Mutagenesis最新文献

{"title":"Mutagenicity of N-nitroso-fluoxetine and N-nitroso-varenicline in human HepaRG cell models.","authors":"Ji-Eun Seo, Hannah S Xu, Javier R Revollo, Jaime A Miranda-Colon, Aisar H Atrakchi, Timothy J McGovern, Karen L Davis Bruno, David A Keire, Robert H Heflich, Xiaoqing Guo","doi":"10.1093/mutage/geag012","DOIUrl":"10.1093/mutage/geag012","url":null,"abstract":"<p><p>Nitrosamine drug substance-related impurities (NDSRIs) have raised significant concern among the pharmaceutical industry and regulatory agencies, prompting a need to establish methods to determine the mutagenic risks associated with these substances. As human, metabolically competent HepaRG cells previously showed promise in evaluating the mutagenicity of a small-molecule nitrosamine impurity, N-nitroso-dimethylamine (NDMA), this study evaluated the suitability of HepaRG cells for mutagenesis assessment of NDSRIs. HepaRG cells, cultured in both two-dimensional (2D) and three-dimensional (3D) spheroid formats, were exposed to N-nitroso-fluoxetine and N-nitroso-varenicline for either 3 days or 14 days. DNA damage was evaluated using the comet assay, clastogenicity/aneugenicity was measured with the micronucleus (MN) assay, and mutagenesis was assessed using high-fidelity sequencing (HiFi-seq). N-Nitroso-fluoxetine and N-nitroso-varenicline were cytotoxic, produced DNA damage, and increased mutation frequency in both 2D and 3D HepaRG models. Both compounds increased MN formation only at the highest concentration in 3D spheroids after the 14-day exposure. Benchmark concentration (BMC) analysis indicated that, despite overlapping confidence intervals between 2D and 3D HepaRG cultures, in most instances BMC values tended to be lower in 3D than in 2D cultures after both 3-day and 14-day treatments. In addition, the 14-day treatments of both 2D and 3D HepaRG cultures with N-nitroso-fluoxetine resulted in higher levels of mutagenesis than the 3-day treatments, while 3-day and 14-day treatments with N-nitroso-varenicline produced similar mutagenesis responses. These findings demonstrate the feasibility of employing HepaRG cells with HiFi-seq as a mammalian cell assay for assessing NDSRI mutagenesis.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"175-188"},"PeriodicalIF":3.1,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271429","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":"Induction of genotoxic damage and ROS production in HCT116 TP53+/+ and HCT116TP53-/- colorectal cancer cell lines by anticancer drugs.","authors":"Chiara Naldoni, Irene Guidotti, Matilde Matteoli, Domenica Di Bello, Viola Scatolini, Veronica Esposti, Aurora Falaschi, Roberto Scarpato","doi":"10.1093/mutage/geag014","DOIUrl":"10.1093/mutage/geag014","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) play a dual role in cancer biology, contributing to both tumor progression and therapeutic responses. Many chemotherapeutic agents exert their cytotoxic effects through ROS generation, although the extent and biological relevance of this process remain influenced by cellular context, including the functional status of tumor suppressor genes such as TP53. In this study, we investigated the induction of genomic damage and oxidative stress in two isogenic human colorectal cancer cell lines-HCT116TP53+/+ and HCT116TP53-/--after exposure to four commonly used anticancer agents: oxaliplatin (OXA), irinotecan (IRI), paclitaxel (PAC), and 5-fluorouracil (5-FU). Drug concentrations were selected to ensure cell viability while inducing genotoxicity. Genome damage was assessed by micronucleus (MN) assay. ROS production was measured using the BODIPY581/591 C11 lipid peroxidation fluorescent probe. Our results showed that OXA and IRI induced both significant MN formation and robust ROS production in a dose-dependent manner, while PAC predominantly triggered genomic damage with limited ROS generation. Conversely, 5-FU exhibited marginal (or no) effect on both endpoints. Notably, with regard to the extent of ROS accumulation and MN induction, no significant differences were detected under the tested conditions between the two HCT116 cell lines. This suggests that under non-cytotoxic conditions, p53 is not a critical modulator of oxidative responses to these agents. Overall, our data reveal a drug-specific pattern of genome and oxidative damage in HCT116 colorectal cancer cells, emphasizing the importance of considering drug mechanism of action in evaluating redox responses. These insights may contribute to the development of targeted combinatorial therapies aimed at modulating oxidative stress, especially in TP53-mutated tumors.