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Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05 Page 5 of 16

Figure 3. Soft tissue sarcomas (STS) are thought to be derived from lineage committed mesenchymal stem cells. Aberrant EZH2
expression and/or activity is believed to prevent normal terminal differentiation, leading to continued proliferation and poorly
differentiated phenotypes in STS.

constitutes only one out of many other causes of EZH2 dysregulation and subsequent pathogenesis .
[25]

CORRELATIONS OF EZH2 WITH CLINICAL FEATURES
EZH2 upregulation
Higher levels of EZH2 have been noted in MPNST tumours and MPNST cell lines, compared to normal
human Schwann cells . The same phenomena were detected in RMS tumour samples and cell lines, with
[5]
[26]
little or no EZH2 expression observed in normal skeletal muscle tissue , benign rhabdomyoma or tumour-
adjacent skeletal muscle . This is also true for leiomyosarcoma, where EZH2 exhibited elevated levels with
[20]
high sensitivity and specificity in malignant tissues in contrast to benign leiomyoma or normal
myometrium . Another study investigating the expression of EZH2 in embryonal (ERMS) and alveolar
[20]
(ARMS) RMS cell lines and patient samples showed similar findings demonstrating high upregulation of the
RNA in comparison to myoblasts as a control .
[27]

Prognosis
In STS prognosis is usually poor, dependent on other factors such as stage of malignancy and tumour size at
time of detection, the patient’s age, localisation of the tumour and presence/ absence of metastatic lesions.
In the prognosis of SS, high levels of EZH2 protein are associated with worse clinical outcome, especially in
[28]
the poorly differentiated subtype . In a study including 104 patient-derived tumour samples (with 27
having prior chemotherapy, 25 radiotherapy and 13 both) of mixed STS: SS, leiomyosarcomas, RMS,
epithelioid sarcomas, malignant fibrous histiocytomas, myxofibrosarcomas and liposarcomas, higher levels
of EZH2 protein were independently correlated with unfavourable prognosis for each STS type .
[29]

Metastasis
[28]
In studies comprising 55 SS primary tumour samples without preoperative chemo- or radiotherapy , and
29 SS tumour samples (22/29 treated with chemotherapy and radiation following surgery) , higher levels of
[30]
EZH2 and H3K27me3 as examined by immunohistochemistry (IHC) were observed in patients where
distant metastasis has occurred [28,30] . EZH2 was also significantly associated with distant metastasis in other