NAR cancer最新文献

{"title":"Integrative multi-omics profiling and machine learning reveal enhancer RNA signatures for early detection and prognostic stratification in breast cancer.","authors":"Junhuan Xia, Jingwen Tian, Yuting Cao, Suhan Zhang, Weiye Qian, Yanan Qi, Hao Huang","doi":"10.1093/narcan/zcag026","DOIUrl":"10.1093/narcan/zcag026","url":null,"abstract":"<p><p>Current breast cancer biomarkers rely predominantly on protein-coding transcriptomes, leaving the regulatory information encoded by enhancer RNAs (eRNAs) largely unexploited. Here, we profiled eRNA expression across 1073 The Cancer Genome Atlas Breast Cancer (TCGA-BRCA) samples integrated with The Cancer eRNA Atlas annotations, using GTEx healthy breast tissue (<i>n</i> = 179) as a curated normal reference. For prognostic stratification, least absolute shrinkage and selection operator (LASSO)-Cox regression identified a 10-eRNA signature that stratified patients into high- and low-risk groups in both training (<i>P</i> <.0001) and independent testing cohorts (<i>P</i> = 0.0022), with a 3-year time-dependent area under the curve (AUC) of 0.743. Multivariate Cox analysis confirmed the signature as an independent predictor [hazard ratio = 3.176, 95% confidence interval (CI): 2.075-4.864, <i>P</i> <.001]. Multi-omics network integration linked these prognostic eRNAs to regulatory hubs centered on the <i>ESR1</i>/<i>FOXA1</i>/<i>GATA3</i>/<i>AR</i> axis. For early-stage detection, we developed a 19-eRNA panel via bootstrap LASSO feature selection and benchmarked ten classifiers; a Multilayer Perceptron achieved the best generalization (AUC = 0.959, 95% CI: 0.925-0.986) on an independent cohort (GSE225846). Both modules were deployed in eRNACare, a publicly accessible web application for individualized survival and tumor probability scoring. These findings establish eRNAs as a complementary noncoding layer to conventional messenger RNA classifiers, with clinical potential for breast cancer risk stratification, therapeutic guidance, and early detection.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag026"},"PeriodicalIF":4.6,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP3 remodels RISC occupancy to control microRNA targeting in leukemia.","authors":"Lyna E S Kabbani, Shruti Kapoor, Gunjan Sharma, Martin Gutierrez, Zachary T Neeb, Amit K Jaiswal, Alexander J Ritter, Sol Katzman, Jordyn E Feldman, Dinesh S Rao, Jeremy R Sanford","doi":"10.1093/narcan/zcag025","DOIUrl":"10.1093/narcan/zcag025","url":null,"abstract":"<p><p>IGF2BP3 is an oncofetal RNA-binding protein that promotes leukemogenesis, but the mechanisms by which it remodels post-transcriptional gene regulation remain incompletely understood. Because IGF2BP3 binds extensively within 3' untranslated regions and has been implicated in microRNA (miRNA)-mediated regulation, we asked whether IGF2BP3 controls access of the RNA-induced silencing complex (RISC) to endogenous messenger RNA (mRNA) targets in leukemia cells. Using AGO2 miR-eCLIP in control and IGF2BP3-deficient MLL-AF4 B-lymphoblastic leukemia cells, we found that loss of IGF2BP3 broadly redistributes AGO2 occupancy toward 3' UTRs of IGF2BP3-bound transcripts. AGO2 gains were enriched near miRNA target sites and on transcripts associated with proliferative and oncogenic pathways. Chimeric AGO2-miRNA reads revealed transcript- and miRNA-specific remodeling of RISC interactions, with enhanced miR-181 occupancy on oncogenic transcripts following IGF2BP3 loss. Functionally, miR-181a overexpression impaired leukemic cell growth, partially phenocopying IGF2BP3 deletion. Motif analyses indicated that IGF2BP3 and AGO2 converge on related 3' UTR sequence environments, while biochemical competition assays demonstrated that purified IGF2BP3 can displace AGO2-containing RISC complexes from a shared RNA substrate. Together, these findings support a model in which IGF2BP3 restricts RISC access to select 3' UTR regulatory elements, thereby reshaping miRNA-target interactions and sustaining leukemic gene expression programs. Rather than acting solely as an mRNA stabilizing factor, IGF2BP3 functions as a transcript-selective regulator of RISC accessibility in leukemia.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag025"},"PeriodicalIF":4.