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Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 June 2025) | Viewed by 11379

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Special Issue Editors

Dr. Laura Mariuzzi

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Guest Editor

Institute of Pathology, Medical Area Department, University of Udine-Azienda Sanitaria Universitaria Friuli Centrale-ASUFC, P.le S. Maria della Misericordia, 15-33100 Udine, Italy
Interests: histopathology; gynecological cancers; breast cancer; molecular biology; tissue regeneration; stem cell biology

Dr. Alessandro Mangogna

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Pathology Resident at the Institute of Pathology, Medical Area Department, University of Udine-Azienda Sanitaria Universitaria Friuli Centrale-ASUFC, P.le S. Maria della Misericordia, 15-33100 Udine, Italy
Interests: pathology; cancer research; gynecological cancers; neuroendocrine tumors; immuno-oncology; tumor microenvironment; complement system

Dr. Maria Orsaria

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Guest Editor

Institute of Pathology, Medical Area Department, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), P.le S. Maria della Misericordia, 15-33100 Udine, Italy
Interests: pathology; cancer research; gynecological cancers; gestational trophoblastic disease; breast cancer; feto-placental pathology; perinatal pathology

Special Issue Information

Dear Colleagues,

Ovarian and endometrial cancers are the most prevalent and deadliest gynecological malignancies worldwide, constituting a great challenge for all who participate in patient diagnosis and treatment. Over recent years, conventional therapeutic options, such as surgery, chemotherapy, and radiotherapy, have been overcome by emerging approaches, allowing development towards a more comprehensive overview of cancer etiology and evolution. Advances in the treatment of gynecological neoplasms have fueled passionate debate in conversations including not only surgeons, oncologists, and radiotherapists, but also other professional figures, such as pathologists, molecular biologists, and geneticists. Thus, multi-disciplinarity has become the ace in the hole in terms of establishing increasingly personalized treatments. Patients life expectancy is rising, opening new questions for the management of cancer survivors.

Although relatively rare, gestational trophoblastic disease represents another serious public health issue for women of reproductive age. In particular, tumors arising from extraembryonic tissues are extraordinary with respect to their fetal origin (semi-allograft) and the maternal tissue matrix (endomyometrium) that supports their growth. Gestational trophoblastic disease consists of well-defined diagnostic entities of a proliferative disorder of the placenta, of which hydatidiform moles are common lesions. Even with available ancillary studies, including ploidy and immunohistochemistry analyses, histological diagnosis of molar pregnancies can be challenging in a significant percentage of the cases. PCR-based short-tandem repeat DNA genotyping has emerged as a powerful ancillary tool for the precise diagnosis and subclassification of gestational trophoblastic diseases, particularly hydatidiform moles. As lesions of gestational origin, the inherited paternal genome, with or without copy number alterations, is the fundamental molecular basis for the diagnostic applications of DNA genotyping. Genotyping is now considered the gold standard in confirming and subtyping sporadic hydatidiform moles. Beyond hydatidiform moles, DNA genotyping also has fundamental applications in the diagnosis or prognostic assessment of gestational trophoblastic tumors, particularly gestational choriocarcinoma.

Malignant transformation in gestational trophoblastic tumors is likely a multistep process involving multiple genetic alterations, as with other human cancers, and may involve the activation of oncogenes and inactivation of tumor suppressor genes. In addition, expression of telomerase activity, altered expression of cell–cell adhesion molecules, and abnormal expression of matrix metalloproteinases have also been reported in gestational trophoblastic disease. These represent the disruption of the delicate balance and regulation of cellular processes, including proliferation, differentiation, apoptosis, and invasion.

In this Special Issue, we invite experts in the field to review the current diagnostic, therapeutic, and experimental models of gynecological cancers. We invite the submission of research articles that help to clarify the mechanisms underlying tumor heterogeneity/microenvironment, the diverse molecular signatures of gynecological cancers (epigenome, immune landscape, dysregulation of phylogenetically conserved signaling pathways), and the relative contribution of cancer stem cells. Additionally, we welcome studies conducted to unveil the molecular alterations exhibited by tumor cells, the proposal of novel targets for cancer therapy, and the mechanisms of action of drugs and drug candidates (including off-target effects and drug repurposing). In addition, we aim to promote the diffusion of review articles that highlight new findings in the above areas and underline similarities or cross-comparisons between gynecological cancers and other human malignancies.

