Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin

Abstract

Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM) However, genomic changes associated with progression from WD to DD have not been well-defined. Therefore, we selected patients with matched WD and DD tumors for extensive genomic profiling in order to understand their clonal relationships and to delineate any defining alterations for each entity. Exome and transcriptomic sequencing was performed for 17 patients with both WD and DD diagnoses. Somatic point and copy-number alterations were integrated with transcriptional analyses to determine subtype-associated genomic features and pathways. The results were, on average, that only 8.3% of somatic mutations in WD liposarcoma were shared with their cognate DD component. DD tumors had higher numbers of somatic copy-number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors. HMGA2 and CPM rearrangements occur more frequently in DD components. The shared somatic mutations indicate a clonal origin for matched WD and DD tumors and show early divergence with ongoing genomic instability due to continual generation and selection of neochromosomes. Stochastic generation and subsequent expression of fusion transcripts from the neochromosome that involve adipogenesis genes such as HMGA2 and CPM may influence the differentiation state of the subsequent tumor.

Keywords: overgrowth.

Figure 1.

Whole-exome profiling of concurrent well-differentiated (WD) and dedifferentiated (DD) liposarcomas. (A,B) Representative hematoxylin and eosin stains of liposarcomas used in this study: WD and DD. (C) Boxplots of the total numbers of somatic mutations called by MuTect when comparing tumors with their matched normal samples. Only fresh frozen cases of WD (left) and DD (right) liposarcomas were included here. A paired t-test comparing the somatic mutation burdens between WD and DD liposarcomas was not significant (P = 0.36). (D) Venn diagram example showing the number of somatic mutations in patient 3 (DWN3) as called by MuTect.

Figure 2.

Somatic copy-number alterations in concurrent WD and DD liposarcomas. (A) Focal amplifications and (B) deletions in WD samples as determined by GISTIC 2.0. (C) Focal amplifications and (D) deletions in DD samples as determined by GISTIC 2.0. (E) Gene-level burdens of gains and (F) losses in WD (left) and DD (right) samples, both fresh frozen and FFPE.

Figure 3.

Differentially expressed genes between WD and DD liposarcomas. (A) Volcano plot denoting the genes that are significantly higher in expression in WD liposarcomas (red; 357 genes) and in DD liposarcomas (blue; 395 genes). Gene Set Enrichment Analysis (GSEA) plots of pathways that are significantly more highly expressed in (B) DD and (C) WD tumors based on GSEA analysis.

Figure 4.

Number of fusion transcripts in concurrent WD and DD liposarcomas. (A) Boxplots of the total number of fusion transcripts called by at least two callers. (B) Circos plots of these consensus fusion calls in the WD and DD tumors from patient DWN-6. (C) The proportion of fusion transcripts that occur on Chromosome 12.