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA <i>RAMS11</i>-dependent <i>NOTCH3</i> activation drives tumor progression in non-small cell lung cancer.","authors":"Gejae G Jeffers, Yesol Kim, Nicole M White, Li Lin, Emily B Rozycki, Amy Ly, Christopher A Maher","doi":"10.1093/narcan/zcag020","DOIUrl":"10.1093/narcan/zcag020","url":null,"abstract":"<p><p>Lung cancer is currently the leading cause of cancer-related deaths worldwide. Approximately 85% of lung cancer patients have non-small cell lung cancer (NSCLC), and >50% of these patients present with metastasis at their initial diagnosis. Despite advances in our understanding of lung cancer oncogenesis, the mechanism by which lung cancer becomes aggressive and leads to patient death is still poorly characterized. We found that long noncoding RNA RNA-associated with metastasis 11 (<i>RAMS11</i>) (<i>LINC01564</i>) is significantly upregulated in lung cancer patients compared to healthy patients. Here, we demonstrate that <i>RAMS11</i> is critical for NSCLC tumor progression by regulating expression of <i>NOTCH3</i>, a key driver of tumorigenic potential. Mechanistically, <i>RAMS11</i> is essential for NRF2 chromatin binding and the associated deposition of the active enhancer mark, H3K27ac, at the <i>NOTCH3</i> enhancer region. Functional analysis revealed <i>RAMS11-</i>NRF2-dependent activation of <i>NOTCH3</i> signaling enforces a tumor-initiating capacity, characterized by enhanced self-renewal capabilities and tumor initiation ability, thereby supporting malignant proliferation. Moreover, disruption of <i>RAMS11</i> signaling markedly suppressed tumorigenic growth and sensitized NSCLC cells to cisplatin-induced apoptosis, uncovering a potential therapeutic vulnerability to more effectively target NSCLC patients. Collectively, these findings reveal a previously unknown role of <i>RAMS11</i> in NSCLC progression and chemotherapy resistance.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag020"},"PeriodicalIF":4.6,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motif-centered analyses reveal universal and tissue-specific mutagenic mechanisms operating in the human body.","authors":"Safia Mahabub Sauty, Yun-Chung Hsiao, Leszek J Klimczak, Dmitry A Gordenin","doi":"10.1093/narcan/zcag024","DOIUrl":"10.1093/narcan/zcag024","url":null,"abstract":"<p><p>Somatic mutations are inevitable in human genomes and can lead to cancer initiation and tumor progression. Although many mutagenic processes have been linked to cancer, their activities in normal tissues before malignant transformation remain poorly characterized. Here, we analyzed the mutation profiles of 10,625 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We also identified a second clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other S_N2 electrophiles, in several tissues. Motifs associated with other environmental and chemical mutagens showed sporadic and tissue-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most tissues. Together, our analyses elucidated several cancer-associated mutagenic processes in normal tissues and provided a robust analytical framework for quantifying mutagenic activities from somatic mutation catalogs.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag024"},"PeriodicalIF":4.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vivo</i> selection of anti-glioblastoma DNA aptamer-drug conjugates in an orthotopic patient-derived xenograft model.","authors":"Caroline D Doherty, Sonia Jain, Lauren L Ott, Katie K Bakken, Brandon A Wilbanks, Danielle M Burgenske, Keenan S Pearson, Jessica I Griffith, Zichen Tian, Jeffrey A Meridew, Saigopalakrishna S Yerneni, William F Elmquist, Jann N Sarkaria, Louis J Maher Iii","doi":"10.1093/narcan/zcag022","DOIUrl":"10.1093/narcan/zcag022","url":null,"abstract":"<p><p>Glioblastoma (GBM) is an aggressive, high-grade glioma with a near-universally fatal prognosis. Therapeutic failure is often attributed to the highly selective blood-brain barrier (BBB), the diffuse infiltrative nature of the tumor, and the marked intratumoral heterogeneity of GBM. Although antibody-drug conjugates (ADCs) have shown promise for high-grade gliomas such as GBM, efficacy is limited by ADC size. Aptamers-short, synthetic, single-stranded DNA or RNA molecules-can be ∼6-fold lower in molecular weight than IgG antibodies and have the potential to cross the intact BBB. Unlike other nucleic acid-based therapies, aptamer function arises from three-dimensional shape rather than genetic coding. Here we aim to replace the targeting component of the ADC paradigm with a DNA aptamer, thus creating an aptamer-drug conjugate (ApDC). We employed <i>in vivo</i> SELEX using an orthotopic patient-derived xenograft GBM mouse model and a vast (∼100 trillion 80-mer sequences) ApDC library. We report the results from this first <i>in vivo</i> ApDC selection of its kind. We characterize target tissue binding <i>ex vivo</i>, cell association, biodistribution, and pharmacokinetics from this selection. This study exemplifies an unbiased approach to a problem that rational design has yet to overcome, offering a new direction for GBM therapeutic development.