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"206-215"},"PeriodicalIF":3.1,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504429","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":"How genotoxic is the indoor air environment?","authors":"Kirsty Meldrum, Michael J Burgum, Shareen H Doak, Martin J D Clift","doi":"10.1093/mutage/geag024","DOIUrl":"https://doi.org/10.1093/mutage/geag024","url":null,"abstract":"<p><p>The indoor environment changes based on a variety of different factors, therefore changing the genotoxic potential of that environment. Despite the associations of exposure to outdoor air pollution and links to health impacts, enough is not currently known about the impacts to human health indoor air may have. Due to the variable nature of the indoor environment (multiple things can change this environment, including but not limited to, the use, occupants, materials within the environment, animals, the outside environment and ventilation) this can prove difficult. Indoor particulate matter (PM) of various sizes (PM2.5-PM10 for example) has been shown to induce reactive oxygen species, increase markers in oxidative stress, double strand DNA breaks, and cause 8-oxoguanine lesions in both in vitro and in vivo models (including humans). The particle type and source influence these responses, highlighting heating and cooking fuel sources that may be more genotoxic than others. A similar pattern has also been observed with volatile organic compounds (VOCs) with various mixtures of VOCs and different VOC compositions inducing DNA damage differently, with diet also being a contributing factor to genotoxic potential. A significant knowledge gap in the potential genotoxicity of indoor air pollution is the exposure of various biologicals found indoors. Moulds, other fungi, and allergens are an emerging health risk and are of significant public interest. Little is known about the inhalation toxicology and mechanisms of action of these components, and this is becoming increasing important to understand due to public deaths linked to them. There is overlap with the health effects of outdoor air pollution where there has been much more research focus. Therefore, the aim of this review is to establish what is already known, the potential limitations of the current work and where we should focus research in the future.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308765","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":"Unveiling the Genotoxic Safety and Antioxidant-Mediated DNA Protective Mechanisms of Triammonium Citrate: An Integrated In Vitro and In Silico Approach.","authors":"Emin Öztürk, Hasan Basri İla","doi":"10.1093/mutage/geag025","DOIUrl":"https://doi.org/10.1093/mutage/geag025","url":null,"abstract":"<p><p>Triammonium citrate (TAC) is a citrate salt widely utilized in diverse industrial and dietary applications, leading to widespread human exposure. While related citrate salts have established safety profiles, the specific genotoxic potential and molecular interactions of TAC remain largely unexplored. This study provides the first integrated in vitro and in silico mechanistic safety assessment of TAC. Cell viability, evaluated in NIH/3T3 and MCF-7 cells via the CCK-8 assay, remained above 90% at all tested concentrations (0.25-2 mg/mL). Furthermore, a comprehensive genotoxicity battery-including the Ames test, chromosomal aberration, micronucleus, and sister chromatid exchange assays in human lymphocytes-revealed no mutagenic, clastogenic, or aneugenic activity. Beyond its safety profile, TAC exhibited marked chemoprotective activity, preserving supercoiled plasmid DNA with up to 96% protection against H₂O₂-induced oxidative damage. Molecular docking studies substantiated these findings by predicting moderate binding affinities for DNA replication enzymes (DNA polymerase δ: ΔG = -5.7 kcal/mol; topoisomerase I: ΔG = -5.9 kcal/mol) while showing a preferential affinity for the metabolic enzyme glutamine synthetase (ΔG = -6.1 kcal/mol). These in silico results suggest that TAC does not interfere with critical DNA maintenance machinery. Collectively, these findings establish a robust safety profile for TAC and unveil a previously unrecognized, antioxidant-mediated DNA-protective function, highlighting its potential as a bioactive functional ingredient capable of mitigating oxidative DNA stress.