Comprehensive genetic analysis of a paediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of the RB1 gene.

AIMS: Pleomorphic myxoid liposarcoma (PML) is an exceptionally rare and poorly studied subtype of liposarcoma, occurring typically in children and adolescents. The few previous genetic studies have shown that PML lacks the gene fusions and amplifications that characterize myxoid liposarcoma, atypical lipomatous tumour and de-differentiated liposarcoma. To learn more about its pathogenesis, we performed a comprehensive genetic analysis, including chromosome banding, fluorescence in-situ hybridization, single nucleotide polymorphism (SNP) array analysis, deep sequencing of the exome (WES) complemented by targeted sequencing of hot-spot regions of selected cancer-associated genes and transcriptome sequencing (RNA-seq) of a PML in a 10-year-old boy. METHODS AND RESULTS: Banding analysis revealed a hyperdiploid/hypotriploid karyotype that at SNP array analysis could be shown to derive from a near-haploid ancestral clone. Structural imbalances were few, but included homozygous loss of the RB1 locus; no fusion transcripts were identified at RNA-seq, no somatic mutations were seen at gene panel analysis and the most interesting mutation detected at WES involved KMT2D. CONCLUSION: The results support the notion that PML is a distinct type of liposarcoma, associated with a spectrum of somatic mutations that is different from that in other liposarcoma subtypes. The findings in the present case, combined with previous data, suggest that PML develops through combinations of numerical chromosome aberrations, possibly initialized by haploidization. The results also suggest that inactivation of RB1 is pathogenetically important.