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Biomarkers and Early Detection Strategies of Ovarian Tumors

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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: 30 July 2025 | Viewed by 7772

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Special Issue Editor

Dr. Lukasz Szafron

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Guest Editor

Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
Interests: ovarian tumors; molecular diagnostics; bioinformatics

Special Issue Information

Dear Colleagues,

I am pleased to announce a new Special Issue entitled “Biomarkers and Early Detection Strategies of Ovarian Tumors”, and we wish to to offer authors the opportunity to publish review and original articles related to this scientifically interesting and clinically relevant topic.

Despite the development of new therapies and a better understanding of its biology, ovarian carcinoma (OvCa) remains the leading cause of death in women diagnosed with female genital tract cancers. The American Cancer Society estimates that in 2024, about 19,680 new cases of ovarian cancer will be diagnosed and 12,740 women will die of ovarian cancer in the United States. In other countries, especially those in which cancer prevention, screening, and diagnosis are less developed, the mortality rates due to this malignancy are even higher. This extremely unfavorable outcome of OvCa is mainly caused by the problems with its early detection, when the disease is curable. Apart from OvCa, borderline ovarian tumors (BOTs), considered an intermediate stage between benign tumors and OvCa, also constitute a serious medical problem. BOTs are relatively rare compared to ovarian cancer, but, in contrast to most OvCa, they usually occur in women of reproductive age. Furthermore, some of them may recur, usually as BOTs but sometimes as OvCas.

Considering these facts, the identification of new molecular biomarkers that make qualitative or quantitative alterations to BOTs and OvCas in genomes, methylomes, transcriptomes, proteomes, or metabolomes is of paramount importance in the fight againast these neoplasms. Hopefully, the results of your research studies, when presented in this Special Issue, will provide a groundwork for the development of novel, more effective, and less aggravating methods for ovarian tumor detection, diagnosis, and treatment.

Dr. Lukasz M. Szafron
Guest Editor

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Keywords

biomarker
ovarian cancer
borderline ovarian tumor
genetic variant
epigenetics
transciptomics
proteomics
metabolomics
ovarian tumor prevention
ovarian tumor treatment

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Published Papers (6 papers)

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Research

19 pages, 1906 KiB

Open AccessArticle

Sequential Plasma Metabolome and Proteome Analyses to Develop a Novel Monitoring Strategy for Patients with Epithelial Ovarian Cancer: A Pilot Study

by Eiji Hishinuma, Shogo Shigeta, Naomi Matsukawa, Yasunobu Okamura, Ikuko N. Motoike, Takamichi Minato, Yusuke Shibuya, Jun Yasuda, Kengo Kinoshita, Seizo Koshiba and Muneaki Shimada

Int. J. Mol. Sci. 2025, 26(12), 5435; https://doi.org/10.3390/ijms26125435 - 6 Jun 2025

Viewed by 169

Abstract

Epithelial ovarian cancer (EOC) is diagnosed at an advanced stage in over half of the patients and its prognosis remains unfavorable. CA125, one of the most frequent positive tumor markers in patients with EOC, has certain limitations. Therefore, more accurate clinical biomarkers are needed. Liquid biopsy with cancer related molecules, such as circulating tumor DNA, is a new option for cancer diagnosis and prognosis. We explored the potential of plasma metabolomic and proteomic analyses as novel monitoring methods for the patients with EOC. Of seven patients, six experienced disease recurrence or progression. CA125 plasma measurements were conducted for disease monitoring. Plasma metabolome and proteome analyses were performed using liquid chromatography–tandem mass spectrometry. Ten and four metabolome indicators were significantly increased and decreased in association with chemotherapeutic resistance, respectively. In addition, thirty-seven and nine proteins displayed high and low levels associated with chemotherapeutic resistance, respectively. Several metabolome pathways and protein concentrations corresponded to the clinical course of each patient. This pilot study suggested the potential of the assessment of metabolome and proteome analysis as a useful tool for developing novel monitoring biomarkers for patients with recurrent EOC. Full article

(This article belongs to the Special Issue Biomarkers and Early Detection Strategies of Ovarian Tumors)

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17 pages, 3830 KiB

Open AccessArticle

Identification of Ovarian High-Grade Serous Carcinoma with Mitochondrial Gene Variation

by Jesus Gonzalez Bosquet, Vincent Wagner, Andrew Polio, Katharine E. Linder, David P. Bender, Michael J. Goodheart and Brandon M. Schickling

Int. J. Mol. Sci. 2025, 26(3), 1347; https://doi.org/10.3390/ijms26031347 - 5 Feb 2025

