiated liposarcomas (WDLSs), and frequent differential expression of HMGA2 exons 1-2 versus that of exons 4-5.
Studies of cell cycle controlling proteins that interact with CDK4 and MDM2 revealed an abnormally strong expression of cyclins D1 and E. The selective high-level amplification of the 5'-part of HMGA2, including the DNA-binding domains, suggests that this gene is a major target of amplifications in WDLS.
Moreover, because some features, such as overexpression of HMGA2, are shared by both lipomas and WDLPS, it has been hypothesized that lipomas and WDLPS may form a genetic and morphological continuum.
MDM2 and HMGA2 amplification were found in a subset of stromal cells in the hamartomatous component and in most cells of the well-differentiated liposarcoma.
Since the HMGA2-LPP fusion transcripts are exclusively detectable in benign mesenchymal tumors, testing HMGA2-LPP expression may be useful for differential diagnosis in cases of radiologically-suspected well-differentiated liposarcomas.
On the basis of these findings, the targeting of the HMGA2 protein expression may represent a promising approach for treating the well-differentiated liposarcomas resistant to conventional therapies.
Atypical lipomatous tumors (ALTs) are characterized by supernumerary ring chromosomes and/or giant marker chromosomes, which typically are composed of interspersed, amplified 12q-sequences, are C-band negative, lack alpha-satellite sequences, and display high copy numbers of several oncogenes, including HMGA2 (a.k.a.
Consistent with the suggested role of HMGIC in adipocytic differentiation, most of the novel ectopic sequences were observed in well-differentiated liposarcomas.
This truncation of HMGIC resembles that reported for translocations of HMGIC in benign tumors, including lipomas, and it is striking that the gene was frequently amplified or rearranged in well differentiated liposarcomas, the malignant counterpart of lipomas.