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Page 2 of 9 Keung et al. J Transl Genet Genom 2019;3:8. I https://doi.org/10.20517/jtgg.2019.03

WELL-DIFFERENTIATED AND DEDIFFERENTIATED LPS
Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common
histologic subtypes of LPS [Table 1]. Together they represent 60% of all LPS and often coexist, occurring
in the retroperitoneum and extremities. WDLPS is a typically indolent histologic subtype that presents as
slowly growing masses but can be locally aggressive with minimal to no distant metastatic potential while
[1,2]
DDLPS is a higher grade histology with a potential for faster growth and distant metastatic potential .
Chromosomal translocations and copy number alterations
Although genetic alterations are more complex in DDLPS than WDLPS, both commonly exhibit ring
chromosomes and giant markers with chromosomal amplification of 12q13-15. This segment of chromosome
12q13-15 contains a number of cancer-related genes implicated in tumorigenesis. Included in these are
the genes CDK4, MDM2, and HMGA2 which are consistently amplified and in the recent TCGA genomic
[3]
characterization of adult STS they were reported in 100%, 92%, and 76% of LPS cases, respectively , as well
[4,5]
as CPM and YEATS2 . MDM2 is an E3 ubiquitin protein ligase which promotes degradation of p53 to
prevent apoptosis and/or cell-cycle arrest and may also have effects independent of p53 (such as through
other tumor suppressors such as p21) [6-10] . CDK4 encodes a key regulator of the G1/S cell cycle checkpoint
[4]
and is coamplified with MDM2 in over 90% of patients . YEATS4 and CPM are genes implicated in
dedifferentiation [11,12] ; the former encodes a putative transcription factor required for physiologic suppression
of p53 function while the later encodes a proteolytic enzymes that activates growth factors such as epidermal
growth factor.

[4]
Development of DDLPS is associated with accumulation of additional chromosomal abnormalities .
Copy number alterations are common in DDLPS with deletions reported in chromosome 1p, 11q, 13q, 15q
and 17p and focal amplifications at chromosomes 1q, 5p, 6q, 8q, 11p, 12q, 14q, and 15q [3,11,13] . Recurrent
amplifications of 1p32 and 6q23 with resulting overexpression of JUN and ASK1, respectively, have been
implicated in adipocyte dedifferentiation, have been reported only in DDLPS, and are associated with
worse prognosis [3,14-16] . Chromosomal deletions of tumor suppressor genes including RUNX3 and ARID1A
(1p36), ATM and CHEK1 (11q22-24), and RB1 (13q14.2) have been associated with reduced adipocytic
differentiation, genomic instability, and worse patient outcomes [11,12] .

Mutations
Mutation rates are modest in WDLPS and DDLPS, with few consistently and recurrently mutated genes
across case series [3,11,13,17-19] . No significant differences have been reported in the mutations between WDLPS
and DDLPS to explain the differences in behavior.

Epigenetics
DNA methylation and histone modifications
Studies have reported alterations in LPS methylomes leading to changes in expression of differentiation
pathway genes. Epigenetic silencing via methylation of CEBP - gene was identified in 10 or 42 DDLPS
samples (24%) and treatment with demethylating agents induced cellular apoptosis and increased CEBP -
[18]
expression . More recently, The Cancer Genome Atlas (TCGA) reported that among DDLPS cases included
in the sarcoma analysis, patients whose tumors were hypermethylated compared to hypomethylated had
[3]
shorter disease-specific survival .
Additionally, a small number of other studies describe other epigenetic mechanisms of gene silencing,
including altered histone modifications, that are associated with dedifferentiation and/or tumor growth [20,21] .

MicroRNAs
MicroRNAs (miRNAs) are small non-protein coding RNA molecules that exert regulatory functions on gene
expression. In the context of the RNA-induced silencing complex (RISC), these 21-25 nucleotide long RNA