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

II. L iposarcoma G enomic C lassifications STS have lower average somatic point mutation burdens than epithelial cancers 8 . When examining their karyotypic characteristics, they are classically divided into two major groups: complex and simple 9,10 . The liposarcoma subtypes WDLPS, DDLPS, and PLPS belong to the group of complex karyotypes, which are cells that have undergone steady and constant accumulation of multiple genomic copy number alterations, chromosomal anomalies and various types of rearrangements over time. This genomic instability is ongoing and occurs as a result of aberrations in genes involved in DNA repair, DNA replication and cell cycle regulation such as TP53 11 . The complex karyotypes in these liposarcomas are likely to have arisen from mutations in the TP53 pathway. Both WDLPS and DDLPS have near universal amplification of chr12q, a region that includes MDM2 , which is a gene that directs the protein degradation of TP53 . For PLPS, recurrent mutations in TP53 (7%) and losses of RB1 occur 12,13 . Behavior and changes in the microenvironment can create a permissive context under which liposarcoma form. For instance, over expression of the immune-related cytokine IL-22 in a mouse on a high fat diet led to the only reported spontaneous formation of WDLPS in a mouse model 14 . This implies that the relationship between the microenvironment and tumor may already be established when liposarcoma first form. This would explain why patient-derived WDLPS models have been difficult to establish as this dependence is still not well understood. Since chromosomal imbalances restrict the environment in which cancers can grow 15 , the genomic instability that follows could then solidify this dependence. Those sarcomas with simple karyotypes are nearly diploid; their driver events are typically fusion transcripts expressed via reciprocal chromosomal translocations. In the clinic, these diagnostic fusions are detected by fluorescent in situ hybridization (FISH), fusion panels, and reverse transcription polymerase chain reaction (RT-PCR). MLPS is an example of a liposarcoma with a simple karyotype and that is fusion- driven. It is mostly diploid and defined by a recurrent translocation between chromosomes 12 and 16: t(12;16) (q13;p11) that results in a fusion protein FUS-DDIT3 . III. D egree of A dipocytic D ifferentiation are P athologic M arkers of L iposarcoma Each liposarcoma subtype resembles different stages of adipocytic differentiation (Figure 2). This was first illustrated in an unsupervised analysis of gene expression patterns found in WDLPS, DDLPS, MLPS, PLPS, benign lipoma and normal fat 16 . Three clusters formed: the first included normal fat, lipoma, and WDLPS; the second contained DDLPS and PLPS; and the third included only MLPS. In a complementary study, gene expression profiles of these four major liposarcoma subtypes were compared with those of human mesenchymal stem cells that were undergoing differentiation into mature fat. Each liposarcoma subtype resembled different stages in this process that were akin to their degree of differentiation 17 . For instance, DDLPS expressed genes that were comparable to those that at day 7, which reflects stem cells in their early stages of differentiation, only starting their commitment to becoming fat as compared to cells at day 21, when maturation is almost complete. In support of this, 16 genes from the PPAR γ signaling pathway that leads to adipocytic terminal differentiation were significantly lower in DDLPS than in normal fat 18 . On the contrary, WDLPS was more similar to cells at day 21, when differentiation is almost complete. PLPS closely resemble cells at day 10 while MLPS or round liposarcoma resembled those at day 14. These expression patterns imply that the degree of dedifferentiation of liposarcoma can be related to survival, with higher degree of differentiation leading to improved survival. DNA methylation patterns also reflect these differences in differentiation states. When examining DNA methylation states in 80 various sarcomas in an unsupervised manner, each liposarcoma subtype formed a distinct group 19 . Several distinguishing genes are related to adipocytic differentiation. One example is NNAT , which induces the activation of adipocytic transcription factors CREB and CEBP family 20 and was significantly methylated (hypermethylation) and upregulated in MLPS than in normal fat and other sarcomas 19,21 . Decreased methylation (hypomethylation) and downregulation of NNAT was observed in DDLPS and PLPS, which likely results in a more dedifferentiated state. Another example is the CDKN2A gene, whose CpG island methylation levels are shared by PLPS, DDLPS, and non-neoplastic fat, but not MLPS 19 . In addition, is involved in the oxidative degradation of lipids and may contribute to cancer stem potential. A strong negative correlation between the methylation of and its expression levels was found across several sarcoma subtypes, with the strongest hypermethylation and down regulation for MLPS 19 . © 2022 Global Journals 1 Year 2022 16 Global Journal of Science Frontier Research Volume XXII Issue ersion I VII ( G ) The Genomics of Liposarcoma: A Review and Commentary ALDH1A3 ALDH1A3