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Malentacchi et al. J Cancer Metastasis Treat 2020;6:34 I http://dx.doi.org/10.20517/2394-4722.2020.34 Page 13 of 18

lncRNA AND circRNA AND OTHER small nuclear/nucleolar RNA IN LB
There are currently no studies available relating other circulating RNAs, namely lncRNA, piRNA, small
nuclear (snRNA), and small nucleolar (snoRNA), to EC. The last three classes are also known as snc/
snRNAs due to the fact that they are located in the cell nucleus and are fundamental in RNA-RNA
remodeling, spliceosome assembly, and translation processes (i.e., post-transcriptional modification of
rRNA). The class of snoRNAs named “U(n)” (i.e., U1 and U2-U12), due to their high Uridyl content,
is involved in the spliceosome complex. These particular RNAs are 60-300 nt long and are transcribed
from intronic sequences of coding and noncoding genes. Some of them are used to normalize the relative
quantification of miRNA in tissues and fluids. Although they do not properly represent “housekeeping”
due to their change and different pre-analytical phase, no specific studies have been conducted on these
[88]
biomolecules to evaluate their possible function as biomarkers .

Concerning lncRNAs, they are involved in chromatin remodeling, gene expression and transcription,
and protein-protein interaction, and their role in cancer is known with respect to snRNAs. Since this is a
new field, for EC, pilot studies concerning circulating lncRNA are only relative to colon cancer and their
prospective use [100] .

Noteworthy, a peculiar class of lncRNA is represented by circRNAs characterized by a covalent linkage,
which gives them a specific circular form and makes them biologically stable and resistant to RNases. They
were recently investigated in several cancer tissues including EC. A recent paper highlights their differential
display in a pilot study aiming to analyze three samples of EC in comparison to corresponding adjacent
non-cancerous tissue and focused on has-circ_0039569, which has been significantly correlated with tumor
[88]
differentiation .
Recently, circRNAs - hsa_circ_0109046 and hsa_circ_0002577 - were suggested as potentially investigable
biomarkers in LB of EC [101] .

ROLE OF LB IN THE MONITORING AND TREATMENT OF ENDOMETRIAL CANCER
Patients with EC progression after first-line chemotherapy have a poor prognosis. Until now, no targeted
therapies are in use for ECC treatment, although several phosphoinositide 3-kinase inhibitors are under
investigation and in clinical trials. As for lung cancer, the evaluation of specific circulating mutations may
give information concerning the success of the therapy and related to the development of specific molecular
resistance or new clones [102] . Several studies have found that the genotyping results derived from tissue
biopsy analysis differ from those derived from LB. The concordance rates for metastatic cancer patients and
for patients with primary tumors were 83.3% and 78.3%, respectively. These discrepancies may be related
to intra-tumor heterogeneity, indicating that the assessment on tissue can cause misinterpretations, while
LB may reflect mutations and changes occurring in tumor that cannot be revealed in the primary biopsy.
Thereby, LB may offer new prospective for monitoring tumor development, the efficacy of therapy, and the
[36]
arise of treatment resistance .

CONCLUSION
In 2013, the Cancer Genome Atlas Research Network (TCGA) suggested implementing a classification
[10]
with molecular characterization , which can be useful to define targeted therapy and monitor cancer
development and treatment; nevertheless, today, there are no targeted therapies: in fact, there is no
[11]
molecular target for treatment, detection, or monitoring . LB represents a novel tool, due to the minimally
invasive- or non-invasive procedure for biomarker collection, overcoming the limit of classical tissue
biopsy and allowing the monitoring of tumor burden, the efficacy of therapy, the arise of resistance, and the
development of cancer change, relapse, and metastasis.