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24 pages, 1459 KB

Open AccessArticle

Genomic Predictors of Platinum Resistance and Survival in High-Grade Serous Ovarian Carcinoma: Insights from an Explorative Targeted Next-Generation Sequencing Analysis

by Carmela De Marco, Valentina Rocca, Simona Migliozzi, Claudia Veneziano, Francesca Gualtieri, Annamaria Cerantonio, Tahreem Arshad Butt, Gianluca Santamaria, Maria Teresa De Angelis, Annalisa Di Cello, Roberta Venturella, Fulvio Zullo and Giuseppe Viglietto

Cancers 2026, 18(9), 1390; https://doi.org/10.3390/cancers18091390 - 28 Apr 2026

Abstract

Background: High-grade serous ovarian carcinoma (HG-SOC) remains the most lethal gynecological malignancy, largely due to intrinsic or acquired resistance to platinum-based chemotherapy. Although large-scale sequencing studies have delineated the genomic landscape of HG-SOC, clinically actionable biomarkers predictive of platinum response and outcome are [...] Read more.

Background: High-grade serous ovarian carcinoma (HG-SOC) remains the most lethal gynecological malignancy, largely due to intrinsic or acquired resistance to platinum-based chemotherapy. Although large-scale sequencing studies have delineated the genomic landscape of HG-SOC, clinically actionable biomarkers predictive of platinum response and outcome are still lacking. This study aimed to identify genomic alterations associated with platinum sensitivity, resistance, or refractoriness, and to assess their prognostic relevance. Methods: Tumor DNA from 24 HG-SOC patients with optimal cytoreductive resection, classified as platinum-sensitive (n = 9), platinum-resistant (n = 8), or platinum-refractory (n = 7) underwent targeted next-generation sequencing of 409 cancer-associated genes. Somatic variants were filtered and classified for oncogenicity using established criteria incorporating predicted functional impact, REVEL scores, and population allele frequencies. Associations between mutational profiles, platinum response, and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Key findings were validated in the TCGA ovarian serous carcinoma (TCGA-OV) dataset using survival analyses. Results: A total of 1367 protein-altering somatic variants across 301 genes were identified. While TP53 mutations were ubiquitous, platinum-resistant and platinum-refractory tumors showed enrichment of pathogenic alterations affecting DNA repair, transcriptional regulation, epigenetic modification, and oncogenic signaling, including FANCA, ATF1, MAF, NCOA2, PIK3CA, and TET1. Mutations in these genes were associated with reduced overall survival in exploratory analyses (median 2.5–9 months vs. 27.5–45 months). Multivariate analysis identified FANCA and ATF1 as potential independent predictors in exploratory modeling. In the TCGA-OV cohort, patients harboring pathogenic variants in a multi-gene panel derived from this study (excluding BRCA1/2) exhibited significantly worse survival compared with both BRCA1/2-mutated cases and the overall cohort. Conclusions: This exploratory study identifies a set of genomic alterations converging on transcriptional and epigenetic regulation, DNA repair, and oncogenic signaling that are associated with platinum resistance and adverse prognosis in HG-SOC. Independent validation in TCGA supports the potential clinical relevance of this mutational signature. These findings warrant further validation in larger prospective cohorts and functional studies to clarify their role as biomarkers of aggressive disease and therapeutic vulnerability. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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17 pages, 3397 KB

Open AccessArticle

Identification of the Carcinogenic Process from Lobular Endocervical Glandular Hyperplasia to Gastric-Type Adenocarcinoma of the Uterine Cervix via Whole-Exome Sequencing

by Airi Kuruma, Tatsuo Masuda, Kazuaki Sato, Kansuke Kido, Daisuke Motooka, Naoko Komura, Takeshi Yokoi, Kosuke Yoshihara, Yasuto Kinose, Kae Hashimoto, Kenjiro Sawada, Eiichi Morii, Tadashi Kimura and Michiko Kodama

Cancers 2026, 18(4), 651; https://doi.org/10.3390/cancers18040651 - 17 Feb 2026

Viewed by 565

Abstract

Background: Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare malignancy with poor clinical outcomes. However, the carcinogenic processes involved remain unclear. Methods: Normal cervical glands, lobular endocervical glandular hyperplasia (LEGH), and GAS from the same patients were collected using [...] Read more.