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278112","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":"Potassium bromate as a probable human Carcinogen: multi-organ toxicity and chemopreventive potential of dietary antioxidants-a comprehensive review.","authors":"Saima Nazir, Mir Kaisar Ahmad","doi":"10.1093/mutage/geag022","DOIUrl":"https://doi.org/10.1093/mutage/geag022","url":null,"abstract":"<p><p>Potassium bromate (KBrO₃), classified as a probable human carcinogen, has long been used as a flour-improving and oxidizing agent in baking and food processing industries. It is also generated as a by-product during ozonation of drinking water, raising concerns about widespread, low-dose exposure. Experimental studies consistently demonstrate that KBrO₃ induces multiple-organ toxicity primarily through oxidative stress-mediated mechanisms. Exposure to KBrO₃ leads to excessive generation of reactive oxygen species, resulting in depletion of glutathione reserves, enhanced lipid peroxidation, and oxidative DNA damage. Such genotoxic effects include DNA strand breaks, micronuclei formation, and chromosomal aberrations, which collectively contribute to its well-documented carcinogenic and mutagenic potential. Consequently, these molecular alterations promote renal, hepatic, and thyroid tumor formation reported in experimental animal models, while emerging epidemiological evidence suggests possible associations between chronic dietary exposure to KBrO₃ and gastrointestinal malignancies in humans. However, recent research has thoroughly investigated the chemopreventive potential of dietary antioxidants in mitigating KBrO₃-induced toxicity, highlighting their ability to attenuate oxidative damage through enhancement of endogenous antioxidant defenses, modulation of the key cytoprotective signaling pathways and restoration of cellular redox homeostasis. With continued usage of KBrO₃ and the inconsistency of regulatory enforcement worldwide, strengthening risk assessment, surveillance and preventive strategies-particularly the substitution of KBrO₃ with safer alternatives and the promotion of antioxidant-rich diets is crucial to reduce long term carcinogenic risk and safeguard global public health.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006162","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":"Antioxidant effects of melatonin on obese mice.","authors":"Luiza Martins Longaretti, Marina Lummertz Magenis, Adriani Paganini Damiani, Ângela Caroline da Luz Beretta, Isadora de Oliveira Monteiro, Otávio Lúcio Possamai, Gilson Pires Dorneles, Alessandra Peres, Gustavo de Bem Silveira, Paulo César Lock Silveira, Vanessa Moraes de Andrade","doi":"10.1093/mutage/geag007","DOIUrl":"10.1093/mutage/geag007","url":null,"abstract":"<p><p>Overweight and obesity have been increasing drastically in recent years due to the growing consumption of fast food. Obese individuals exhibit reduced antioxidant defenses, which can lead to DNA damage. Thus, studies have been conducted to mitigate obesity-related complications. Animal research has used the cafeteria diet (CAF) as an obesity induction model, as it mimics human consumption of ultra-processed foods. Currently, complementary dietary strategies are being explored to prevent and/or alleviate obesity-related complications, particularly through natural compounds with anti-obesity effects. Among these, melatonin (MEL) has gained attention due to its antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of MEL supplementation on biochemical, genotoxic, and inflammatory parameters in mice fed a CAF diet. A total of 60 male Swiss mice were divided into six experimental groups (n = 10): (i) Standard Diet-fed standard chow for 21 weeks; (ii) SD + MEL-fed standard chow and supplemented with MEL for 24 weeks; (iii) CAF-fed CAF for 21 weeks; (iv) CAF + MEL-fed CAF and supplemented with MEL; (v) CAF/CAF + MEL-fed CAF for the first 17 weeks, then continued CAF while starting MEL supplementation for the last 4 weeks, totaling 17 weeks of CAF; (vi) CAF + MEL/CAF-fed CAF and supplemented with MEL for the first 17 weeks, then stopped MEL supplementation for the last 4 weeks, totaling 21 weeks. Blood samples were collected at 17 and 21 weeks to assess DNA damage, lipid profile (triglycerides, total cholesterol, and HDL), liver function (ALT and AST), inflammatory markers (TNF-α and IL-10), fasting glucose, and insulin tolerance in all six groups. At the end of the experiment, animals were euthanized, and liver, kidney, adipose tissue, and bone marrow were collected for further analyses, including the Comet Assay, Micronucleus Test, oxidative stress