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag022"},"PeriodicalIF":4.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STN1 upregulation promotes PARPi resistance in BRCA2-deficient cancer cells via replication fork protection and suppression of ssDNA gap formation.","authors":"Zubair Ahmed Laghari, Na Li, Serdar Gayybov, Qi-En Wang, Weihang Chai","doi":"10.1093/narcan/zcag023","DOIUrl":"10.1093/narcan/zcag023","url":null,"abstract":"<p><p>PARPi are effective therapy for BRCA1/2 mutant cancers, yet recurrent PARPi resistance frequently develops. The underlying mechanism of PARPi resistance remains largely unresolved. Here, we identify STN1, a component of the CTC1/STN1/TEN1 (CST) complex, as a modulator of PARPi resistance in BRCA2-deficient cells. RNA sequencing (RNA-seq) analysis of PARPi-resistant cancer cells from BRCA2-mutated backgrounds shows largely distinct transcriptomic profiles with limited overlap, suggesting multiple routes to resistance. Notably, STN1 is consistently upregulated in resistant cells. We observe that overexpression of STN1 enhances olaparib resistance in multiple BRCA2-deficient cell lines and alleviates DNA damage under replication stress. Mechanistically, we find that STN1 overexpression increases RAD51 loading to stalled replication forks while restricting MRE11 recruitment in BRCA2-deficient cells, thereby protecting stalled forks from nascent-strand degradation. Furthermore, STN1 overexpression rescues the accumulation of single-stranded DNA (ssDNA) gaps, a major determinant of PARPi sensitivity in BRCA2-deficient cells. Taken together, these findings suggest that elevated STN1 levels can partially compensate for BRCA2 loss by stabilizing stalled replication forks and limiting ssDNA gap accumulation. Our study uncovers a STN1-dependent pathway of replication stress tolerance that promotes PARPi resistance, highlighting STN1 as a potential biomarker and mechanistic contributor to therapeutic resistance in BRCA2-mutated cancers.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag023"},"PeriodicalIF":4.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic cell free DNA profiles of cerebral spinal fluid from lung cancer metastasis to the brain.","authors":"Tianqi Chen, Xiangqi Bai, Georgiana Burnside, Thy Trang Hoang Trinh, Melanie Hayden Gephart, Hanlee P Ji, Billy T Lau","doi":"10.1093/narcan/zcag021","DOIUrl":"10.1093/narcan/zcag021","url":null,"abstract":"<p><p>Cerebrospinal fluid (CSF) is a liquid biological medium immersing the brain and spinal canal. For patients with metastatic cancer from the lung, tumor cells release their cell-free DNA (cfDNA) into the CSF. We applied a nanopore single-molecule sequencing approach to analyze the fragmentation, methylation, and hydroxymethylation patterns present in CSF-derived cell-free DNA from patients with metastatic lung cancer to the brain. We compared the cancer cfDNA finding to non-cancer healthy controls and their CSF cell-free DNA. Among cancer patients, we observed enriched mono-nucleosome levels and significantly higher mono-/trinucleosome ratios in cancer patients. Comparison with plasma-derived cfDNA further confirmed the unique fragmentation features of CSF-derived cfDNA. Distinct methylation and hydroxymethylation patterns were observed between cancer and control CSF samples. We observed significantly lower degree of hydroxymethylation in cancer patients compared with healthy controls and the affected genes had different pathway profiles. Overall, CSF cfDNA in patients with non-small cell lung cancer brain metastases had distinct profiles of DNA fragmentation, methylation, and hydroxymethylation.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 3","pages":"zcag021"},"PeriodicalIF":4.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.","authors":"Lee J Pribyl, Jennifer E Kay, Joshua J Corrigan, Lindsay B Volk, Monét Norales, Norah A Owiti, Evan A Kowal, Ishwar N Kohale, Ilana S Nazari, Matilda R Swanson, Aimee C Moise, Duanduan Ma, Stuart S Levine, Emily M Michelsen, Robert G Croy, Timothy Ragan, Dorothea K Torous, Svetlana L Avlasevich, Stephen D Dertinger, Sebastian E Carrasco, Leona D Samson, John M Essigmann, Forest M White, Bevin P Engelward","doi":"10.1093/narcan/zcag014","DOIUrl":"10.1093/narcan/zcag014","url":null,"abstract":"<p><p><i>N</i>-Nitrosodimethylamine (NDMA), a probable human carcinogen, induces toxic and mutagenic DNA <i>O</i> ⁶-methylguanine (<i>O</i> ⁶MeG) adducts that are repaired by <i>O</i> ⁶-methylguanine-DNA methyltransferase (MGMT). To elucidate how early-life environmental mutagenic exposures promote latent liver