Genome Medicine最新文献

{"title":"DNA methylation biomarkers-based pan-cancer classifier: predictive modeling for cancer classification.","authors":"Jan Bińkowski, Tomasz K Wojdacz","doi":"10.1186/s13073-026-01650-w","DOIUrl":"10.1186/s13073-026-01650-w","url":null,"abstract":"<p><strong>Background: </strong>Machine-learning (ML) driven molecular diagnostics based on omics data has a potential to revolutionize personalized medicine. However, implementation of ML into diagnostic protocols is hindered by methodological challenges which often lead to inflated performance assessment of models during development followed by poor performance of these models in implementation phase. Here, we aimed to develop and validate a pan-cancer classification framework based on DNA methylation data, that addresses methodological challenges of omics data powered ML.</p><p><strong>Methods: </strong>We curated a primary dataset of DNA methylation profiles for 10756 samples, that included 54 healthy and cancer tissue types and validation dataset comprising data for 2306 samples from 28 independent studies. The classification framework was build using custom biomarkers selection strategy based on effect size metric that considers variance and class imbalance. The ML models were trained, tuned and evaluated using nested cross-validation approach. Local outlier factor algorithm was built into the inference pipelines to identify and filter samples displaying technical or biological anomalies. Additionally, for methodological validation of our framework we used methylation profiles for 3905 central nervous system (CNS) tumors.</p><p><strong>Results: </strong>We found that relatively simple ML models outperformed complex algorithms such as deep neural network. A logistic regression classifier achieved a balanced accuracy (BACC) of 0.90 to classify 54 cancer and healthy tissue types using methylation levels at 1208 CpG sites. Similarly, our CNS tumor classifier also based on logistic regression algorithm reached a BACC of 0.94 across 59 CNS tumor subtypes. The anomaly filtering improved performance across all categories of samples tested.</p><p><strong>Conclusions: </strong>Our study demonstrates that DNA methylation profiling, when combined with carefully controlled ML practices allows for development of robust solutions that might substantially increase the efficacy of oncological diagnosis. Finally, we deployed our inference pipelines for public access via secure web platform - https://opp.pum.edu.pl/ .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics profiling of the diabetic human heart reveals coupled dysregulation in lipid metabolism, mitophagy, and extracellular matrix remodeling.","authors":"Qiuhan Lu, Shulin Tang, Sijia Fang, Yuwen Wu, Liang Chen, Mintong Liang, Jiaqi Chen, Pengju Wen, Leigang Jin, Jianshe Yu, Feng Jiao, Yueheng Wu, Guozhi Jiang","doi":"10.1186/s13073-026-01668-0","DOIUrl":"10.1186/s13073-026-01668-0","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cardiomyopathy (DbCM) is a major complication of type 2 diabetes whose molecular basis in human hearts remains poorly understood. This study aimed to define the multi-omics landscape of DbCM in the human myocardium.</p><p><strong>Methods: </strong>We performed integrated transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic analysis on left ventricular tissues from matched Chinese cohorts: DbCM (n = 11), non-diabetic cardiomyopathy (n = 11), and healthy donors (n = 4). Key findings were validated by histological assessment and western blotting of candidate proteins. External validation was conducted using public datasets, and phenotypic support was derived from mouse models.</p><p><strong>Results: </strong>Multi-omics profiling revealed distinct, coordinated dysregulation in DbCM. Proteomics and transcriptomics profiling revealed a rewired fatty acid oxidation-mitophagy axis characterized by elevated acyl-CoA synthetase long-chain family member 1 (ACSL1) and suppressed fatty acid synthase (FASN), impaired mitochondrial quality control marked by a significant reduction in the mitophagy regulator BNIP3L, which showed a strong inverse correlation with ACSL1, and disrupted extracellular matrix homeostasis, with specific downregulation of key structural components (COL5A1, COL5A2, and fibrillin-1). Metabolomics confirmed enhanced but incomplete fatty acid oxidation, evidenced by triglyceride depletion and accumulation of acylcarnitines and lipotoxic lipids. Integrated multi-omics identified impaired BNIP3L-associated mitophagy as a potential molecular node associated with lipid metabolic dysregulation with mitochondrial dysfunction.