evaluation, and Western blot. Results showed that CAF induced an inflammatory state, characterized by increased TNF-α and decreased IL-10, along with alterations in lipid and liver profiles. Additionally, CAF led to DNA damage in multiple tissues and insulin resistance. MEL supplementation for 17 weeks reversed these changes. In the last 4 weeks of the experiment, CAF was associated with oxidative stress and damage in the liver, kidney, and bone marrow. MEL effectively attenuated these obesity-related alterations, primarily by modulating proteins involved in homologous and non-homologous DNA repair pathways. In conclusion, the findings demonstrate that MEL is a potent antioxidant and may be a promising candidate for reducing biochemical and genetic alterations associated with obesity.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"119-141"},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150173","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":"Mutagenicity of 5-hydroxycytosine in human cells.","authors":"Tetsuya Suzuki, Ann Hirota, Shigenori Iwai, Hiroyuki Kamiya","doi":"10.1093/mutage/geag004","DOIUrl":"10.1093/mutage/geag004","url":null,"abstract":"<p><p>Base damage in DNA constitutes a major source of mutations, and consequently leads to cancers. In human cells, 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) induces targeted G → T transversions, and untargeted base substitution mutations at positions distant from the damaged site (action-at-a-distance mutations). OGG1 is a base excision repair enzyme and suppresses the former mutations, but is involved in the latter mutations' process. In this study, 5-hydroxycytosine (CO), another oxidized base removed by base excision repair, was incorporated into the inside and outside regions of the supF gene, and the CO-plasmid DNAs were transfected into human U2OS cells. The damaged cytosine base caused base substitution mutations at the lesion site, and seemed to induce the action-at-a-distance mutations at a lower frequency than the oxidized guanine base. These results indicated that CO is mutagenic in human cells. In addition, the (6-4) photoproduct of 5'-TpT-3', the lesion repaired by another type of DNA repair pathway, nucleotide excision repair, did not cause the action-at-a-distance mutations.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"101-109"},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106370","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":"Assessment of mutagenic potential of puberulic acid contaminated in red yeast rice (beni-koji) health food supplements.","authors":"Kei-Ichi Sugiyama, Ayako Furuhama, Katsuyoshi Horibata, Masataka Tsuda, Kazuki Izawa, Genichiro Tsuji, Yosuke Demizu, Kohei Matsushita, Takeshi Toyoda, Yoko Hirabayashi, Yoshiro Saito, Masamitsu Honma","doi":"10.1093/mutage/geag005","DOIUrl":"10.1093/mutage/geag005","url":null,"abstract":"<p><p>In March 2024, a food poisoning incident in Japan was traced to red yeast rice (beni-koji) supplements contaminated with puberulic acid (PA), a mycotoxin produced by Penicillium adametzioides. Although PA was implicated in renal dysfunction in both humans and rats, its mutagenic potential had not been clarified. Here, we comprehensively assessed the mutagenicity of PA using a tiered approach that combined in silico, in vitro, and in vivo methods. In silico quantitative structure-activity relationship analyses predicted PA to be mutagenic, and in vitro Ames tests confirmed the positive finding. In contrast, in vivo assays, including the transgenic rodent gene mutation assay in mice and the Pig-a assay in rats, demonstrated no induction of mutations in kidney, glandular stomach, and blood cells, even at high exposure levels. Collectively, these findings indicate that PA is mutagenic in vitro bacterial tests, but not in mammalian in vivo systems, suggesting that the overall concern for mutagenicity in humans is low.