Heterogeneity of Genetic Alterations in Dedifferentiated Liposarcoma
AE Horvai, S DeVries, R Roy, RJ O'Donnell, F Waldman. UCSF, San Francisco, CA
Background: Liposarcoma is the most common soft tissue sarcoma in adults. Progression from well-differentiated liposarcoma to a dedifferentiated form is a rare, but well documented, phenomenon. Amplification of chromosome subregion 12q13-q15 is present in both well- and dedifferentiated liposarcomas and the resulting amplifications of cell cycle regulators MDM2 and CDK4 may promote tumorigenesis. However, the genetic changes that distinguish between well- and dedifferentiated liposarcomas, and may provide insight into progression, are less well understood. The relationships between genetic changes and either clinical presentation or tumor grade are also unknown.
Design: We used array comparative genomic hybridization to study the genetic changes in 29 cases of dedifferentiated liposarcoma. Well-differentiated and dedifferentiated components were microdissected and separately analyzed, allowing pairwise comparisons of genetic data and differentiation. Genetic changes were also compared to clinical presentation, grade and expression of MDM2 and CDK4.
Results: All 29 cases showed amplification of 12q13-15. Using unsupervised hierarchical clustering, the tumors could be resolved into three categories based on the severity of genomic aberrations. The paired well-differentiated and dedifferentiated components differed with respect to the total number of amplifications (p=0.008). High level amplifications of 1q23-24 and 6q21-23 were present in 5 cases each (17%) but no genetic changes were statistically significant in separating well-differentiated and dedifferentiated components. In four cases (14%), a well-differentiated liposarcoma preceded the dedifferentiated liposarcoma by 1-5 years (secondary). Eight cases (28%) were classified as low-grade dedifferentiation. Interestingly, secondary presentation and grade correlated with the frequency of genetic changes at 4 and 6 specific loci, respectively (p=0.01). Secondary tumors also showed more total genomic variability than primary tumors (p=0.026). CDK4 and MDM2 immunopositivity demonstrated a synergistic effect on amplification at 12q13-15.
Conclusions: Dedifferentiated liposarcomas are genetically heterogeneous tumors with reproducible changes, but none that uniformly distinguish the well- and dedifferentiated components. The relationship between presentation, grade and genetic changes may reflect differences in tumor initiation, factors that control genomic instability or the background genotype of the tumor.
Category: Bone & Soft Tissue
Monday, March 9, 2009 8:30 AM
Platform Session: Section E, Monday Morning