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Cancers
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Genetics and Epigenetics of Gynecological Cancer
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Genetics and Epigenetics of Gynecological Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 5525

Special Issue Editor

Dr. Carmela De Marco

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, “Magna Græcia” University of Catanzaro, 88100 Catanzaro, Italy
Interests: ovarian cancer; platinum drug resistance; cancer NGS; extracellular matrix; heparan sulphates

Special Issue Information

Dear Colleagues,

Gynecologic cancers are the most commonly diagnosed cancers in women, but their clinical management remains difficult. The great heterogeneity of these malignancies suggests that different pathogenetic mechanisms underlie their development, hampering the efficacy of therapeutic strategies. The identification of actionable genetic alterations in gynecologic cancers has not advanced much compared with other solid cancers, and survival rates have remained relatively unchanged over the past decade. Moreover, in recent years, it has become apparent that epigenetic alterations, in combination with or as an alternative to inherited genetic variations and acquired somatic gene mutations, can destabilize normal cellular control mechanisms, predisposing to or promoting cancer. Understanding the true balance between these two types of alterations in cancer cells will help improve diagnosis and therapy.

The goal of this Special Issue is to provide insights into the epigenetic and genetic alterations of cancer cells in gynecologic malignancies to gain further insight into the regulation of gene expression and to identify predictive biomarkers for response to tailored therapies.

In this Special Issue, original research articles and review papers are welcome. Research areas may cover a variety of topics, from identifying novel oncogenic drivers and epigenetic modifiers and characterizing their mechanisms to developing innovative diagnostic and therapeutic strategies. The use of advanced technologies is also encouraged (e.g., omics platforms, single-cell sequencing, liquid biopsy analysis, etc.).

I look forward to receiving your contributions.

Dr. Carmela De Marco
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gynecologic cancers
  • epigenetics
  • genetics
  • immunogenetics
  • predisposing mutations
  • biomarkers
  • targeted therapies
  • chemoresistance

Published Papers (6 papers)

