*5.2. Prognostic Biomarkers for Endometrial Cancer*

There is no screening method for EC for the general population. Women with LS and their first-degree relatives are offered annual screening with TVUS and endometrial biopsy from the age of 35 years [90,105].

There are several types of biomarkers: gene-based biomarkers, proteins biomarkers, and hormonal biomarkers [105]. Gene-based biomarkers include the following: *PTEN*, *TP53*, microribonucleic acids (microRNAs), circulating tumor DNA, and DNA methylation. Protein biomarkers include *pRb2/p130*, *Ki 67*, *ARID1A*, cell adhesion molecules (CAMs), phosphohistone-H3 (*pHH3*), angiotensin factors, etc. The most commonly mutated genes detected in EC patients using Tao brush samples were *PTEN* and *TP53* [83].

One of the gene-based biomarkers, *PTEN* tumor suppressor, antagonizes the phosphoinositol-3-kinase/AKT signaling pathway, suppressing cell survival as well as cell proliferation [105]. A recent study suggests that *PTEN* expression in endometrial hyperplasia can be used as an early warning of heightened cancer risk [105,195]. Complete loss of *PTEN* protein expression is most commonly found in EC and endometrial hyperplasia with cytological atypia.

Another potentially useful molecular biomarker is *TP53*, which belongs to cell cycle proteins [105], and triggers cellular responses that can lead to cell-cycle arrest, senescence, differentiation, DNA repair, apoptosis, and inhibition of angiogenesis [196]. The role of *TP53* in EC and hyperplasia has been studied, showing that TP53 gene mutation is present in EC, but it is absent in endometrial hyperplasia [105,197].

The expression of the cell cycle regulator *pRb2/p130* was evaluated in EC and endometrial hyperplasia and was found to be highly expressed in the proliferative endometrium and in hyperplasia without atypia, but it was downregulated in secretory endometrium, atypical hyperplasia, and EC [105,197].

The most promising serum biomarker for EC is human epididymis protein 4 (HE4) [105]. A number of studies have looked at HE4 as a prognostic marker for EC [86,105,198,199]. Diagnostic levels range between 50 and 70 pmol/L, with a minimum 78% sensitivity and 100% specificity, even in early-stage disease [105,198]. Serum HE4 levels are found to

be significantly higher in advanced stages of EC [105,199] and are predictive for disease recurrence [105].

There are many novel biomarkers under investigation. Introduction of them into clinical practice could improve timely EC diagnosis, treatment outcomes, and surveillance of EC patients.