Viewed by 839

Abstract

Women diagnosed with advanced-stage ovarian cancer have a much worse survival rate than women diagnosed with early-stage ovarian cancer, but the early detection of this disease remains a clinical challenge. Some recent reports indicate that genetic variations could be useful for the early detection of several malignancies. In this pilot observational retrospective study, we aimed to assess whether mitochondrial DNA (mtDNA) variations could discriminate the most frequent type of ovarian cancer, high-grade serous carcinoma (HGSC), from normal tissue. We identified mtDNA variations from 20 whole-exome sequenced (WES) HGSC samples and 14 controls (normal tubes) using the best practices of genome sequencing. We built prediction models of cancer with these variants, with good performance measured by the area under the curve (AUC) of 0.88 (CI: 0.74–1.00). The variants included in the best model were correlated with gene expression to assess the potentially affected processes. These analyses were validated with the Cancer Genome Atlas (TCGA) dataset, (including over 420 samples), with a fair performance in AUC terms (0.63–0.71). In summary, we identified a set of mtDNA variations that can discriminate HGSC with good performance. Specifically, variations in the MT-CYB gene increased the risk for HGSC by over 30%, and MT-CYB expression was significantly decreased in HGSC patients. Robust models of ovarian cancer detection with mtDNA variations could be applied to liquid biopsy technology, like those which have been applied to other cancers, with a special focus on the early detection of this lethal disease. Full article

(This article belongs to the Special Issue Biomarkers and Early Detection Strategies of Ovarian Tumors)

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12 pages, 2241 KiB

Open AccessArticle

Molecular Subgroups of HRD Positive Ovarian Cancer and Their Prognostic Significance

by Tatiana Kekeeva, Irina Dudina, Yulia Andreeva, Alexander Tanas, Alexey Kalinkin, Victoria Musatova, Natalia Chernorubashkina, Svetlana Khokhlova, Tatiana Tikhomirova, Mikhail Volkonsky, Sergey Kutsev, Dmitry Zaletaev and Vladimir Strelnikov

Int. J. Mol. Sci. 2024, 25(24), 13549; https://doi.org/10.3390/ijms252413549 - 18 Dec 2024

Cited by 2 | Viewed by 1194

Abstract

Homologous recombination repair deficiency (HRD) is involved in the development of high-grade serous ovarian carcinoma (HGSOC) and its elevated sensitivity to platinum-based chemotherapy. To investigate the heterogeneity of the HRD-positive HGSOC we evaluated the HRD status, including BRCA mutations, genomic scar score, and methylation status of BRCA1/2 genes in 352 HGSOC specimens. We then divided the HRD-positive cohort into three molecular subgroups, the BRCA mutation cohort (BRCA+), BRCA1 methylation cohort (Meth+), and the rest of the HRD+ cohort (HRD+BRCA-Meth-), and evaluated their first-line chemotherapy response, benefit from olaparib, and progression-free survival (PFS). HRD-positive status was detected in 65% (228/352) of samples. The first group, BRCA+, accounted for 45% (102/228) of HRD positive cases and showed the best outcome in platinum therapy (ORR 96%), the highest olaparib benefit (p = 0.006) and the highest median PFS (46 months). The frequency of the second cohort, Meth+, among HRD-positive patients was 23% (52/228). Patients with Meth+ HGSOC showed a significantly poorer outcome, with a median PFS of 19 months, a significantly lower ORR to platinum therapy (84%) and a modest, but not significant, benefit from olaparib maintenance. The third HRD+BRCA-Meth- group accounted for 32% (74/228) of HRD-positive patients and showed an ORR to platinum therapy similar to that of the BRCA+ group (90%), a higher, but not statistically significant, benefit from olaparib and a median PFS of 23 months. In conclusion, Meth+ subgroup had poor outcomes in terms of chemotherapy response, olaparib benefit, and PFS compared to the other HRD+ subgroups, requiring a more thorough follow-up. Full article

(This article belongs to the Special Issue Biomarkers and Early Detection Strategies of Ovarian Tumors)

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12 pages, 2746 KiB

Open AccessArticle

A Sensitive and Transparent Method for Tumor-Informed Detection of Circulating Tumor DNA in Ovarian Cancer Using Whole-Genome Sequencing

by Christine Fribert Thusgaard, Sepideh Sadegh, Kirsten Marie Jochumsen, Torben Arvid Kruse and Mads Thomassen

Int. J. Mol. Sci. 2024, 25(24), 13349; https://doi.org/10.3390/ijms252413349 (registering DOI) - 12 Dec 2024

Viewed by 1117

Abstract

Circulating tumor DNA (ctDNA) is a biomarker that could potentially improve the survival rate of ovarian cancer (OC), e.g., by monitoring treatment response and early relapse detection. However, an optimal method for ctDNA analysis in OC remains to be established. We developed a method for tumor-informed single-nucleotide variant detection of ctDNA in OC using whole-genome sequencing. Tumor and plasma samples obtained at the time of diagnosis from 10 patients with OC were included. The tested method involved applying basic filters with different cut-offs of read depth, allelic depth, and variant allele frequency of tumor and normal DNA. In addition, we applied a new filtering approach using plasma samples from the other included OC patients (the plasma pool) for specific removal of artefacts. The basic filters with varying cut-offs showed minor improvement in signal-to-noise ratio (S2N). However, the addition of the plasma pool filter resulted in a considerable ctDNA signal improvement, indicated by both S2N and z-score. This study demonstrates a promising method for ctDNA detection in OC patients using a tumor-informed approach for whole-genome sequencing. Despite the limited number of patients involved, the results suggest a significant potential of the method for ctDNA signal detection in patients with OC. Full article