Background: Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare malignancy with poor clinical outcomes. However, the carcinogenic processes involved remain unclear. Methods: Normal cervical glands, lobular endocervical glandular hyperplasia (LEGH), and GAS from the same patients were collected using laser microdissection for whole-exome sequencing. Single nucleotide variants (SNVs) and copy number alterations (CNAs) were analyzed. Phylogenetic trees were constructed based on the SNV and CNA profiles. Results: Analysis of seven matched samples demonstrated higher frequency of somatic mutations in the exonic regions in GAS than in LEGH. CNAs were prevalent in GAS but rare in LEGH. The phylogenetic analyses revealed various branching patterns. However, in three cases, the data suggested a sequential transition from LEGH to GAS, potentially associated with mutations in receptor-type protein tyrosine phosphatases such as PTPRF and PTPRT. STK11 and ARID1A mutations were present in LEGH, with an increased variant allele frequency observed in GAS. In contrast, SMAD4 and SMAD2 showed frequent loss-of-function–type alterations in GAS, including copy-number loss, but were not detected in LEGH. Conclusions: These findings provide insights into the genomic landscapes of LEGH and GAS and suggest potential molecular markers for this transition, which may inform future diagnostic and therapeutic research. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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35 pages, 5516 KB

Open AccessArticle

Synergistic Antitumor Activity of Curcumin and the PARP1 Inhibitor PJ34 in Platinum-Sensitive and Resistant Ovarian Cancer Cells

by Aşkın Evren Güler, Mehmet Cudi Tuncer and İlhan Özdemir

Cancers 2026, 18(4), 620; https://doi.org/10.3390/cancers18040620 - 13 Feb 2026

Viewed by 671

Abstract

Background/Objectives: Ovarian cancer remains a highly lethal malignancy, largely due to the development of therapeutic resistance, particularly in advanced disease. Combination strategies targeting complementary molecular pathways may enhance antitumor efficacy and help overcome resistance. The present study aimed to systematically evaluate the anticancer [...] Read more.

Background/Objectives: Ovarian cancer remains a highly lethal malignancy, largely due to the development of therapeutic resistance, particularly in advanced disease. Combination strategies targeting complementary molecular pathways may enhance antitumor efficacy and help overcome resistance. The present study aimed to systematically evaluate the anticancer effects of the PARP1 inhibitor PJ34 and the natural polyphenol curcumin, administered alone and in combination, in platinum-sensitive and relatively platinum-resistant ovarian cancer models, with an emphasis on quantitative synergy assessment and functionally supported, hypothesis-generating mechanistic insight. Materials and Methods: Cell viability was evaluated using the MTT assay, and IC₅₀ values were derived from dose–response curves. Drug interactions were quantitatively analyzed using the Chou–Talalay method, including combination index (CI) and dose reduction index (DRI) calculations. Intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA-based assays. Cell migration was assessed using scratch-wound assays. Apoptosis was evaluated using Annexin V/PI flow cytometry, caspase-3 activity assays, and quantitative real-time PCR (RT-qPCR) analysis of apoptosis-related genes (Bax, Bcl-2, Caspase-3, Caspase-9, and p53). To further validate the findings under physiologically relevant conditions, three-dimensional (3D) tumor spheroid models were employed, and ROS involvement was functionally interrogated using N-acetyl-L-cysteine (NAC) rescue experiments to assess ROS-associated contributions rather than direct causality. Results: PJ34 and curcumin each reduced cell viability in a dose-dependent manner, whereas their combination produced a synergistic antiproliferative effect with reduced IC₅₀ values. Synergism was particularly pronounced in relatively platinum-resistant SKOV-3 cells. Combination treatment significantly enhanced regulated apoptotic cell death, as demonstrated by increased apoptotic fractions, elevated caspase-3 activity, and an increased Bax/Bcl-2 ratio, with minimal necrosis. While PJ34 moderately increased intracellular ROS levels and curcumin reduced oxidative stress, the combination was associated with the normalization of ROS levels to near-control values. In 3D tumor spheroid models, combined treatment induced marked spheroid shrinkage, loss of structural integrity, and reduced viability, indicating a preservation of synergistic cytotoxic effects beyond two-dimensional (2D) conditions. NAC pretreatment partially attenuated, but did not fully rescue, the cytotoxic effects of the combination, indicating a ROS-associated, but not exclusively ROS-dependent, mechanism of action. In addition, the combination markedly inhibited cell migration in both ovarian cancer cell lines. Conclusions: This preclinical provides evidence that combined PARP1 inhibition and curcumin treatment can exert synergistic antitumor effects in ovarian cancer models, including relatively platinum-resistant disease, through the coordinated suppression of proliferation, induction of regulated apoptosis, and inhibition of migration. The integration of quantitative synergy analysis, 3D spheroid validation, and ROS-rescue experiments provides functionally supported, hypothesis-generating mechanistic insight and supports further evaluation of PARP inhibitor–curcumin combinations as a mechanistic proof-of-concept in advanced preclinical models. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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26 pages, 4060 KB

