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Advances in Gynecological Cancers 2.0

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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 (30 November 2023) | Viewed by 13235

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Dr. Michalis Liontos

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Guest Editor

Department of Clinical Therapeutics, Division of Oncology, Alexandra Hospital, National and Kapodistrian University of Athens, 10679 Athens, Greece
Interests: ovarian cancer; personalized medicine; DNA damage response; DNA repair mechanisms; uterine cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

New insights into the underlying biology of gynecological cancers, revealed by studying gene expression profiles, have unequivocally improved their clinical management. Maintenance therapy with poly(ADP- ribose) polymerase inhibitors (PARPi) and/or bevacizumab for high-grade serous ovarian cancer patients, responding to platinum-based chemotherapy, represents an excellent example of targeted therapy successfully translated into the daily clinical oncology practice. Notwithstanding the good initial responses, both the inevitable tumor’s clonal evolution and the ultimate resistance emergence indicate an arguable hindrance to these novel therapies, resulting in disease relapse. At present, the efficacy of subsequent treatment strategies is diminished, whereas immunotherapy has not yet provided a clinical benefit.

On the other hand, for patients with recurrent or metastatic endometrial and cervical cancer, immune checkpoint inhibitors (ICIs) represent an emerging treatment option with promising durability. Furthermore, several ongoing trials featuring immune checkpoint blockade explore its potential in the adjuvant and neoadjuvant setting. The identification of predictive biomarkers along with an in-depth understanding of molecular mechanisms behind both treatment response and resistance are of paramount importance.

This Special Issue of the International Journal of Molecular Sciences aims to highlight important advances in gynecological cancer patients’ management over the past decade as well as future challenges, with regard to tailored, personalized treatment guidance for these patients, in the decades to come.

Dr. Michalis Liontos
Guest Editor

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Keywords

ovarian cancer
DNA damage repair (DDR) pathways
PARP inhibitors
endometrial cancer
cervical cancer
immunotherapy
biomarkers

Published Papers (7 papers)

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Research

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13 pages, 1031 KiB

Open AccessArticle

CA-125 KELIM as an Alternative Predictive Tool to Identify Which Patients Can Benefit from PARPi in High-Grade Serous Advanced Ovarian Cancer: A Retrospective Pilot Diagnostic Accuracy Study

by Dimitrios Zouzoulas, Dimitrios Tsolakidis, Panagiotis Tzitzis, Kimon Chatzistamatiou, Vasilis Theodoulidis, Iliana Sofianou, Grigoris Grimbizis and Eleni Timotheadou

Int. J. Mol. Sci. 2024, 25(10), 5230; https://doi.org/10.3390/ijms25105230 - 11 May 2024

Viewed by 384

Abstract

BRCA mutation and homologous recombination deficiency (HRD) are the criteria for the administration of PARP inhibitor (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy. Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org. A total of 39 patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64–0.97) and the specificity was 0.83, 95% CI (0.59–0.96). On the other hand, when assuming KELIM as a continuous index test, the area under the curve (AUC) was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%. KELIM score seems to be a new, cheaper, and faster tool to identify patients that can benefit from PARPi maintenance therapy. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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16 pages, 3007 KiB

Open AccessArticle

A Multi-Omics Approach Revealed Common Dysregulated Pathways in Type One and Type Two Endometrial Cancers

by Valeria Capaci, Lorenzo Monasta, Michelangelo Aloisio, Eduardo Sommella, Emanuela Salviati, Pietro Campiglia, Manuela Giovanna Basilicata, Feras Kharrat, Danilo Licastro, Giovanni Di Lorenzo, Federico Romano, Giuseppe Ricci and Blendi Ura

Int. J. Mol. Sci. 2023, 24(22), 16057; https://doi.org/10.3390/ijms242216057 - 7 Nov 2023

