Environmental and Molecular Mutagenesis最新文献

{"title":"A Hybrid Machine Learning Ensemble for Predicting Genetic Predisposition to Lung Cancer Based on Polymorphisms in the Mismatch DNA Repair Genes","authors":"Abhay Bagla,&nbsp;Sidhartha Singh,&nbsp;Heena Kansal,&nbsp;Anup Kumar Gupta,&nbsp;Siddharth Sharma,&nbsp;Puneet Gupta,&nbsp;Vivek Gupta","doi":"10.1002/em.70083","DOIUrl":"10.1002/em.70083","url":null,"abstract":"<div>\u0000 \u0000 <p>The application of machine learning approaches has shown promising results in cancer prediction. In the present study, data for nine gene-based features that include <i>MLH1</i> (rs1800734), <i>MSH3</i> (rs26279), <i>MSH6</i> (rs3136228), and several variants within <i>MSH2</i> (rs2303423, rs4987188, rs17217772, rs63749993, rs2303426, and rs2303428), along with four additional features (Age, Gender, Smoking, and Pack Years) were used as input to develop a predictive model for assessing individual susceptibility to lung cancer. NumPy, Pandas, Scikit-learn, and Matplotlib were major libraries used during the modeling process. The models included CatBoost, XGBoost, gradient boosting, random forest, support vector machine (SVM), K-nearest neighbors (KNN), Gaussian Naive Bayes, and logistic regression, with their performance evaluated using stratified 5-fold cross-validation. The highest accuracy in predicting cancer predisposition was achieved by CatBoost (0.831 ± 0.014), with Pack Years (27.94%), Age (10.75%), and MLH1 (9.97%) as the major predictors. Precision, recall, and <i>F</i>1-score were also used to assess performance, and all were within the range of 0.83–0.84. The models were further tested for performance across histological subtypes, gender, and smoking status. Gradient Boosting (0.868 ± 0.028) and Random Forest (0.902 ± 0.020) yielded the highest accuracy as histological subtype classifiers in ADCC and SCLC, respectively. When modeled using sex-stratified and smoking-status-specific models, the ensemble methods significantly outperformed logistic regression and Gaussian Naive Bayes, with MMR gene variants (<i>MLH1</i>, <i>MSH2</i>) emerging as key modulators of histology and risk stratification. This highlights the potential of ensemble methods to bridge the gap between genetic epidemiology and molecular pathology, enabling more accurate risk assessment.</p>\u0000 </div>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 8-9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Serum Per- and Polyfluoroalkyl Substances (PFAS) With Epigenetic Age and DNA Methylation in US Airport Firefighters","authors":"Lauren M. Ward,&nbsp;Jaclyn M. Goodrich,&nbsp;Miriam M. Calkins,&nbsp;Shawn C. Beitel,&nbsp;Antonia M. Calafat,&nbsp;Alberto J. Caban-Martinez,&nbsp;Paola Louzado-Feliciano,&nbsp;Julianne Cook Botelho,&nbsp;Melissa Furlong,&nbsp;Randy Krause,&nbsp;Rob Matthis,&nbsp;Jeff Hughes,&nbsp;Jefferey L. Burgess","doi":"10.1002/em.70085","DOIUrl":"https://doi.org/10.1002/em.70085","url":null,"abstract":"<p>Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in a variety of consumer and industrial applications for their water- and oil-resistant properties. Firefighters can be exposed to PFAS as part of their job through gear, aqueous film-forming foams (AFFFs) used to extinguish aircraft and liquid fuel fires, along with exposure through other combustible materials during fire suppression activities. PFAS exposure has been linked to a variety of health conditions including cancer, obesity, reproductive issues, and immunosuppression. Epigenetic modifications may be one mechanism underlying PFAS toxicity. In this study, we used epigenetic indicators to assess association of PFAS serum concentrations with (1) epigenetic aging and (2) DNA methylation at loci within genes related to immune function. Blood leukocyte DNA methylation was quantified via the Infinium EPIC array from 184 participants in the Fire Fighter Cancer Cohort Study involved in aircraft rescue and firefighting, and serum PFAS was measured via on-line solid phase extraction liquid chromatography isotope dilution tandem mass spectrometry. We observed inverse associations between PFAS concentrations and epigenetic clocks including between serum linear perfluorooctanoic acid (n-PFOA) with four epigenetic clocks (<i>p</i> &lt; 0.05); however, most did not remain significant in sensitivity analyses. Associations (<i>q</i> &lt; 0.1) were observed between perfluorodecanoic acid, n-PFOA, sum of branched perfluorooctane sulfonic acid isomers and differential methylation of specific loci within 34 immune-related genes. Further research can help to better understand the functional impacts of the observed differential methylation on immune health.