tumorigenesis, we performed longitudinal studies in wild-type and MGMT-deficient (<i>Mgmt</i> ^-/-) mice. Neonatal mice received NDMA intraperitoneally on postnatal days 8 and 15 and were followed for up to 10 months post-exposure. Phenomics, transcriptomics, phosphoproteomics, spatial transcriptomics, and histopathology revealed that NDMA exposure in <i>Mgmt</i> ^-/- mice produced a nine-fold increase in liver tumors, including hepatocellular carcinomas and adenomas. Early molecular profiling revealed elevated <i>O</i> ⁶MeG adducts, sustained γH2AX activation, and increased micronucleus formation in <i>Mgmt</i> ^-/- livers. Transcriptomics showed persistent interferon response and immune cell infiltration, particularly in <i>Mgmt</i> ^-/- mice, up to 10 months post-exposure. Clonal expansion, quantified by RaDR-GFP expression, was significantly higher in NDMA-exposed <i>Mgmt</i> ^-/- mice. Spatial transcriptomics of clonally expanded cells demonstrated activation of oncogenic and inflammatory pathways. These findings demonstrate that acute early-life NDMA exposure drives persistent DNA damage signaling, chronic interferon activation, and clonal expansion that together promote MGMT-dependent hepatocarcinogenesis. Collectively, these processes link early environmental mutagen exposure to long-term premalignant evolution and tumor emergence, and define mechanistic biomarkers and potential interception targets for NDMA-induced liver cancer.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag014"},"PeriodicalIF":4.6,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13288108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of CHTF18-RFC2/5 leads to replicative gaps and sensitivity to PARP inhibitors.","authors":"Lauryn Buckley-Benbow, Meryem Ozgencil, Alessia Tardocchi, Alessandro Agnarelli, Roberto Bellelli","doi":"10.1093/narcan/zcag013","DOIUrl":"10.1093/narcan/zcag013","url":null,"abstract":"<p><p>The use of PARP inhibitors (PARPi) has profoundly changed the treatment of BRCA1/BRCA2-mutated cancers. Despite this, acquired resistance to PARPi has become a major challenge in the clinic. Hence, a more detailed understanding of the mechanisms underlying PARPi sensitivity is crucially needed. Here, we show that loss of the alternative clamp loader complex CHTF18-RFC2/5 leads to a remarkable sensitization to PARPi. Loss of CHTF18 is not associated with defective RAD51 foci formation excluding a defect in homologous recombination. On the contrary, treatment with PARPi triggers replicative gap accumulation in CHTF18 knockout (KO) cells. By performing transient silencing experiments, we highlight PARP1-PARP2 trapping at replicative gaps as a major determinant of sensitivity to these compounds. Crucially, loss of 53BP1 does not rescue PARPi sensitivity in CHTF18 KO cells, outlining Polε and the CHTF18-RFC2/5 complex as potential novel targets for cancer therapeutics.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag013"},"PeriodicalIF":4.6,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13231162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148166336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of the structural maintenance of chromosomes 5/6 complex enables tumor mutagenesis.","authors":"Thi Tran, Jiayi Fan, Xiaolan Zhao, Abby M Green","doi":"10.1093/narcan/zcag012","DOIUrl":"10.1093/narcan/zcag012","url":null,"abstract":"<p><p>The structural maintenance of chromosomes (SMC) 5/6 complex is conserved and essential for mammalian development. SMC5/6 germline variants in cells, model organisms, and patients results in genome instability. However, the consequences of somatic SMC5/6 dysfunction in cancer are unknown. We report a pan-cancer analysis of SMC5/6 variants across three databases in which thousands of tumors across all tissue types harbored copy number alteration (CNA) and/or small variants in SMC5/6 genes. We found that deleterious variants-those predicted to cause protein disruption, but not CNAs, in SMC5/6 genes were associated with elevated tumor mutational burden (TMB). Mutagenesis in tumors with deleterious SMC5/6 variants was largely due to polymerase epsilon dysfunction and mismatch repair deficiency. Patients with SMC5/6 gene variants in tumors exhibited improved survival, in part due to a superior response to immunotherapy. Our findings demonstrate that SMC5/6 complex disruption in cancer predicts elevated TMB and susceptibility to immunotherapy, indicating the potential to use SMC5/6 gene status for prognostic implications and tailored therapeutic approaches.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag012"},"PeriodicalIF":4.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}