Cited by 1 | Viewed by 2720

Abstract

Endometrial cancer (EC) is the most frequent gynecologic cancer in postmenopausal women. Pathogenetic mechanisms that are related to the onset and progression of the disease are largely still unknown. A multi-omics strategy can help identify altered pathways that could be targeted for improving therapeutical approaches. In this study we used a multi-omics approach on four EC cell lines for the identification of common dysregulated pathways in type 1 and 2 ECs. We analyzed proteomics and metabolomics of AN3CA, HEC1A, KLE and ISHIKAWA cell lines by mass spectrometry. The bioinformatic analysis identified 22 common pathways that are in common with both types of EC. In addition, we identified five proteins and 13 metabolites common to both types of EC. Western blotting analysis on 10 patients with type 1 and type 2 EC and 10 endometria samples confirmed the altered abundance of NPEPPS. Our multi-omics analysis identified dysregulated proteins and metabolites involved in EC tumor growth. Further studies are needed to understand the role of these molecules in EC. Our data can shed light on common pathways to better understand the mechanisms involved in the development and growth of EC, especially for the development of new therapies. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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10 pages, 699 KiB

Open AccessArticle

Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer

by Edith Borcoman, Elizabeth Santana dos Santos, Catherine Genestie, Patricia Pautier, Ludovic Lacroix, Sandrine M. Caputo, Odile Cabaret, Marine Guillaud-Bataille, Judith Michels, Aurelie Auguste, Alexandra Leary and Etienne Rouleau

Int. J. Mol. Sci. 2023, 24(14), 11570; https://doi.org/10.3390/ijms241411570 - 18 Jul 2023

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Abstract

Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the ‘second hit’ event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01–0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the ‘second hit’ of BRCA1/2-related tumorigenesis. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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15 pages, 3555 KiB

Open AccessArticle

AhRR and PPP1R3C: Potential Prognostic Biomarkers for Serous Ovarian Cancer

by Alessandra Ardizzoia, Andrea Jemma, Serena Redaelli, Marco Silva, Angela Bentivegna, Marialuisa Lavitrano and Donatella Conconi

Int. J. Mol. Sci. 2023, 24(14), 11455; https://doi.org/10.3390/ijms241411455 - 14 Jul 2023

Cited by 1 | Viewed by 1423

Abstract

The lack of effective screening and successful treatment contributes to high ovarian cancer mortality, making it the second most common cause of gynecologic cancer death. Development of chemoresistance in up to 75% of patients is the cause of a poor treatment response and reduced survival. Therefore, identifying potential and effective biomarkers for its diagnosis and prognosis is a strong critical need. Copy number alterations are frequent in cancer, and relevant for molecular tumor stratification and patients’ prognoses. In this study, array-CGH analysis was performed in three cell lines and derived cancer stem cells (CSCs) to identify genes potentially predictive for ovarian cancer patients’ prognoses. Bioinformatic analyses of genes involved in copy number gains revealed that AhRR and PPP1R3C expression negatively correlated with ovarian cancer patients’ overall and progression-free survival. These results, together with a significant association between AhRR and PPP1R3C expression and ovarian cancer stemness markers, suggested their potential role in CSCs. Furthermore, AhRR and PPP1R3C’s increased expression was maintained in some CSC subpopulations, reinforcing their potential role in ovarian cancer. In conclusion, we reported for the first time, to the best of our knowledge, a prognostic role of AhRR and PPP1R3C expression in serous ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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14 pages, 2016 KiB

Open AccessArticle

NOVAprep-miR-Cervix: New Method for Evaluation of Cervical Dysplasia Severity Based on Analysis of Six miRNAs

by Margarita Kniazeva, Lidia Zabegina, Andrey Shalaev, Olga Smirnova, Olga Lavrinovich, Igor Berlev and Anastasia Malek

Int. J. Mol. Sci. 2023, 24(11), 9114; https://doi.org/10.3390/ijms24119114 - 23 May 2023