Open AccessArticle

A Validated Proteomic Signature of Basal-like Triple-Negative Breast Cancer Subtypes Obtained from Publicly Available Data

by Cristina Furlan, Maria Suarez-Diez and Edoardo Saccenti

Cancers 2025, 17(16), 2601; https://doi.org/10.3390/cancers17162601 - 8 Aug 2025

Cited by 1 | Viewed by 2392

Abstract

Background: Basal-like breast cancer (BLBC) is a highly aggressive molecular subtype characterized by the strong expression of a gene cluster found in the basal or outer epithelial layer of the adult mammary gland. Patients with BLBC typically face a poor prognosis, with a [...] Read more.

Background: Basal-like breast cancer (BLBC) is a highly aggressive molecular subtype characterized by the strong expression of a gene cluster found in the basal or outer epithelial layer of the adult mammary gland. Patients with BLBC typically face a poor prognosis, with a shorter disease-free period and overall survival. Methods: In this study, we explored the proteomic profiles of BLBC patients using publicly available data from two large cohorts of breast cancer patients. By integrating cluster analysis, predictive modeling, protein differential abundance expression, and network analysis, we identified and validated the presence of two distinct subgroups, characterized by 256 upregulated and 99 downregulated proteins. Results: We report the upregulation of spliceosome components, especially SNRPG and its partners (BUD13, CWC15, SNRNP70, ZMAT12), indicating altered splicing activity between TNBC subgroups. Collagen proteins (COL1A1, COL1A2, COL3A1, COL11A1) were associated with tumor progression and metastasis. Proteins in the CCT complex and microtubule-associated proteins (TUBA1C, TUBB) were linked to cytoskeletal structure and chemotherapy resistance. Aminoacyl-tRNA synthetases (DARS1, IARS1, KARS1) may also play a role in TNBC development. Conclusions: These findings suggest the existence of novel molecular signatures that could improve TNBC classification, prognosis, and potential therapeutic targeting. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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17 pages, 1808 KB

Open AccessArticle

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://doi.org/10.3390/cancers16081561 - 19 Apr 2024

Cited by 12 | Viewed by 3783

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 KB

Open AccessArticle

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://doi.org/10.3390/cancers16071417 - 5 Apr 2024

Cited by 5 | Viewed by 3508

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 KB

Open AccessArticle

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://doi.org/10.3390/cancers15245762 - 8 Dec 2023

Cited by 9 | Viewed by 4906

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 KB

Open AccessArticle

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://doi.org/10.3390/cancers15245718 - 6 Dec 2023

Cited by 2 | Viewed by 2672

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 KB

Open AccessArticle

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://doi.org/10.3390/cancers15225416 - 14 Nov 2023

Cited by 5 | Viewed by 1938

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 KB

Open AccessArticle

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://doi.org/10.3390/cancers15215188 - 28 Oct 2023

Cited by 4 | Viewed by 3715

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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Review

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44 pages, 2570 KB

Open AccessReview

The Underlying Mechanisms and Emerging Strategies to Overcome Resistance in Breast Cancer

by Krishnaswamy Kannan, Alagarsamy Srinivasan, Aarthi Kannan and Nawab Ali

Cancers 2025, 17(17), 2938; https://doi.org/10.3390/cancers17172938 - 8 Sep 2025

Cited by 11 | Viewed by 7368

Abstract

Despite advances in early detection and targeted therapies, breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide. Resistance develops through the interplay of tumor-intrinsic heterogeneity and tumor-extrinsic influences, including the tumor microenvironment and immune–metabolic interactions. This complexity drives therapeutic [...] Read more.