Dr. Laura Mariuzzi
Dr. Alessandro Mangogna
Dr. Maria Orsaria
Guest Editors

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Keywords

ovarian cancer
endometrial cancer
gestational trophoblastic disease
prognostic factors
oncogenes
molecular genetics and genomics
DNA genotyping
cancer stem cells
epigenomics
signaling pathways
extracellular vesicles
tumour heterogeneity
tumour microenvironment
immune checkpoint inhibitors
new targets
molecular target

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Published Papers (7 papers)

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Research

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13 pages, 2054 KiB

Open AccessArticle

Sensitive Detection of Gynecological Cancer Recurrence Using Circulating Tumor DNA and Digital PCR: A Comparative Study with Serum Biochemical Markers

by Nour Balasan, Feras Kharrat, Giovanni Di Lorenzo, Emmanouil Athanasakis, Anna Monica Bianco, Andrea Conti, Maria Teresa Di Stazio, Giulia Butera, Stefania Cicogna, Alessandro Mangogna, Federico Romano, Giuseppe Ricci and Adamo Pio d’Adamo

Int. J. Mol. Sci. 2024, 25(22), 11997; https://doi.org/10.3390/ijms252211997 - 8 Nov 2024

Cited by 1 | Viewed by 1517

Abstract

Early detection of recurrences in gynecological cancers is crucial for women’s health. Circulating tumor DNA (ctDNA) analysis through liquid biopsy offers a promising approach for monitoring disease progression and identifying relapses. This study investigated the utility of digital Polymerase Chain Reaction (dPCR) for ctDNA detection in three gynecological cancer patients with clinically confirmed relapses during a two-year post-surgical follow-up. Patient-specific tumor mutations were identified through whole-exome sequencing (WES) and confirmed via Sanger sequencing. dPCR probes targeting these mutations were used to quantify the ctDNA levels in plasma samples collected throughout the follow-up period, and the findings were compared with standard serum biochemical markers. In two patients, persistent positive dPCR signals for the selected mutations were detected after tumor removal, with ctDNA levels progressively increasing even after post-surgical chemotherapy. Notably, dPCR identified elevated ctDNA levels before an increase in the cancer antigen 125 (CA125) biochemical marker was observed. In the third patient, no ctDNA signals from the two selected mutations were detected despite clinical evidence of recurrence, suggesting the emergence of new mutations. While this study highlights the promise of dPCR for early recurrence detection in gynecological cancers, it also underscores the critical need for comprehensive mutation panels to overcome the inherent challenges posed by tumor heterogeneity and the emergence of new mutations during disease progression. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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23 pages, 4985 KiB

Open AccessArticle

The Clinical Significance of CRNDE Gene Methylation, Polymorphisms, and CRNDEP Micropeptide Expression in Ovarian Tumors

by Laura Aleksandra Szafron, Roksana Iwanicka-Nowicka, Agnieszka Podgorska, Arkadiusz M. Bonna, Piotr Sobiczewski, Jolanta Kupryjanczyk and Lukasz Michal Szafron

Int. J. Mol. Sci. 2024, 25(14), 7531; https://doi.org/10.3390/ijms25147531 - 9 Jul 2024

Cited by 4 | Viewed by 1984

Abstract

CRNDE is an oncogene expressed as a long non-coding RNA. However, our team previously reported that the CRNDE gene also encodes a micropeptide, CRNDEP. The amino acid sequence of CRNDEP has recently been revealed by other researchers, too. This study aimed to investigate genetic alterations within the CRNDEP-coding region of the CRNDE gene, methylation profiling of this gene, and CRNDEP expression analysis. All investigations were performed on clinical material from patients with ovarian tumors of diverse aggressiveness. We found that CRNDEP levels were significantly elevated in highly aggressive tumors compared to benign neoplasms. Consistently, a high level of this micropeptide was a negative, independent, prognostic, and predictive factor in high-grade ovarian cancer (hgOvCa) patients. The cancer-promoting role of CRNDE(P), shown in our recent study, was also supported by genetic and epigenetic results obtained herein, revealing no CRNDEP-disrupting mutations in any clinical sample. Moreover, in borderline ovarian tumors (BOTS), but not in ovarian cancers, the presence of a single nucleotide polymorphism in CRNDE, rs115515594, significantly increased the risk of recurrence. Consistently, in BOTS only, the same genetic variant was highly overrepresented compared to healthy individuals. We also discovered that hypomethylation of CRNDE is associated with increased aggressiveness of ovarian tumors. Accordingly, hypomethylation of this gene’s promoter/first exon correlated with hgOvCa resistance to chemotherapy, but only in specimens with accumulation of the TP53 tumor suppressor protein. Taken together, these results contribute to a better understanding of the role of CRNDE(P) in tumorigenesis and potentially may lead to improvements in screening, diagnosis, and treatment of ovarian neoplasms. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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27 pages, 12242 KiB