Cited by 1 | Viewed by 1389

Abstract

Cervical cancer is one of the most common gynecological malignancies and it is preventable through the yearly diagnosis and management of pre-cancerous cervical disease. The profile of miRNA expression in cervical epithelium cells is altered with cervical dysplasia development and further progression. The NOVAprep-miR-CERVIX is a new approach for the assessment of cervical dysplasia through the analysis of six marker miRNAs. This study aims to evaluate theperformance and diagnostic potency of the new method. Cytological smears from 226 women (NILM, n.114; HSIL, n.112) were included in the study. A VPH test was performed with RealBest DNAHPV HR screen Kit, six marker miRNAs (miR-21, -29b, -145, -451a, -1246, -1290) were assayed using NOVAprep-miR-CERVIX kit. Obtained data were analyzed using the Delta Ct method and random forest machine learning algorithm. The results of the quantitative analysis of six microRNAs were expressed as a miR-CERVIX parameter, which ranged from 0 to 1, where “0” corresponded to the healthy cervical epithelium, while “1” corresponded to high-grade squamous intraepithelial dysplasia. The average value of miR-CERVIX differed in groups of NILM and HSIL samples (0.34 vs. 0.72; p < 0.000005). An estimation of miR-CERVIX allowed for the differentiation between healthy and pre-cancerous samples with sensitivity of 0.79 and specificity of 0.79, as well as to confirm HSIL with specificity of 0.98. Interestingly, the HSIL group included HPV(+) and HPV(−) samples, which were statistically significantly different in terms of miR-CERVIX value. Analysis of CC-associated miRNAs in material of cervical smear might serve as an additional method for the evaluation of cervical dysplasia severity. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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12 pages, 1099 KiB

Open AccessArticle

Triaging HPV-Positive Cervical Samples with p16 and Ki-67 Dual Stained Cytology within an Organized Screening Program—A Prospective Observational Study from Western Norway

by Irene Tveiterås Øvestad, Ingvild Dalen, Marie S. Andersland, Olav K. Vintermyr, Pia Moltu, Jannicke M. Berland, Emilius A. M. Janssen and Hans Kristian Haugland

Int. J. Mol. Sci. 2023, 24(8), 7158; https://doi.org/10.3390/ijms24087158 - 12 Apr 2023

Cited by 5 | Viewed by 1579

Abstract

The implementation of high-risk human papillomavirus testing (hrHPV testing) as a screening method in substitute for cytology has evoked the need for more sensitive and less objective tests for the triage of HPV-positive women. In a cohort of 1763 HPV-positive women, the potential of immunocytochemical p16 and Ki-67 dual staining as compared to cytology, alone or in combination with HPV partial genotyping, was tested for triage of women attending a cervical cancer screening program. Performance was measured using sensitivity, specificity, and positive and negative predictive values. Comparisons were assessed using logistic regression models and the McNemar test. Dual staining was evaluated in a prospectively collected study cohort of 1763 HPV-screened women. For triage of CIN2+ and CIN3+, NPV and sensitivity, 91.8% and 94.2% versus 87.9% and 89.7%, respectively, were significantly higher using dual staining together with HPV 16/18 positive, as compared to cytology (p < 0.001). The specificities, however, were lower for dual staining as compared to cytology. Conclusions: Dual staining is safer for decision-making regarding HPV-positive women’s need for follow-up with colposcopy and biopsy, as compared to cytology. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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Review

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23 pages, 1868 KiB

Open AccessReview

Immune Tumor Microenvironment in Ovarian Cancer Ascites

by Diana Luísa Almeida-Nunes, Ana Mendes-Frias, Ricardo Silvestre, Ricardo Jorge Dinis-Oliveira and Sara Ricardo

Int. J. Mol. Sci. 2022, 23(18), 10692; https://doi.org/10.3390/ijms231810692 - 14 Sep 2022

Cited by 14 | Viewed by 3576

Abstract

Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology. Full article

(This article belongs to the Special Issue Advances in Gynecological Cancers 2.0)

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