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"110-118"},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13107177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125728","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":"Evaluating DNA damage in peripheral blood lymphocytes: a promising biomarker for diagnosis, prognosis, and treatment monitoring in colorectal cancer.","authors":"Ana Rita Guedes, Renato Cunha, Amélia M Silva, Isabel Gaivão","doi":"10.1093/mutage/geag001","DOIUrl":"10.1093/mutage/geag001","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a major health challenge due to its late-stage diagnosis and the variability in patient prognosis. This study explores the potential of DNA damage in peripheral blood lymphocytes (PBLs) as a biomarker for CRC, comparing it with standard clinical parameters. We assessed DNA strand breaks using the alkaline comet assay in 27 CRC patients at diagnosis and posttreatment, comparing these levels with 31 healthy controls. Patients received 5-fluorouracil (5-FU)-based chemotherapy (with irinotecan or oxaliplatin), radiotherapy, or combined chemoradiotherapy. At diagnosis (t0), DNA damage in PBLs was significantly higher in CRC compared to healthy controls (mean ± SD %DNA in tail: CRC 27.9 ± 14.0%; controls 6.5 ± 3.8%; P = .001), and independently of common confounding factors (sex, age, smoking, and alcohol consumption). Crucially, the prognostic signal came from baseline (t0): 6 of 27 patients relapsed/metastasized within 8-10 months, and high-DNA-damage basal levels were the only significant prognostic predictor (P = .0137), yielding an infinitely elevated odds ratio (95% CI: ≥2.203) and 100% sensitivity. In stark contrast, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) showed limited performance. At t0, among patients with available serum data (n = 23), most values were below clinical cut-offs: CEA 3 ng/ml (14/23, 61%); CA19-9 37 U/ml (19/23, 83%). Prognostic sensitivities were 50.0% (CEA) and 16.7% (CA19-9). Posttreatment (t1) increases in DNA damage are pharmacodynamically expected with DNA-damaging therapy. t1 values were higher in patients who relapsed (P < .001), whereas the within-patient change (Δ = t1 - t0) was not associated with outcome (P = .148); these posttreatment findings are exploratory. Evaluating DNA damage in PBLs, therefore, offers a valuable noninvasive biomarker for early detection, treatment monitoring, and short-term risk stratification in CRC, warranting validation in larger, stage-balanced cohorts.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"91-100"},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934287","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":"Patterns of chromosomal instability and epigenetic alterations in colorectal cancer progression: from high-grade dysplasia to liver metastases.","authors":"Katerina Saskova, Mattias Landfors, Viktor Hlavac, Karolina Seborova, Jan Bruha, Katerina Honkova, Kristyna Tomasova, Saba Selvi, Jana Drabova, Fernanda S Hackenhaar, Torbjörn K Nilsson, Pavel Vodicka, Anna Valickova, Vaclav Liska, Sanja A Farkas, Sofie Degerman, Michal Kroupa","doi":"10.1093/mutage/geag010","DOIUrl":"10.1093/mutage/geag010","url":null,"abstract":"<p><p>Chromosomal instability (CIN), impaired telomere biology, and aberrant DNA methylation are implicated in colorectal cancer (CRC) development. Tracking these alterations from precancerous lesions through tumors to metastases may reveal biomarkers of CRC initiation and progression. Tissue samples from 44 patients with either high-grade colorectal dysplasia (HGA; n = 13) or advanced metastatic CRC (n = 31) were analyzed. CIN was assessed in all patients using either low-coverage whole-exome sequencing or microarray-based comparative genomic hybridization. In a subset of patients, genome-wide CpG methylation profiling (n = 19) and telomere length measurements (n = 15) were performed. CIN was detected in 85% of HGA patients, spanning focal CNVs in MALAT1 (46%) to recurrent alterations on chromosomes 11, 13, and 20, with PTK6 being the most frequently amplified (61%). CIN was comparable between primary tumors and synchronous metastases but was significantly elevated in metachronous cases. DEK was amplified in all metastases but the aberration was absent in primaries, irrespective of tissue chronicity. Methylation profiling distinguished HGA from adjacent non-dysplastic mucosa (9859 differentially methylated CpGs) and unrelated tumor tissues (17 638 CpGs), whereas primary tumors and metastases differed at only five CpG sites. Both primary tumors and metastases appeared epigenetically younger than colonic mucosa. Metastases exhibited significantly shorter telomeres than both primary tumors (P = .019) and colonic mucosa (P = .001). The amplification of PTK6 may serve as an early biomarker detectable at the HGA stage, while DEK amplification appears crucial for metastatic progression and may represent a therapeutic target. Further validation is needed.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"156-166"},"PeriodicalIF":3.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181153","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}