Global Journal of Science Frontier Research, G: Bio-Tech & Genetics, Volume 22 Issue 2

peripheral nerve sheath tumor (MPNST) 8 . DDLPS has overall poorer survival, likely due to these increased burdens of mutations and copy number alterations 2-4 . Further reduced local relapse-free survival was observed in DDLPS patients with loss of chr19q13 or chr9p22-24 or chr17q21 96 . When integrating both copy number and methylation alterations in a set of DDLPS (TCGA-SARC), disease-specific survival rate was significantly longer in one subgroup, cluster K3 (chr6q25.1 amplified and fewer unbalanced chromosome segments than K2) that shared a particular pattern of copy number alterations. Clusters K1 (JUN amplified) and K2 (TERT amplified and chromosomally unstable) had worse survival than K3 8 . This group had the lowest levels of immature dendritic cell infiltration. Overall, the study suggested that copy number alterations and methylation impacted survival and may be used as predictive biomarkers for DDLPS. VII. M yxoid L iposarcoma (MLPS) Myxoid liposarcoma are the most common liposarcoma in young patients under age 22 6 . The characteristic pathological features of myxoid liposarcoma are stellate spindle cells, signet-ring lipoblasts, “crow’s feet” vascular network 102 , and markers of immature adipogenicity 103 . Transitional areas of increased cellularity can occur 104 with other patterns: round cell, pseudoacinar, lipoblast-rich, island, lipomatous, stromal hemangiopericytoma-like characteristics 105 . The presence of small blue round cells in more than 5% of the tumor is considered the “round-cell” subtype 104 , which is more aggressive with poorer prognosis that metastasizes more frequently to the bone rather than to other tissue sites 104 . Within a background of a mostly quiet karyotype, the diagnostic molecular feature found in more than 95% of tumors is the reciprocal translocation t(12;16) (q13;p11): FUS-DDIT3 (TLS-CHOP) 106 . There are at least 10 known variants, of which the major categories involve breakpoints nearexon 5 or exon 7/8 of FUS , while other breakpoints occur after exon 4, 8, 13 in DDIT3 107 . These breakpoints eliminate the RNA-binding domain of FUS, which is then replaced by the DNA- binding domain of DDIT3 along with the rest of DDIT3 that includes a leucine zipper dimerization domain 108 . Only variants with breakpoints near or after exon 13 have an intact RNA-binding domain from FUS in the fusion protein. Figure 6: FUS-DDIT3 fusion transcript isoforms. FUS exons are shown in green, while DDIT3 exons are in blue The FUS-DDIT3 fusion can transform mesenchymal cells in mice 109 , partly by stimulating eIF4E expression, which results in down regulation of the PPAR γ and C/EBP α pathways, thereby inhibiting adipocytic differentiation 110 . It can also activate the IGFR1/PI3K/AKT pathway 110 and repress miR-486, which may result in upregulation of PAI-1, a molecular that is involved in tumor invasion and metastasis 111 . An alternative mouse model demonstrated that expressing FUS-DDIT3 under a mesoderm promoter Prx1 within a p53 null background results in synergy in tumor formation 112 . This may explain the poorer likelihood of survival in myxoid liposarcoma patients with TP53 mutations 113 . Therefore, mutation in TP53 may contribute to a more aggressive tumor in the context of this translocation. An alternative translocation event, EWSR1- DDIT3 (t(12;22)(q13;q12)), occurs in a minority of patients (4-5% in both pediatric and adult) (4-5%) with at least 4 known transcript isoforms 114 . FUS and EWSR1 are functionally interchangeable since either gene fused to DDIT3 induced tumors in a xenograft model 115 . In fact, FUS and EWSR1 are paralogs, belonging to the FET family of general RNA-binding proteins that also includes TAF15 116 . Together, these proteins appear to interact in a single complex 117,118 with a myriad of roles in RNA splicing, association with RNA helicases, DNA damage response, miRNA processing, RNA transport, © 2022 Global Journals 1 Year 2022 22 Global Journal of Science Frontier Research Volume XXII Issue ersion I VII ( G ) The Genomics of Liposarcoma: A Review and Commentary