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Research

17 pages, 1808 KiB  
Article
NGS-Guided Precision Oncology in Breast Cancer and Gynecological Tumors—A Retrospective Molecular Tumor Board Analysis
by Niklas Gremke, Fiona R. Rodepeter, Julia Teply-Szymanski, Sebastian Griewing, Jelena Boekhoff, Alina Stroh, Thomas S. Tarawneh, Jorge Riera-Knorrenschild, Christina Balser, Akira Hattesohl, Martin Middeke, Petra Ross, Anne-Sophie Litmeyer, Marcel Romey, Thorsten Stiewe, Thomas Wündisch, Andreas Neubauer, Carsten Denkert, Uwe Wagner and Elisabeth K. M. Mack
Cancers 2024, 16(8), 1561; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16081561 - 19 Apr 2024
Viewed by 410
Abstract
Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological [...] Read more.
Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological malignancies referred to our center’s MTB from 2018 to 2023. The analysis covered patient characteristics, next-generation sequencing (NGS) results, MTB recommendations, therapy received, and clinical outcomes. Results: Sixty-three patients (77.8%) had metastatic disease, and forty-four patients (54.3%) had previously undergone three or more lines of systemic treatment. Personalized treatment recommendations were provided to 50 patients (63.3%), while 29 (36.7%) had no actionable target. Ultimately, 23 patients (29.1%) underwent molecular-matched treatment (MMT). Commonly altered genes in patients with pan-gyn tumors (BC and gynecological malignancies) included TP53 (n = 42/81, 51.9%), PIK3CA (n = 18/81, 22.2%), BRCA1/2 (n = 10/81, 12.3%), and ARID1A (n = 9/81, 11.1%). Patients treated with MMT showed significantly prolonged progression-free survival (median PFS 5.5 vs. 3.5 months, p = 0.0014). Of all patients who underwent molecular profiling, 13.6% experienced a major clinical benefit (PFSr ≥ 1.3 and PR/SD ≥ 6 months) through precision oncology. Conclusions: NGS-guided precision oncology demonstrated improved clinical outcomes in a subgroup of patients with gynecological and breast cancers. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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14 pages, 1051 KiB  
Article
Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia–Telangiectasia Mutated Variant Carriers
by Rayan Bensenane, Arnaud Beddok, Fabienne Lesueur, Alain Fourquet, Mathilde Warcoin, Marine Le Mentec, Eve Cavaciuti, Dorothée Le Gal, Séverine Eon-Marchais, Nadine Andrieu, Dominique Stoppa-Lyonnet and Youlia Kirova
Cancers 2024, 16(7), 1417; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16071417 - 05 Apr 2024
Viewed by 559
Abstract
The Ataxia–Telangiectasia Mutated (ATM) gene is implicated in DNA double-strand break repair. Controversies in clinical radiosensitivity remain known for monoallelic carriers of the ATM pathogenic variant (PV). An evaluation of the single-nucleotide polymorphism (SNP) rs1801516 (G-A) showed different results regarding late subcutaneous fibrosis [...] Read more.
The Ataxia–Telangiectasia Mutated (ATM) gene is implicated in DNA double-strand break repair. Controversies in clinical radiosensitivity remain known for monoallelic carriers of the ATM pathogenic variant (PV). An evaluation of the single-nucleotide polymorphism (SNP) rs1801516 (G-A) showed different results regarding late subcutaneous fibrosis after breast radiation therapy (RT). The main objective of this study was to evaluate acute and late toxicities in carriers of a rare ATM PV or predicted PV and in carriers of minor allele A of rs1801516 facing breast RT. Fifty women with localized breast cancer treated with adjuvant RT between 2000 and 2014 at Institut Curie were selected. Acute and late toxicities in carriers of a rare PV or predicted PV (n= 9), in noncarriers (n = 41) and in carriers of SNP rs1801516 (G-A) (n = 8), were examined. The median age at diagnosis was 53 years old and 82% of patients had an invasive ductal carcinoma and 84% were at clinical stage I–IIB. With a median follow-up of 13 years, no significant difference between carriers and noncarriers was found for acute toxicities (p > 0.05). The same results were observed for late toxicities without an effect from the rs1801516 genotype on toxicities. No significant difference in acute or late toxicities was observed between rare ATM variant carriers and noncarriers after breast RT for localized breast cancer. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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19 pages, 523 KiB  
Article
Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome
by Pavlina Chrysafi, Chinmay T. Jani, Margaret Lotz, Omar Al Omari, Harpreet Singh, Katherine Stafford, Lipisha Agarwal, Arashdeep Rupal, Abdul Qadir Dar, Abby Dangelo and Prudence Lam
Cancers 2023, 15(24), 5762; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15245762 - 08 Dec 2023
Viewed by 1269
Abstract
Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic [...] Read more.
Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18–80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (p-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08–2.25; family breast: OR: 1.68; CI: 1.08–2.60, family ovarian OR: 2.29; CI: 1.04–5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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16 pages, 2841 KiB  
Article
Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair
by Juliana Calheiros, Liliana Raimundo, João Morais, Ana Catarina Matos, Sonia Anna Minuzzo, Stefano Indraccolo, Emília Sousa, Marta Correia da Silva and Lucília Saraiva
Cancers 2023, 15(24), 5718; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15245718 - 06 Dec 2023
Cited by 1 | Viewed by 938
Abstract
Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. [...] Read more.
Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. The xanthonoside XGAc was previously described as a potent inhibitor of cancer cell growth. Herein, we explored its antitumor activity against triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC) cells as a single agent and in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. We demonstrated that XGAc inhibited the growth of TNBC, ovarian and PDAC cells by inducing cell cycle arrest and apoptosis. XGAc also induced genotoxicity, inhibiting the expression of DNA repair proteins particularly involved in homologous recombination, including BRCA1, BRCA2 and RAD51. Moreover, it displayed potent synergistic effects with olaparib in TNBC, ovarian cancer and PDAC cells. Importantly, this growth inhibitory activity of XGAc was further reinforced in a TNBC spheroid model and in patient-derived ovarian cancer cells. Also, drug-resistant cancer cells showed no cross-resistance to XGAc. Additionally, the ability of XGAc to prevent cancer cell migration was evidenced in TNBC, ovarian cancer and PDAC cells. Altogether, these results highlight the great potential of acetylated xanthonosides such as XGAc as promising anticancer agents against hard-to-treat cancers. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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16 pages, 1383 KiB  
Article
Associations between Single Nucleotide Polymorphisms from the Genes of Chemokines and the CXCR2 Chemokine Receptor and an Increased Risk of Endometrial Cancer
by Wioletta Izabela Wujcicka, Agnieszka Zając, Krzysztof Szyłło, Hanna Romanowicz, Beata Smolarz and Grzegorz Stachowiak
Cancers 2023, 15(22), 5416; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15225416 - 14 Nov 2023
Viewed by 886
Abstract
Significant relationships with endometrial cancer were demonstrated, both for CCL2, CCL5, and CXCL8 chemokines and for the chemokine receptor CXCR2. The reported case-control study of genetic associations was designed to establish the role of selected single nucleotide polymorphisms (SNPs) of [...] Read more.
Significant relationships with endometrial cancer were demonstrated, both for CCL2, CCL5, and CXCL8 chemokines and for the chemokine receptor CXCR2. The reported case-control study of genetic associations was designed to establish the role of selected single nucleotide polymorphisms (SNPs) of the CCL2, CCL5, CXCL8, and CXCR2 genes in the onset and progression of endometrial cancer. This study was conducted on 282 women, including 132 (46.8%) patients with endometrial cancer and 150 (53.2%) non-cancerous controls. The genotypes for CCL2 rs4586, CCL5 rs2107538 and rs2280789, CXCL8 rs2227532 and −738 T>A, and CXCR2 rs1126580 were determined, using PCR-RFLP assays. The AA homozygotes in CCL5 rs2107538 were associated with more than a quadruple risk of endometrial cancer (p ≤ 0.050). The GA heterozygotes in the CXCR2 SNP were associated with approximately threefold higher cancer risk (p ≤ 0.001). That association also remained significant after certain adjustments, carried out for age, diabetes mellitus, arterial hypertension, or endometrial thickness above 5 mm (p ≤ 0.050). The A-A haplotypes for the CCL5 polymorphisms and T-A-A haplotypes for the CCL2 and CCL5 SNPs were associated with about a twofold risk of endometrial cancer (p ≤ 0.050). In conclusion, CCL2 rs4586, CCL5 rs2107538 and rs2280789, and CXCR2 rs1126580 demonstrated significant associations with an increased risk of endometrial cancer. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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9 pages, 397 KiB  
Article
MLH1 Methylation Testing as an Integral Component of Universal Endometrial Cancer Screening—A Critical Appraisal
by Anna Plotkin, Ekaterina Olkhov-Mitsel and Sharon Nofech-Mozes
Cancers 2023, 15(21), 5188; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15215188 - 28 Oct 2023
Viewed by 1113
Abstract
MLH1/PMS2 loss due to MLH1 promoter hypermethylation (MLH1-PHM) is the most common cause of mismatch repair (MMR) deficiency in endometrial cancer (EC). This study aimed to determine the proportion of MLH1-deficient EC with PHM, assess the impact of the reflex [...] Read more.
MLH1/PMS2 loss due to MLH1 promoter hypermethylation (MLH1-PHM) is the most common cause of mismatch repair (MMR) deficiency in endometrial cancer (EC). This study aimed to determine the proportion of MLH1-deficient EC with PHM, assess the impact of the reflex MLH1-PHM testing strategy, and evaluate the associated costs within the publicly funded Canadian healthcare system. In a cohort of 2504 EC samples, 534 (21.4%) exhibited dual MLH1/PMS2 loss, prompting MLH1-PHM testing. Among 418 cases with available testing results, 404 (96.7%) were MLH1-hypermethylated, while 14 (3.3%) were non-methylated. The incidence of MLH1 non-methylated cases in our cohort was 14/2504 (0.56%) of all ECs, underscoring the prevalence of hypermethylation-driven MLH1/PMS2 loss in ECs universally screened for MMR deficiency. Reflex MLH1-PHM testing incurs substantial costs and resource utilization. Assay cost is CAD 231.90 per case, amounting to CAD 123,834.60 for 534 cases, with 30 tests needed per additional candidate for MLH1 germline analysis (CAD 6957.00 per candidate). This raises a provocative question: can we assume that the majority of the MLH1-deficient ECs are due to PHM and forgo further testing in healthcare systems with finite resources? It is imperative to assess resource utilization efficiency and explore optimized approaches that encompass clinical correlation, family history and judicious utilization of methylation testing to ensure it is provided only to those who stand to benefit from it. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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