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 8-9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trp53 Deficiency Increases the Frequency of Hprt Mutant T Lymphocytes Following High-LET Iron Particle Irradiation of Mice","authors":"Vernon E. Walker,&nbsp;Dale M. Walker,&nbsp;Vasily N. Dobrovolsky,&nbsp;Louise Lutze-Mann","doi":"10.1002/em.70084","DOIUrl":"10.1002/em.70084","url":null,"abstract":"<p>Charged particles like iron-56 ions impose health risks in long-term manned space exploration. This study was designed to define the impact of <i>Trp53</i> status upon the manifestation of mutations in the <i>hypoxanthine-guanine phosphoribosyltransferase</i> (<i>Hprt</i>) gene in splenic T-cells following exposure of <i>Trp53</i> wild-type, hemizygous, and nullizygous <i>lacZ</i> transgenic mice to 1 Gy ⁵⁶Fe particles. In male and female mice necropsied at 2, 4, and 8 weeks postexposure, <i>Hprt</i> mutant frequencies in splenic T-cells (measured via the <i>Hprt</i> mutation cloning assay) increased significantly over time to peak at 4 weeks postexposure before decreasing to lower but still elevated levels. Mutagenic potency estimates based upon the change in mutant frequency over time in exposed versus respective control groups showed that the total mutagenic response depended upon the <i>Trp53</i> genetic status, with the mutagenic burden of 1 Gy being threefold and 5.3-fold greater in <i>Trp53</i>^+/− and <i>Trp53</i>^−/− mice, respectively, compared to <i>Trp53</i>^+/+ mice.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 8-9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Damage and Micronucleus Induction by Small-Molecule Nitrosamine Drug Impurities and Nitrosamine Drug Substance-Related Impurities in HepaRG Cells","authors":"Hannah S. Xu,&nbsp;Ji-Eun Seo,&nbsp;Xilin Li,&nbsp;Nan Mei,&nbsp;Aisar H. Atrakchi,&nbsp;Karen L. Davis Bruno,&nbsp;Sruthi T. King,&nbsp;Robert T. Dorsam,&nbsp;Naomi L. Kruhlak,&nbsp;Kelly Brant,&nbsp;Robert H. Heflich,&nbsp;Xiaoqing Guo","doi":"10.1002/em.70082","DOIUrl":"10.1002/em.70082","url":null,"abstract":"<div>\u0000 \u0000 <p>Nitrosamine drug impurities, including both small-molecule nitrosamines and nitrosamine drug substance-related impurities (NDSRIs), are members of a cohort of concern for pharmaceutical safety assessment. As the toxicity of most nitrosamine impurities requires metabolic activation by cytochrome P450 enzymes, this study used human HepaRG cells, which have metabolic activity similar to that of human hepatic cells, to evaluate methods for nitrosamine safety assessment. The genotoxicity of four small-molecule nitrosamines, <i>N-</i>bis(2,2-diethoxyethyl) nitrous amide (BDEA), <i>N</i>-nitrosodiphenylamine, <i>N,N</i>-nitroso-<i>N</i>-ethylaniline (NEPA), and 1-methyl-4-nitrosopiperazine (MNP), and five NDSRIs, <i>N</i>-nitroso-bumetanide, <i>N</i>-nitroso-ciprofloxacin, <i>N</i>-nitroso-dabigatran etexilate, <i>N</i>-nitroso-desmethyl-diphenhydramine, and <i>N</i>-nitroso-sertraline, was evaluated in two-dimensional (2D)/attached and three-dimensional (3D)/spheroid HepaRG cell cultures using two high-throughput genetic toxicity assays, the CometChip DNA damage assay and the flow-cytometric micronucleus (MN) assay. These test substances exhibited a range of responses in other genotoxicity assays, including strong positive, negative, and inconclusive results. Following a 24-h treatment, two NDSRIs, <i>N</i>-nitroso-desmethyl-diphenhydramine and <i>N</i>-nitroso-sertraline, and two small-molecule nitrosamines, BDEA and MNP, induced DNA damage, with the small-molecule nitrosamines positive only in 3D HepaRG spheroids. MN formation was detected only in spheroids exposed to <i>N</i>-nitroso-desmethyl-diphenhydramine. Benchmark concentration (BMC) values derived from the DNA damage data were lower for the genotoxic NDSRIs compared to the genotoxic small-molecule nitrosamines, which correlated with higher cytotoxicity for the NDSRIs. These results show that, while HepaRG spheroids were a more sensitive model for the hazard identification of small-molecule nitrosamines, the responses produced by NDSRIs were more complex, with NDSRIs tested producing similar levels of DNA damage in 2D and 3D cultures and inducing MN formation only in 3D spheroids.