Dedifferentiated liposarcoma (DDLPS) is an adipogenic sarcoma composed of a high-grade non-lipogenic (dedifferentiated, DD) component and a juxtaposed well-differentiated (WD) component. Amplification of the 12q13-15 region, including the MDM2 and CDK4 genes, is a common feature of both components, and it is generally accepted that the DD component has transitioned from the preexisting WD component, while a clear trigger for dedifferentiation has not been elucidated.
We performed multi-region genome (whole exome sequencing, WES), epigenome (DNA methylation microarray), and transcriptome (RNA sequencing) analyses on 3 cases of DDLPS (∼10 regions/case).
WES analysis identified an average of 66 genomic alterations (44 somatic mutations and 22 somatic copy number alterations) in the samples. The 12q13-15 amplification was present in all the samples. In 2 of the 3 cases, there were a few (4 and 2) genomic alterations common to all samples, while samples from the same component (WD or DD) shared much more genomic alterations. This result indicated clonal evolution with very early separation into WD and DD components. A phylogenetic tree generated from DNA methylation pattern was consistent with that from the mutation pattern. The DNA methylation pattern of the WD samples was similar to that of normal fat, whereas the DD samples showed case-specific demethylation. RNA sequencing analysis showed case-specific expression patterns of adipogenesis-related genes, some of which correlated with the methylation status of CpG islands.
We report the first multi-region analysis of DDLPS. Our analyses demonstrated very early branching of the WD and DD tumor clones at least in some DDLPS cases. In addition, case-to-case differences in expression and DNA methylation patterns of adipogenesis-related genes suggested that case-specific DNA methylation alterations contributed to dedifferentiation.
The authors.
AMED (Japan Agency for Medical Research and Development) JSPS (Japan Society for the Promotion of Science).
H. Ichikawa: Financial Interests, Personal, Research Grant: Ono Pharmaceutical Company, Healios Company, Eisai Company, Chugai Pharmaceutical Company. All other authors have declared no conflicts of interest.