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

PI3K/AKT pathway on tumor initiation would also explain why PIK3CA amplification by fluorescent in situ hybridization (FISH) is associated with older age, larger tumor size, and shorter disease-free survival duration in liposarcoma, without distinction for a particular subtype 34 . These models also illustrate how compounding gene losses can affect the nature and aggressiveness of the liposarcoma that is formed. This is further supported by the higher number of gene losses in DDLPS as compared to WDLPS 35 . TP53 and RB1 also alter the ability of mesenchymal cells to differentiate. Knocking out TP53 in mesenchymal stem cells (MSC) prevents the expression of PPAR γ , a key gene in directing adipocytic differentiation 36 . Instead, these MSC cells become more prone to osteogenic differentiation 36 . Without RB1 , stem cells can no longer differentiate efficiently 37 . RB1 either pushes osteogenic differentiation in MSCs through RUNX2 or prevents adipocytic differentiation by inhibiting PPAR γ 36,38 . Since Li-Fraumeni is an example of a syndrome with germline predisposition to developing multiple types of cancer including liposarcoma, there may be other germline risk factors to be identified. Out of 4,432 unique liposarcoma records in SEER (1973-2015 cohort), 2968 (0.00063%) had a recording of other concurrent cancers. Liposarcoma have concurrent diagnoses in ovarian cancer 39 , hereditary nonpolyposis colorectal cancer 40 , Muire-Torre syndrome 41 , multiple myeloma 42 and CLL (also our recent unpublished data and infiltration in TCGA-SARC sample) 8 . Identifying these predisposition genes will enable us to interpret mutations in sporadic cases, as illustrated by the discovery of the telomere protection gene, POT1 , as predisposing to angiosarcoma and cardiac sarcomas 39 . V. T elomeres in L iposarcoma S urvival and P ersistence Strategies to sustain cell survival include the elongation of chromosome ends: the telomeres. There are various Telomere Maintenance Mechanisms (TMM) including reactivation of the telomerase enzyme that serves to lengthen telomeres or the process of Alternative Lengthening of Telomeres (ALT) that employs homologous recombination methods to lengthen short telomeres. Activating mutations within the TERT promoter that encodes telomerase occur in a subset of MLPS 43 . On the other hand, inactivating mutations and copy number losses in genes involved in ALT ( ATRX ) are detected in a subset of all liposarcomas, most frequently in DDLPS 44 . Several assays are used to assess the activity of ALT within cells, which include: pulse field gel electrophoresis, terminal restriction fragment (TRF) Southern-blot analysis to measure telomere lengths, quantification of single-stranded circular DNA structures (C-circles) consisting of telomeric CCCTAA repeats, and immnofluorescence to identify the presence of ALT- associated promyelocytic leukemia bodies (APB). In all subtypes of liposarcoma, patients with ALT positivity as measured by these assays have worse progression-free and disease-specific survival rates 44-47 . DDLPS is often the subtype cited with more ALT+ than WDLPS 48 . VI. W ell- D ifferentiated (WDLPS) and D edifferentiated L iposarcoma (DDLPS) Precursor or immature adipocytes are termed, “lipoblasts” 49 . Their gene expression patterns are most similar to those of nonmalignant adipocytes 50 . Well- differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas are distinguishable from benign lipoblastoma and lipoma through karyotyping and breakpoint mapping. Lipoblastoma can have histological similarities with liposarcoma but is discriminated by an inversion involving the PLAG1 gene on chr8 51,52 . Both lipoma and liposarcoma can have rearrangements or alterations on chr12. However, the breakpoints in lipoma appear to be more distal than in MLPS, WDLPS, and DDLPS 53 with rearrangements involving HMGA2 , rather than amplification of the entire gene. Therefore, the breakpoint location serves to identify disease type and severity within the adipose tissue. More recently, lipomas were shown to have low mutation burden, low copy number alterations (CNA) and share mutations with liposarcoma in APC , RYR2 , and MAPK7 54 . There is evidence that WDLPS and DDLPS share a common origin based on shared point mutations from which each subtype develops in an evolutionary divergence 35,55 . There are patients who transition from WDLPS to DDLPS and very rarely, others who go from a diagnosis of DDLPS to WDLPS. In fact, each liposarcoma tumor is a mixture of both subtypes with one dominating over the other at different times. This common origin and plasticity are attributed to the presence of extraneous supernumerary ring or rod chromosomes within the nucleus, called “neochromosomes”, amidst otherwise diploid-looking genomes. The neochromosomes are also common in atypical lipomatous tumors and have occasionally been reported in lipoblastoma 56-58 . Whole genome sequencing of two isolated neochromosomes from a liposarcoma cell line revealed that they have no true centromeres and are therefore unstable 59 . Upon closer molecular assessment using copy number microarrays and spectral karyotyping, these neochromosomes are derivations of chr12q13-15 along with other chr6q23 60-62 . The observation of chr12 amplifications in both WDLPS and DDLPS is nearly universal 63 . A minimum number of 20 copies per cell was observed © 2022 Global Journals 1 Year 2022 18 Global Journal of Science Frontier Research Volume XXII Issue ersion I VII ( G ) The Genomics of Liposarcoma: A Review and Commentary DAXX chromosomes, most commonly chr1q21-22 and