</p><p><strong>Conclusions: </strong>This human multi-omics study defines DbCM by the concurrent dysregulation of cardiac fuel metabolism, mitochondrial quality control, and matrix remodeling, offering novel mechanistic insights and highlighting ACSL1 and BNIP3L as potential therapeutic targets for diabetes-associated cardiac dysfunction.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13353004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide meta-analysis across East Asian and European populations provides insights into the molecular basis of lung cancer.","authors":"Meng Zhu, Caochen Zhang, Yuting Han, Chen Jin, Sunan Miao, Jing Zhang, Linnan Gong, Yuanlin Mou, Chen Ji, Yating Fu, Erbao Zhang, Canqing Yu, Dianjianyi Sun, Yue Jiang, Jiaping Chen, Ling Yang, Yiping Chen, Huaidong Du, Robin Walters, Iona Millwood, Juncheng Dai, Zhengming Chen, Zhibin Hu, Jun Lv, Guangfu Jin, Christopher I Amos, Hongbing Shen, Liming Li, Hongxia Ma","doi":"10.1186/s13073-026-01666-2","DOIUrl":"10.1186/s13073-026-01666-2","url":null,"abstract":"<p><strong>Background: </strong>The genetic architecture of lung cancer (LC) varies substantially across populations. However, the limited ancestral diversity of existing discovery cohorts hampers comprehensive characterization of ancestry-specific risk mechanisms and limits the transferability of polygenic risk scores (PRSs) across populations. In addition, the interplay between germline variants and somatic mutations in LC remains poorly characterized.</p><p><strong>Methods: </strong>We performed a cross-ancestry genome-wide association meta-analysis (GWMA) studies comprising 53,650 LC cases and 486,210 controls of East Asian (EAS) and European (EUR) ancestry. PRSs of cross-ancestry were developed and validated in the UK Biobank (UKB) and China Kadoorie Biobank (CKB). Fine-mapping and expression quantitative trait locus (eQTL) colocalization were conducted to prioritize candidate susceptibility genes. Gene-set based PRSs were calculated based on pathway enrichment analyses, telomere and smoking-related GWASs and supporting literature, and their association with somatic mutations and prognostic metrics were studied. Functional validation of novel locus was performed to elucidate the mechanisms of LC.</p><p><strong>Results: </strong>Cross-ancestry GWMA identified 36 independent variants across 30 loci, including one novel locus, and revealed remarkable differences in genetic correlations with smoking behaviors between East Asians and Europeans. PRS-CSx derived from the meta-analysis outperformed previous models in both the two biobanks (UKB: HR = 1.27, 95%CI: 1.23-1.31; CKB: HR = 1.26, 95%CI: 1.19-1.34). Susceptibility genes were grouped into four pathways: telomere maintenance, smoking behavior, epithelial cell biology, and DNA damage response. Corresponding gene-set-based PRSs were significantly associated with tumor mutation burden, mutational signatures, key driver mutations, and patient survival. Finally, functional assays further demonstrated that two variants at the novel locus at 16q23.3 regulate MPHOSPH6 expression and protein function, influencing telomere length and LC risk.</p><p><strong>Conclusions: </strong>Our study systematically elucidates the shared and distinct genetic architectures of LC between EAS and EUR populations, introduces PRS-CSx for effective LC risk stratification underscoring its clinical implications across diverse ancestries. Additionally, we uncover a novel mechanism by which functional genetic variants located in MPHOSPH6 contribute to LC susceptibility, and provide comprehensive insights into the interplay between germline and somatic mutations in LC.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unprocessed U1 snRNAs as a biomarker of INTS11- and BRAT1-related neurodevelopmental disorders.","authors":"Beatrice Valtorta, Zuzana Polackova, Reza Maroofian, Aveeva Herold, Irem Karagoz, Maha S Zaki, Denisa Bronisova, Meijiang Liao, Mina Zamani, Annarita Scardamaglia, Nine Collomb, Lidia Lopez-Jimenez, Maria J Barrero, Julian Schröter, Steffen Syrbe, Marion Heidi Vallanger, Sofia Douzgou Houge, Yasemin Alanay, Ozlem Akgun-Dogan, Julie Vogt, Michael Muriello, Yvonne M C Hendriks, Alexandra Afenjar, Nadirah Damseh, Rauan Kaiyrzhanov, Marcello Niceta, Marco Tartaglia, Manju A Kurian, Nataliya Di Donato, Grace Yoon, Henry Houlden, Éric Samarut, Hana Hanzlikova","doi":"10.1186/s13073-026-01667-1","DOIUrl":"10.1186/s13073-026-01667-1","url":null,"abstract":"<p><strong>Background: </strong>Disrupted RNA processing is increasingly recognized as a key driver of severe neurodevelopmental disorders. Variants in the Integrator catalytic subunit INTS11 and its binding partner BRAT1 lead to clinically overlapping phenotypes, yet only the molecular function of INTS11 has been relatively well characterized. In contrast, the mechanistic contribution of BRAT1 to RNA metabolism and disease has remained unclear, leaving major gaps in variant interpretation and diagnostic classification.