</p>\u0000 </div>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 8-9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of the Genotoxic Potential of Three Microcystin Variants (-LR, -RR, and -LF) by High Content Analysis and Micronucleus Assay in a Human Hepatic Cell Line","authors":"Rym Merabet,&nbsp;Sylvie Huet,&nbsp;Rachelle Lanceleur,&nbsp;Ludovic Le Hégarat,&nbsp;Djamel-Eddine Benouareth,&nbsp;Valérie Fessard,&nbsp;Kevin Hogeveen","doi":"10.1002/em.70081","DOIUrl":"10.1002/em.70081","url":null,"abstract":"<div>\u0000 \u0000 <p>Microcystins (MCs) are cyclic hepatotoxins produced by various species of cyanobacteria that inhibit serine/threonine protein phosphatases. Their structure includes two variable amino acids, leading to 329 variants. MC-LR was considered the most toxic variant and has been extensively investigated, other variants, differing in hydrophobicity, could possess unique behavior and toxicity. The aim of the current study was to compare the toxicity and genotoxicity of 3 MC variants (MC-LR, -RR and -LF), in human liver HepaRG cells. Both undifferentiated and differentiated HepaRG cells were treated for 24 h with concentrations up to 50 μM for MC-LR and -RR and up to 6.25 μM for MC-LF. Using a high content analysis-based approach, cell count and apoptosis (active caspase-3) were quantified, in addition to three markers of DNA damage: γH2AX, p53 phospho S15 and ATM phospho S1981. A significant increase in all these markers was observed in differentiated HepaRG cells, correlating with the onset of cytotoxicity. The potency of the three variants to induce micronuclei (MN) was further assessed in differentiated HepaRG cells after 24 h of exposure to concentrations up to 25 μM, revealing a concentration-dependent increase with all variants. The responses in HepaRG cells treated with MC-LF were consistently observed at lower concentrations compared to MC-LR and MC-RR across all endpoints investigated, including micronucleus formation and DNA damage markers. An increase of pH 3 staining was also observed with the 3 variants, suggesting an aneugenic effect. The higher in vitro genotoxic potency of MC-LF compared to MC-LR needs to be confirmed in vivo.</p>\u0000 </div>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 8-9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silymarin Protects Against Daunorubicin-Induced DNA Damage in an In Vivo Comet Assay","authors":"Muhammad Mustafa,&nbsp;Aiman Tariq,&nbsp;Muhammad Khisroon,&nbsp;Aiman Mehroon,&nbsp;Aaliya Saleem,&nbsp;Bushra Arshad","doi":"10.1002/em.70080","DOIUrl":"https://doi.org/10.1002/em.70080","url":null,"abstract":"<div>\u0000 \u0000 <p>Daunorubicin is an anthracycline chemotherapy drug that is active against leukemias but has significant effects on normal cells, leading to long-term toxicity. The flavanolignan silymarin, which is extracted from milk thistle, has well-known antioxidant and cytoprotective effects. This study examined the protective activity of silymarin against daunorubicin-induced primary damage to DNA in lymphocytes of rats. Adult Wistar rats were divided into four groups and administered silymarin by oral gavage and daunorubicin by a single intraperitoneal injection. Isolation of peripheral-blood lymphocytes was followed by alkaline single-cell gel electrophoresis (comet assay). The amount of DNA damage was determined as the percentage of DNA in the comet tail and was analyzed at the animal level using parametric and nonparametric statistics. DNA migration was extensive when treated with daunorubicin. The administration of silymarin in combination significantly reduced this damage, and it changed the profile of cellular damage from extreme to mostly moderate. There was no significant increase in DN damage in animals given silymarin. Silymarin has a clear antigenotoxic effect in vivo in the presence of daunorubicin, and it could be a useful chemoprotective adjuvant.</p>\u0000 </div>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 8-9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parental Tetracycline Exposure Induces Genotoxic Damage and Fitness Deficits in Daphnia magna Offspring","authors":"Buse Ceyda Öncel,&nbsp;Çiğdem Akın Pekşen,&nbsp;Beste Tunca,&nbsp;Zeynep Kavasoğlu,&nbsp;Özlem Darcansoy İşeri","doi":"10.1002/em.70077","DOIUrl":"https://doi.org/10.1002/em.70077","url":null,"abstract":"<p>Antibiotics contaminating aquatic environments is a challenge for the ONE Health initiative as it poses a risk to biodiversity. Tetracyclines are toxic to a wide range of organisms. The objective of this study was to assess the growth, individual fitness and DNA damage following a short-term exposure to tetracycline in <i>Daphnia magna</i>. Additionally, the long-term effects of DNA damage on population growth rate and individual fitness parameters in the offspring for intergenerations were evaluated. The results indicated that <i>D. magna</i> has a significant effect on tetracycline-induced fertility impairment, resulting in reduced survival and reproductive capacity of the parental groups and impaired growth and development of the offspring. Furthermore, tetracycline treatment resulted in a significant reduction in individual fitness, as