OBJECTIVES: Endometrial cancer (EC) is the most common malignancy of the female genital tract in developed countries, yet preventive screening remains unavailable, and diagnostic approaches are largely limited to symptomatic women. Despite advancements in precision oncology, the biology of precancerous lesions is less understood compared to advanced disease. To address this gap, we conducted a prospective case-control study analysing uterine lavage fluid from women undergoing diagnostic evaluation. The study included 257 participants: 80 diagnosed with endometrial intraepithelial neoplasia (EIN), 89 with early-stage EC, and 88 healthy controls. Using targeted next-generation sequencing, we examined genetic alterations in 22 selected genes associated with EC development. RESULTS: Our findings did not confirm a direct association between specific genetic mutations in uterine lavage fluid and the presence of EIN or early-stage EC (p = 0.501). Mutations were detected in both cases and controls, with a higher overall mutation burden observed in controls, suggesting potential background genomic alterations unrelated to EC development. In conclusion, while molecular profiling of uterine lavage fluid remains a promising concept for non-invasive diagnosis, our results highlight significant challenges in specificity. Further studies with larger cohorts and additional biomarkers are necessary to clarify its diagnostic relevance and clinical applicability.

• Keywords
• DNA sequencing, Endometrial cancer, Endometrial intraepithelial neoplasia, Precancer screening, Uterine lavage fluids,
• MeSH
• Adult MeSH
• Carcinoma in Situ * genetics   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   MeSH
• Endometrial Neoplasms * genetics   diagnosis   pathology   MeSH
• Prospective Studies MeSH
• Aged MeSH
• Case-Control Studies MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers, Tumor * MeSH

The prevention and early diagnostics of precancerous stages are key aspects of contemporary oncology. In cervical cancer, well-organized screening and vaccination programs, especially in developed countries, are responsible for the dramatic decline of invasive cancer incidence and mortality. Cytological screening has a long and successful history, and the ongoing implementation of HPV triage with increased sensitivity can further decrease mortality. On the other hand, endometrial and ovarian cancers are characterized by a poor accessibility to specimen collection, which represents a major complication for early diagnostics. Therefore, despite relatively promising data from evaluating the combined effects of genetic variants, population screening does not exist, and the implementation of new biomarkers is, thus, necessary. The introduction of various circulating biomarkers is of potential interest due to the considerable heterogeneity of cancer, as highlighted in this review, which focuses exclusively on the most common tumors of the genital tract, namely, cervical, endometrial, and ovarian cancers. However, it is clearly shown that these malignancies represent different entities that evolve in different ways, and it is therefore necessary to use different methods for their diagnosis and treatment.

• Keywords
• cervical cancer, endometrial cancer, liquid biopsy, ovarian cancer, precancer,
• Publication type
• Journal Article MeSH
• Review MeSH

Epithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic phenotype. Anterior gradient protein 2 (AGR2) maintains the epithelial phenotype and blocks the induction of EMT, thus playing an undeniable role in tumor progression. However, the mechanism through which AGR2 expression is regulated, not only during EMT, but also in the early stages of cancer development, remains to be elucidated. In the present study, we show an inverse correlation of AGR2 with ZEB1 (zinc finger enhancer binding protein, δEF1) that was verified by analysis of several independent clinical data sets of lung adenocarcinomas. We also identified the ZEB1 binding site within the AGR2 promoter region and confirmed AGR2 as a novel molecular target of ZEB1. The overexpression of ZEB1 decreased the promoter activity of the AGR2 gene, which resulted in reduced AGR2 protein level and the acquisition of a more invasive phenotype of these lung cancer cells. Conversely, silencing of ZEB1 led not only to increased levels of AGR2 protein, but also attenuated the invasiveness of tumor cells. The AGR2 knockout, vice versa, increased ZEB1 expression, indicating that the ZEB1/AGR2 regulatory axis may function in a double negative feedback loop. In conclusion, we revealed for the first time that ZEB1 regulates AGR2 at the transcriptional level, while AGR2 presence contributes to ZEB1 mRNA degradation. Thus, our data identify a new regulatory mechanism between AGR2 and ZEB1, two rivals in the EMT process, tightly associated with the development of metastasis.

• Keywords
• AGR2, EMT, ZEB1, cancer,
• Publication type
• Journal Article MeSH