Despite advances in early detection and targeted therapies, breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide. Resistance develops through the interplay of tumor-intrinsic heterogeneity and tumor-extrinsic influences, including the tumor microenvironment and immune–metabolic interactions. This complexity drives therapeutic evasion, metastatic progression, and poor outcomes. Resistance mechanisms include drug efflux, genetic mutations, and altered signaling pathways. Additional contributors are cancer stem cell plasticity, exosomal RNA transfer, stromal remodeling, epigenetic alterations, and metabolic reprogramming. Microbial influences and immune evasion further reduce treatment effectiveness. Collectively, these processes converge on regulated cell death (RCD) pathways—apoptosis, ferroptosis, and pyroptosis—where metabolic shifts and immune suppression recalibrate cell death thresholds. Nutrient competition, hypoxia-driven signaling, and lactate accumulation weaken antitumor immunity and reinforce resistance niches. In this review, we synthesize the genetic, metabolic, epigenetic, immunological, and microenvironmental drivers of BC resistance within a unified framework. We highlight the convergence of these mechanisms on RCD and immune–metabolic signaling as central principles. Artificial intelligence (AI) is emphasized as a cross-cutting connector that links major domains of resistance biology. AI supports early detection through ctDNA and imaging, predicts efflux- and mutation-driven resistance, models apoptotic and ferroptotic vulnerabilities, and stratifies high-risk patients such as TNBC patients. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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19 pages, 1339 KB

Open AccessReview

The Tumour Microenvironment and Epigenetic Regulation in BRCA1 Pathogenic Variant-Associated Breast Cancers

by Jun Yu Tay, Josh Xingchong Ho, Fan Foon Cheo and Jabed Iqbal

Cancers 2024, 16(23), 3910; https://doi.org/10.3390/cancers16233910 - 21 Nov 2024

Cited by 7 | Viewed by 2563

Abstract

Background/Objectives: BRCA1 pathogenic variant (PV)-associated breast cancers are most commonly seen in hereditary genetic conditions such as the autosomal-dominant Hereditary Breast and Ovarian Cancer (HBOC) syndrome, and rarely in sporadic breast cancer. Such breast cancers tend to exhibit greater aggressiveness and poorer [...] Read more.

Background/Objectives: BRCA1 pathogenic variant (PV)-associated breast cancers are most commonly seen in hereditary genetic conditions such as the autosomal-dominant Hereditary Breast and Ovarian Cancer (HBOC) syndrome, and rarely in sporadic breast cancer. Such breast cancers tend to exhibit greater aggressiveness and poorer prognoses due to the influence of BRCA1 pathogenic variants (PVs) on the tumour microenvironment. Additionally, while the genetic basis of BRCA1 PV breast cancer is well-studied, the role of epigenetic mediators in the tumourigenesis of these hereditary breast cancers is also worth exploring. Results: PVs in the BRCA1 gene interact with stromal cells and immune cells, promoting epithelial–mesenchymal transition, angiogenesis, and affecting oestrogen levels. Additionally, BRCA1 PVs contribute to breast cancer development through epigenetic effects on cells, including DNA methylation and histone acetylation, leading to the suppression of proto-oncogenes and dysregulation of cytokines. In terms of epigenetics, lysine-specific demethylase 1 (LSD-1) is considered a master epigenetic regulator, governing both transcriptional repression and activation. It exerts epigenetic control over BRCA1 and, to a lesser extent, BRCA2 genes. The upregulation of LSD-1 is generally associated with a poorer prognosis in cancer patients. In the context of breast cancer in BRCA1/2 PV carriers, LSD-1 contributes to tumour development through various mechanisms. These include the maintenance of a hypoxic environment and direct suppression of BRCA1 gene expression. Conclusions: While LSD-1 itself does not directly cause mutations in BRCA1 or BRCA2 genes, its epigenetic influence sheds light on the potential role of LSD-1 inhibitors as a therapeutic approach in managing breast cancer, particularly in individuals with BRCA1/2 PVs. Targeting LSD-1 may help counteract its detrimental effects and provide a promising avenue for therapy in this specific subgroup of breast cancer. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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12 pages, 911 KB

Open AccessEditor’s ChoiceReview

The Role of Circulating Tumor DNA in Ovarian Cancer

by Anna Golara, Mateusz Kozłowski and Aneta Cymbaluk-Płoska

Cancers 2024, 16(18), 3117; https://doi.org/10.3390/cancers16183117 - 10 Sep 2024

Cited by 7 | Viewed by 3201

Abstract

Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options [...] Read more.

Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options available to individuals with ovarian cancer, depending on the disease’s stage. Tumor DNA that circulates in a patient’s bodily fluids has been studied recently as a possible novel biomarker for a number of cancers, as well as a means of quantifying tumor size and evaluating the efficacy of cancer therapy. The most significant alterations that we could find in the ctDNA of ovarian cancer patients—such as chromosomal instability, somatic mutations, and methylation—are discussed in this review. Additionally, we talk about the utility of ctDNA in diagnosis, prognosis, and therapy response prediction for these patients. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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