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Page 4 of 9 Keung et al. J Transl Genet Genom 2019;3:8. I https://doi.org/10.20517/jtgg.2019.03

Mutations
In addition to the nearly ubiquitous presence of a chromosomal translocation, a subset of myxoid LPS (15%)
are also characterized by mutations or amplifications of PIK3CA, which encodes the catalytic subunit of
[12]
phosphatidylinositol 3-kinase (PI3K) . Patients with tumors harboring PIK3CA mutations have shorter
disease-specific survival compared to those with wild-type PIK3CA. Thus, the PI3K pathway in patients
with myxoid LPS with PIK3CA mutations is an attractive therapeutic target. PTEN deletion has also been
described [12,39] . Additionally, myxoid LPS are also characterized by expression of the cancer-testis antigen,
[35]
NY-ESO-1 , and patients with myxoid LPS are candidates for various immunotherapy trials targeting NY-
ESO-1 [40,41] .

Epigenetic alterations
There have been limited studies investigating the epigenetics of myxoid LPS [11,42-44] . Epigenetic silencing of
p14ARF, a p53 target, by promoter methylation has been reported as a common event in both myxoid and
pleomorphic LPS.

MicroRNAs
As in the case for well-differentiated and dedifferentiated LPS, miRs dysregulation has also been
demonstrated in myxoid/round cell LPS. miR-155 is a strong oncogene that has been shown to be
[26]
overexpressed in myxoid/round cell LPS . miR-486, which interacts with plasminogen activator inhibitor 1
(PAI-1), a promoter of cellular proliferation and invasion, is downregulated in myxoid LPS [45,46] .

PLEOMORPHIC LPS
Pleomorphic LPS are the rarest histologic subtype of LPS, representing ~5% of cases, and associated with the
worst prognosis [Table 1] [1,47-50] . Pleomorphic LPs typically arise in the extremities, although less commonly
[4]
can occur in the trunk or retroperitoneum . Up to 50% of patients develop metastatic disease and disease-
[51]
specific survival is poor .
Chromosomal translocations and copy number alterations
Our current understanding of the molecular pathology of pleomorphic LPS is poor. They characteristically
harbor diverse complex genomic changes and chromosomal rearrangements without unifying molecular
alterations nor targetable aberrations. Deletion of 13q14.2-5, which contains RB1, has been described in up to
half of pleomorphic LPS [12,52] .

Mutations
Mutations or loss of TP53 is frequently seen in pleomorphic LPS, unlike in LPS subtypes where TP53 loss is
uncommon. Loss of NF1 is also seen in some patients [12,47] .

Epigenetic alterations
There is not much known about the epigenetics of pleomorphic LPS [11,42] . As noted before, promoter
methylation resulting in epigenetic silencing of p14ARF has been reported as a common event in both
myxoid and pleomorphic LPS.

MicroRNAs
As in the case for well-differentiated and dedifferentiated LPS, miRs dysregulation has also been
demonstrated in pleomorphic LPS. miR-155 is a strong oncogene that has been shown to be overexpressed in
[26]
pleomorphic LPS .

THERAPEUTIC OPPORTUNITIES AND CONSIDERATIONS
Despite our increasing understanding of the genomic alterations across LPS subtypes, their implications
for LPS management and translation into novel therapeutics in the clinic has, to date, remained limited.