Whole Genome Analyses of a Well-Differentiated Liposarcoma Reveals Novel SYT1 and DDR2 Rearrangements

Abstract

Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.

Integrated exome and RNA sequencing of dedifferentiated liposarcoma

“…Surgical excision is the primary treatment modality used for DDLPS, as DDLPS exhibits a low response rate to conventional chemotherapeutic reagents 4 . To date, several analyses have unveiled genomic characteristics common to DDLPS, including the amplification of 12q13-15, that are also frequently found in WDLPS 5–10 . These studies have also identified a number of genes within 12q13-15, including HOXC13, MDM2 , HMGA2 , CDK4 , and CPM , as being key to the development of DDLPS and WDLPS; a number of additional genomic occurrences, such as the loss of 11q23 and the gain of 6q23 and 1p32, have been defined as genomic abnormalities that are specific to DDLPS 6,8,11–17 .…”

Human transposons are an abundant supply of transcription factor binding sites and promoter activities in breast cancer cell lines

“…Similar oncogene activation by L1-ASP has been reported in other cancer types, such as MET activation in bladder cancer [35, 78, 79]. SYT1 is a protein-coding gene found to facilitate the export of the oncogenic growth factor FGF-1 [71]. The promoter activity of L1PA2- SYT1 in breast cancer cell lines coincided with its increased DNAse sensitivity and decreased DNA methylation, suggesting the L1PA2- SYT1 element can promote expression of the proto-oncogene SYT1 .…”

Defining a role for lung function associated gene GSTCD in cell homeostasis

“…It is also thought to function in the adult nervous system and the gene has been associated with schizophrenia. Whole genome analysis revealed a gene fusion between UHMK1 and DDR2 In well-differentiated liposarcoma [32]. IL6RInterleukin 6 receptormRNA: Yes 30 TPMProtein: N/AThe receptor of IL6 which is involved in the regulation of the immune response.…”