evidenced by the significant reduction in maximum body length of <i>D. magna</i> in both tetracycline-exposed generations. <i>D. magna</i> was exposed to concentrations of 25, 50, 100, 200, and 400 mg/L for periods of 24–72 h, with the objective of determining the concentrations that would not be lethal and yet would induce DNA damage. Tetracycline concentrations of 50 and 25 mg/L did not result in excessive levels of cytotoxicity within 72 h. P, F1, and F1 offspring born between 48 and 72 h were tested for DNA damage. <i>D. magna</i> appears to recover from DNA damage, but concerns have been raised about using tetracycline repeatedly in water, as it can lead to higher concentrations and longer exposure times for lots of organisms.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 5-7","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bergamot Leaf Extract Is Associated With Reduced Hepatic DNA Strand Breaks in Diet-Induced Obese Rats","authors":"Luan H. S. Moreira,&nbsp;Jordanna Cruzeiro,&nbsp;Taynara A. Vieira,&nbsp;Tony F. Grassi,&nbsp;Mariane A. P. Silva,&nbsp;Maria Vitória Destro,&nbsp;Camila R. Corrêa,&nbsp;Mariana G. Braz","doi":"10.1002/em.70074","DOIUrl":"https://doi.org/10.1002/em.70074","url":null,"abstract":"<p>Obesity is a major global public health challenge associated with chronic low-grade inflammation and oxidative stress. Although natural antioxidant compounds have been investigated to mitigate obesity-related molecular damage, the effects of bergamot (<i>Citrus bergamia</i>) leaf extract (BLE) on DNA integrity remains unclear. This study evaluated the effects of BLE on hepatic DNA damage in diet-induced obese rats. Forty Wistar rats were fed either a control or a high-sugar-fat (HSF) diet and treated with BLE by oral gavage. The adiposity index was recorded for all groups, and hepatic DNA damage was assessed using the comet assay. The HSF diet significantly increased both the adiposity index and DNA strand breaks in the liver compared with the control group. Notably, BLE treatment was associated with a lower adiposity index and reduced hepatic DNA strand breaks measured by the comet assay in obese rats (<i>p</i> &lt; 0.05). These findings indicate an association between BLE treatment and reduced hepatic DNA damage in this model of diet-induced obesity.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 5-7","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Approach Methods in Genetic Toxicology","authors":"D. J. Roberts,&nbsp;S. M. Bryce","doi":"10.1002/em.70073","DOIUrl":"10.1002/em.70073","url":null,"abstract":"","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 5-7","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of PARP Inhibitor Resistance: From Replication Gap Biology and Transcription–Replication Conflicts to PROTAC-Based Next-Generation Strategies","authors":"Abinawanto,&nbsp;Alfi Sophian","doi":"10.1002/em.70076","DOIUrl":"10.1002/em.70076","url":null,"abstract":"<div>\u0000 \u0000 <p>Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed precision oncology by exploiting synthetic lethality in homologous recombination (HR)-deficient cancers, with multiple FDA-approved agents targeting <i>BRCA1/2</i>-mutant tumors. Despite initial efficacy, resistance inevitably emerges, limiting long-term clinical benefit. This review synthesizes emerging mechanistic insights into PARPi response and resistance. Recent evidence reframes PARP inhibition cytotoxicity through a transcription–replication conflict model and identifies single-stranded DNA gaps as the primary lethal lesion in HR-deficient cells, rather than double-strand breaks. These findings suggest that resistance reflects restoration of replication gap suppression or resolution of transcription–replication stress. We further highlight DNA ligase III as a collateral vulnerability in <i>53BP1</i>-deficient resistant tumors, and discuss proteolysis-targeting chimera (PROTAC)-based PARP1 degraders as a strategy to overcome resistance and induce alternative cell death pathways. Established resistance mechanisms—including <i>BRCA1/2</i> reversion mutations, shieldin complex loss, <i>RAD51</i> hyperactivation, and pharmacokinetic alterations—are reconsidered within this updated framework. Combination strategies with ATR inhibitors show promising clinical activity in PARPi-resistant HR-deficient ovarian cancer. Finally, we propose an integrated biomarker framework combining HRD scar assays, functional <i>RAD51</i> foci analysis, replication gap profiling, and circulating tumor DNA (ctDNA) monitoring to enable dynamic resistance tracking.</p>\u0000 </div>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"67 5-7","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}