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

Figure 4: An illustration of the heterogeneity within an individual WDLPS or DDLPS due to the presence of neochromsomes. These nuclear neochromosomes are made up of different fragments from various chromosomes, chr12 being the most common and selected for (orange). The lack of true centromeres in these neochromosomes leads to the high probability of unequal segregation during mitosis, much like the random inheritance of mitochondrial DNA in daughter cells Various genes within the region of chr12q amplification ( MDM2 , HMGA2 , YEATS4 , FRS2 , CPM , DDIT3 , PTPRQ ) are implicated in the adipocytic differentiation pathways and in cancer progression. The degree to which each of these genes contribute to liposarcoma formation and progression is yet unclear. Evidence supporting roles for these genes is summarized below and in Tyler et al. 70 . MDM2: The N-terminal region promotes adipocyte differentiation through activation of CREB transcription at the expense of myogenesis in P53 −/− ; mdm2 −/− mouse embryonic fibroblasts 71 . Mdm2 adipocyte- specific knock-in ( Mdm2 -AKI) mice have increased white adipose tissue dysfunction, weight gain and insulin resistance when fed a high-fat diet 72 . CPM: CPM was significantly increased genes in early stages of differentiation when inducing adipogenesis in bone marrow derived human mesenchymal stem cells 73 , adipose tissue-derived human mesenchymal stem cells 73 , and adipose-derived stromal cells 74 . Amplification that included CPM was observed in a large majority of WDLPS and DDLPS patient samples (78%, 39/50) 13 . CPM distinguishes WDLPS and DDLPS from lipoma through having higher protein levels than benign lipoma and normal fat tissue 13 . Knockdown using small interference RNA (siRNA) reduced cell proliferation, cell growth, colony formation, migration and invasion while increasing apoptosis in two of the DDLPS cell lines tested 13 . This finding was recapitulated in eight liposarcoma cell lines that had undergone a genome- wide CRISPER knockout screen (DepMap 22Q2 release) 75,76 . There, CPM was second most enriched dependency for viability among all the liposarcoma lines. DDIT3: DDIT3 (CHOP/GADD153) is a chromatin remodeler that is expressed highly during the last stages of adipocytic differentiation from lipoblasts to adipocytes 77 . When over expressed in primitive sarcoma cells (fibrosarcoma) cells, DDIT3 can induce liposarcoma phenotypes 78 . It is expressed at the protein level in WDLPS, DDLPS, MLPS, PLS, and lipoma 79 . It blocks adipocytic differentiation by direct dominant negative inhibition of CEBP proteins from their target sites as well as preventing the accumulation of CEBPA in cells 80 . FRS2: FRS2 serves to recruit FGF, thereby facilitating FGFR signaling 81 . FGFR signaling is also active during differentiation of mesenchymal stromal cells 82 and human pre-adipocytes 83,84 . However, FRS2 inhibits adipocytic signaling in bone marrow stromal cells in 3D culture 85 .These differing responses to FGFR signaling in cells according to environment and cell type that is receiving the signal may explain why not all liposarcoma have amplification of this gene. HMGA2: FGF signaling also plays a role in HMGA2 expression. HMGA2 is a transcription factor that has relatively low expression in adult tissues as compared to embryonic and mesenchymal stem cells 86,87 . Thus, it is © 2022 Global Journals 1 Year 2022 20 Global Journal of Science Frontier Research Volume XXII Issue ersion I VII ( G ) The Genomics of Liposarcoma: A Review and Commentary