Open AccessArticle

PRKDC-Mediated NHEJ May Play a Crucial Role in Aneuploidy of Chromosome 8-Driven Progression of Ovarian Cancer

by Wenqing Luan, Hongyan Cheng, Haoling Xie, Huiping Liu, Yicheng Wang, Shang Wang, Xue Ye, Honglan Zhu, Fuchou Tang, Yi Li and Xiaohong Chang

Int. J. Mol. Sci. 2024, 25(9), 4825; https://doi.org/10.3390/ijms25094825 - 28 Apr 2024

Cited by 1 | Viewed by 2333

Abstract

High malignancy is a prominent characteristic of epithelial ovarian cancer (EOC), emphasizing the necessity for further elucidation of the potential mechanisms underlying cancer progression. Aneuploidy and copy number variation (CNV) partially contribute to the heightened malignancy observed in EOC; however, the precise features of aneuploidy and their underlying molecular patterns, as well as the relationship between CNV and aneuploidy in EOC, remain unclear. In this study, we employed single-cell sequencing data along with The Cancer Genome Atlas (TCGA) to investigate aneuploidy and CNV in EOC. The technique of fluorescence in situ hybridization (FISH) was employed using specific probes. The copy number variation within the genomic region of chromosome 8 (42754568-47889815) was assessed and utilized as a representative measure for the ploidy status of individual cells in chromosome 8. Differential expression analysis was performed between different subgroups based on chromosome 8 ploidy. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI), and hub–gene analyses were subsequently utilized to identify crucial genes involved. By classifying enriched tumor cells into distinct subtypes based on chromosome 8 ploidy combined with TCGA data integration, we identified key genes driving chromosome 8 aneuploidy in EOC, revealing that PRKDC gene involvement through the mediated non-homologous end-joining pathway may play a pivotal role in disease progression. Further validation through analysis of the GEO and TCGA database and survival assessment, considering both mRNA expression levels and CNV status of PRKDC, has confirmed its involvement in the progression of EOC. Further functional analysis revealed an upregulation of PRKDC in both ovarian EOC cells and tissues, with its expression showing a significant correlation with the extent of copy number variation (CNV) on chromosome 8. Taken together, CNV amplification and aneuploidy of chromosome 8 are important characteristics of EOC. PRKDC and the mediated NHEJ pathway may play a crucial role in driving aneuploidy on chromosome 8 during the progression of EOC. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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Review

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16 pages, 1920 KiB

Open AccessReview

The Role of microRNA in the Prognosis and Diagnosis of Ovarian Cancer

by Mateusz Kozłowski, Dominika Borzyszkowska, Anna Golara, Jerzy Lubikowski and Aneta Cymbaluk-Płoska

Int. J. Mol. Sci. 2025, 26(7), 3413; https://doi.org/10.3390/ijms26073413 - 5 Apr 2025

Viewed by 565

Abstract

Ovarian cancer (OC) is one of the most common cancers in women. Biomarkers for OC are still being sought. The aim of this review was to evaluate microRNAs in the prognosis and diagnosis of OC. We conducted a literature review searching for articles published from January 2014 to September 2024. We included articles presenting the association of microRNAs with ovarian cancer prognosis, where patient survival was shown by the Kaplan–Meier curve, and articles presenting the association of microRNAs with ovarian cancer diagnosis, where the results were presented as an ROC curve. MicroRNAs are promising clinical markers in ovarian cancer patients. As is shown here, expression (high or low) of various miRNAs was differentially associated with survival in OC patients, with some miRNAs being associated with a longer survival and some with a shorter survival. In the absence of diagnostic markers for OC, the raised role of miRNAs in diagnosis seems all the more important. The diagnostic value of miRNAs has been shown, mostly as blood biomarkers, although they have also been evaluated as tissue or urine markers. MiRNAs have an important role as clinical biomarkers for ovarian cancer, not only as single molecules, but also as biomarker pairs or panels of miRNAs. It should be noted that most of the miRNAs reviewed here have been studied once, so despite the promising results, it seems necessary to conduct studies to confirm or negate the results obtained. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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19 pages, 982 KiB