</p><p><strong>Methods: </strong>We employed an integrated genetic, molecular, and in vivo approach to investigate the impact of INTS11 and BRAT1 mutations on U small nuclear RNA (U snRNA) processing. Patient-derived fibroblasts and lymphoblastoid cells were analysed by western blotting, RT-qPCR and fluorescence in situ hybridization to assess U1 snRNA 3'-end processing and nuclear retention. To validate the functional consequences of Integrator deficiency in vivo, we generated and characterized an ints11 knockout zebrafish model.</p><p><strong>Results: </strong>We identified novel biallelic variants in INTS11 and BRAT1 in individuals with overlapping neurodevelopmental features. While defective snRNA processing is anticipated in INTS11 deficiency, this study provides the first direct demonstration of impaired U1 snRNA processing across multiple INTS11-mutated patient cells. Critically, we show that BRAT1 mutations also compromise U1 snRNA 3'-end processing, leading to nuclear accumulation of unprocessed transcripts. These findings provide direct evidence of BRAT1's role in RNA processing and establish Integrator dysfunction as a primary pathogenic mechanism in BRAT1-associated neurological disease. The magnitude of U1 snRNA misprocessing closely correlates with clinical severity across the BRAT1 cohort, highlighting its potential as a diagnostic biomarker. Consistently, the ints11 knockout zebrafish model recapitulates core patient features - including microcephaly, neurodevelopmental defects, and U snRNA processing defects - further validating the causal role of Integrator deficiency in vivo.</p><p><strong>Conclusions: </strong>Our results redefine BRAT1-associated neurological disorders as Integrator-related diseases driven by RNA processing defects. Nuclear accumulation of unprocessed U1 snRNAs emerges as a robust biomarker for variant interpretation, disease severity, and patient stratification, particularly in BRAT1 cases. These findings broaden the clinical and molecular spectrum of Integrator dysfunction and provide a foundation for improved diagnostic and translational approaches.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13335351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient induced pluripotent stem cells identify specificities of a reticular pseudodrusen phenotype in age-related macular degeneration.","authors":"Jenna C Hall, Kavitha Krishna Sudhakar, Maciej Daniszewski, Anne Senabouth, Carla J Abbott, Helena H Liang, Himeesh Kumar, Grace E Lidgerwood, Mehdi Mirzaei, Jessica Yw Ma, Trevor Atkeson, Yumiko Hirokawa, Emeline F Nandrot, Alexander Barnett, Chantal Cazevieille, Gaël Manes, Simon Mountford, Philip Thompson, Erica L Fletcher, Zhichao Wu, Melanie Bahlo, Brendan R E Ansell, Daniel Paull, Alex W Hewitt, Robyn H Guymer, Joseph E Powell, Alice Pébay","doi":"10.1186/s13073-026-01658-2","DOIUrl":"10.1186/s13073-026-01658-2","url":null,"abstract":"<p><p>BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of vision loss. Reticular pseudodrusen (RPD), deposits on the apical side of the retinal pigment epithelium (RPE), signify a distinctive and critical AMD phenotype. Yet, their molecular basis and relationship to the conventional drusen seen in AMD remain unclear. METHODS: We generated induced pluripotent stem cell-derived RPE cells from a clinically phenotyped cohort comprising only individuals with conventional drusen (AMD/RPD-) or with drusen coexisting with RPD (AMD/RPD +). To identify differences between the two cohorts, we performed single-cell transcriptomic, proteomic, quantitative trait locus (QTL) and transcriptome-wide association (TWAS) analyses, together with functional assays. RESULTS: AMD/RPD + RPE cells exhibited enrichment of extracellular matrix (ECM) and hypoxia-responsive pathways, and a relative underrepresentation of mitochondrial and oxidative phosphorylation processes, when compared with AMD/RPD- cells. Genetic analyses supported shared modulation of mitochondrial pathways across AMD, with additional regulatory signals associated with RPD risk. Functionally, all RPE cohorts formed drusen-like deposits in vitro. AMD/RPD- lines generated more basal deposits, whereas AMD/RPD + cells exhibited increased susceptibility to monolayer disruption. CONCLUSIONS: These findings indicate that AMD with and without RPD represent mechanistically distinct entities and provide novel insight into the molecular mechanisms underlying disease heterogeneity in AMD.