(This article belongs to the Special Issue Biomarkers and Early Detection Strategies of Ovarian Tumors)

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19 pages, 7854 KiB

Open AccessArticle

Single-Cell RNA Sequencing of PBMCs Identified Junction Plakoglobin (JUP) as Stratification Biomarker for Endometriosis

by Thomas Andrieu, Angelo Duo, Lea Duempelmann, Magdalena Patzak, Flurina Annacarina Maria Saner, Jitka Skrabalova, Cinzia Donato, Peter Nestorov and Michael D. Mueller

Int. J. Mol. Sci. 2024, 25(23), 13071; https://doi.org/10.3390/ijms252313071 - 5 Dec 2024

Cited by 1 | Viewed by 1689

Abstract

This study aimed to identify unique characteristics in the peripheral blood mononuclear cells (PBMCs) of endometriosis patients and develop a non-invasive early diagnostic tool. Using single-cell RNA sequencing (scRNA-seq), we constructed the first single-cell atlas of PBMCs from endometriosis patients based on 107,964 cells and 25,847 genes. Within CD16⁺ monocytes, we discovered JUP as a dysregulated gene. To assess its diagnostic potential, we measured peritoneal fluid (PF) and serum JUP levels in a large cohort of 199 patients including 20 women with ovarian cancer (OC). JUP was barely detectable in PF but was significantly elevated in the serum of patients with endometriosis and OC, with levels 1.33 and 2.34 times higher than controls, respectively. Additionally, JUP was found in conditioned culture media of CD14⁺/CD16⁺ monocytes aligning with our scRNA-seq data. Serum JUP levels correlated with endometriosis severity and endometrioma presence but were unaffected by dysmenorrhea, menstrual cycle, or adenomyosis. When combined with CA125 (cancer antigen 125) JUP enhanced the specificity of endometriosis diagnosis from 89.13% (CA125 measured alone) to 100%. While sensitivity remains a challenge at 19%, our results suggest that JUP’s potential to enhance diagnostic accuracy warrants additional investigation. Furthermore, employing serum JUP as a stratification marker unlocked the potential to identify additional endometriosis-related genes, offering novel insights into disease pathogenesis. Full article

(This article belongs to the Special Issue Biomarkers and Early Detection Strategies of Ovarian Tumors)

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26 pages, 13371 KiB

Open AccessArticle

An Analysis of Genetic Polymorphisms in 76 Genes Related to the Development of Ovarian Tumors of Different Aggressiveness

by Laura A. Szafron, Piotr Sobiczewski, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk and Lukasz M. Szafron

Int. J. Mol. Sci. 2024, 25(20), 10876; https://doi.org/10.3390/ijms252010876 - 10 Oct 2024

Cited by 2 | Viewed by 1405

Abstract

Borderline ovarian tumors (BOTS) are rare neoplasms of intermediate aggressiveness between cystadenomas and low-grade ovarian cancers (lgOvCa), which they share some molecular resemblances with. In contrast to the most frequent and well-described high-grade ovarian carcinomas (hgOvCa), the molecular background of BOTS and lgOvCa is less thoroughly characterized. Here, we aimed to analyze genetic variants in crucial tumor suppressors and oncogenes in BOTS (with or without the BRAF V600E mutation), lgOvCa, and hgOvCa in two gene panels using next-generation sequencing. Then, we verified the existence of selected polymorphisms by Sanger sequencing. Finally, Western blot analyses were carried out to check the impact of the selected polymorphisms on the expression of the corresponding proteins. Our study contributes to the molecular characterization of ovarian neoplasms, demonstrating divergent polymorphic patterns pointing to distinct signaling pathways engaged in their development. Certain mutations seem to play an important role in BOTS without the BRAF V600E variant (KRAS) and in lgOvCa (KRAS and NRAS), but not in hgOvCa. Additionally, based on multivariable regression analyses, potential biomarkers in BOTS (PARP1) and hgOvCa (FANCI, BRCA2, TSC2, FANCF) were identified. Noteworthy, for some of the analyzed genes, such as FANCI, FANCD2, and FANCI, FANCF, TSC2, the status of BRCA1/2 and TP53, respectively, turned out to be crucial. Our results shed new light on the similarities and differences in the polymorphic patterns between ovarian tumors of diverse aggressiveness. Furthermore, the biomarkers identified herein are of potential use as predictors of the prognosis and/or response to therapy. Full article

(This article belongs to the Special Issue Biomarkers and Early Detection Strategies of Ovarian Tumors)

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