Open AccessReview

Epigenetic Modulation of Estrogen Receptor Signaling in Ovarian Cancer

by Maciej Skrzypczak, Ewa Wolinska, Łukasz Adaszek, Olaf Ortmann and Oliver Treeck

Int. J. Mol. Sci. 2025, 26(1), 166; https://doi.org/10.3390/ijms26010166 - 28 Dec 2024

Cited by 3 | Viewed by 1388

Abstract

Ovarian cancer remains one of the leading causes of cancer-related deaths in women. There are several processes that are described to have a causal relationship in ovarian cancer development, progression, and metastasis formation, that occur both at the genetic and epigenetic level. One of the mechanisms involved in its pathogenesis and progression is estrogen signaling. Estrogen receptors (ER) α, ERβ, and G-protein coupled estrogen receptor 1 (GPER1), in concert with various coregulators and pioneer transcription factors, mediate the effects of estrogens primarily by the transcriptional regulation of estrogen responsive genes, thereby exerting pleiotropic effects including the regulation of cellular proliferation and apoptosis. The expression and activity of estrogen receptors and their coregulators have been demonstrated to be regulated by epigenetic mechanisms like histone modifications and DNA methylation. Here, we intend to summarize and to provide an update on the current understanding of epigenetic mechanisms regulating estrogen signaling and their role in ovarian cancer. For this purpose, we reviewed publications on this topic listed in the PubMed database. Finally, we assess to which extent drugs acting on the epigenetic level might be suitable for the treatment of ovarian cancer. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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13 pages, 548 KiB

Open AccessReview

The Role of Long Non-Coding RNAs in Ovarian Cancer Cells

by Anna Golara, Mateusz Kozłowski and Aneta Cymbaluk-Płoska

Int. J. Mol. Sci. 2024, 25(18), 9922; https://doi.org/10.3390/ijms25189922 - 14 Sep 2024

Cited by 1 | Viewed by 1737

Abstract

Among the most deadly malignancies that strike women worldwide, ovarian cancer is still one of the most common. The primary factor affecting a patient’s survival is early lesion discovery. Unfortunately, because ovarian cancer is a sneaky illness that usually manifests as nonspecific symptoms only in advanced stages, its early detection and screening are challenging. A lot of research is being conducted on effective methods of diagnosing and treating ovarian cancer. Recently, non-coding RNAs (ncRNAs) have gained great popularity, which are considered to be the main regulators of many cellular processes, especially those occurring in cancer. LncRNAs are also being studied for their therapeutic use in the treatment of ovarian cancer and their use in diagnostics and as indicators of poor prognosis. In this article, we reviewed lncRNAs described in the literature that may play an important role in ovarian cancer. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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Other

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8 pages, 951 KiB

Open AccessCase Report

A Case Report to Reflect on the Origins of MMRd Mesonephric-like Ovarian Adenocarcinoma: Can It Be Defined as a Mϋllerian Neoplasm?

by Nicoletta D’Alessandris, Angela Santoro, Michele Valente, Giulia Scaglione, Giuseppe Angelico, Belen Padial Urtueta, Nadine Narducci, Simona Duranti, Francesca Addante, Angelo Minucci and Gian Franco Zannoni

Int. J. Mol. Sci. 2025, 26(11), 5245; https://doi.org/10.3390/ijms26115245 - 29 May 2025

Viewed by 307

Abstract

Mesonephric-like adenocarcinoma (MLA) of ovaries is a new and rare neoplastic entity, recently classified by the World Health Organization. Its morphological and immunohistochemical profile is similar to primitive cervical mesonephric adenocarcinoma, but its origin has not been determined yet. Some authors believe that this neoplasm originates from Wolffian remnants in the ovarian hilum, while others suggest an origin from the Mϋllerian epithelium, followed by a mesonephric trans-differentiation. Starting from a recently diagnosed mismatch repair-deficient ovarian MLA, we try to further develop this line of research. A detailed molecular analysis of the studied tumor helps clarify our ideas. In fact, the typical KRAS mutation was not present. We found mutations in numerous other genes, which are rarely described in the literature or are already described in the endometrioid histotype. We reached some interesting conclusions, which, if supported by future studies, will clarify the true nature of these tumors, allowing for better stratification and a better therapeutic framework. Full article

(This article belongs to the Special Issue Molecular Research on Gynecological Cancers: Ovarian Cancer, Endometrial Cancer, and Gestational Trophoblastic Disease)

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