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13157670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The contribution of rare germline variants to the immune landscape of breast cancer.","authors":"Felipe Rojas-Rodríguez, Sander Canisius, Renske Keeman, Aaron J Bernstein, Amber N Hurson, Thomas U Ahearn, Irene L Andrulis, Antonis C Antoniou, Sabine Behrens, Katarzyna Białkowska, Fiona M Blows, Manjeet K Bolla, Nicola J Camp, Melissa H Cessna, Jenny Chang-Claude, Stephen J Chanock, Joe Dennis, Peter Devilee, Alison M Dunning, Jacek Gronwald, Ute Hamann, Antoinette Hollestelle, Maartje J Hooning, Hugo M Horlings, Agnes Jager, Anna Jakubowska, Brandt Jones, Rudolf Kaaks, Marleen Kok, Jolanta Lissowska, Jan Lubiński, Mehdi Manoochehri, Jodi L Miller, Noor Muhammad, Anna Marie Mulligan, Nadia Obi, Muhammad U Rashid, Hans-Peter Sinn, Carolien H M van Deurzen, Qin Wang, Justin A Williams, Xiaohong R Yang, Douglas F Easton, H Raza Ali, Montserrat García-Closas, Paul D P Pharoah, Mustapha Abubakar, Marjanka K Schmidt","doi":"10.1186/s13073-026-01662-6","DOIUrl":"10.1186/s13073-026-01662-6","url":null,"abstract":"<p><strong>Background: </strong>Many breast cancer predisposition genes are involved in DNA damage repair, leading to genome instability that can impact immunosurveillance, neoantigen formation, and the composition of the tumor immune microenvironment.</p><p><strong>Methods: </strong>Here, we explored associations between germline protein truncating variants (PTVs) in 34 (putative) breast cancer predisposition genes, of which 26 involved in DNA damage repair, with the abundance of four immune cell markers, i.e., CD8 + , FOXP3 + , CD20 + and CD163 + , across 7,969 invasive breast tumors of women of European ancestry.</p><p><strong>Results: </strong>The most apparent associations were those of CD163, a marker of M2-like tumor-associated macrophages, with genes involved in double- and single-strand break DNA repair, and with the 12 known breast cancer predisposition genes combined. Specifically, DNA damage repair genes, BRCA1, BRCA2, PALB2, RAD51D, and MSH6 were associated with a 1.3 to twofold abundance of CD163-positive cells. Estrogen receptor status was found to mediate associations to a limited extent.</p><p><strong>Conclusions: </strong>Our findings support a role of rare pathogenic germline variants involved in DNA damage repair, and particularly those predisposing to breast cancer, in the immune landscape of breast tumors. These insights may help guide the development of immunomodulatory strategies for breast cancer prevention and treatment.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"African ancestry and risk variants associated with triple-negative breast cancer susceptibility in African American women.","authors":"Guochong Jia, Lili Liu, Jie Ping, Peter N Fiorica, Xingyi Guo, Ran Tao, Bingshan Li, Jian Gu, Esther M John, Olufunmilayo I Olopade, Michael F Press, Abenaa M Brewster, Andrew F Olshan, Gary Zirpoli, Ebonee N Butler, Maosheng Huang, Dezheng Huo, Julie R Palmer, Christopher A Haiman, Christine B Ambrosone, Melissa A Troester, Jirong Long, Song Yao, Wei Zheng","doi":"10.1186/s13073-026-01665-3","DOIUrl":"10.1186/s13073-026-01665-3","url":null,"abstract":"<p><strong>Background: </strong>Compared to European American women, African American women are more likely to be diagnosed with triple-negative breast cancer (TNBC). This difference may be partially due to genetic factors. This study aims to investigate associations of African ancestry and risk variants with TNBC among African American women.</p><p><strong>Methods: </strong>We used data from 2,335 TNBC cases, 8,159 estrogen receptor (ER)-positive cases, and 9,814 controls included in the African-ancestry Breast Cancer Genetics (AABCG) Consortium. The proportion of African ancestry (%AFR) and local ancestry were estimated using samples from the 1000 Genomes Project as reference. Logistic regressions were performed for case-control (TNBC vs. control) and case-case (TNBC vs. ER-positive) comparisons, adjusted for age, study, genotype principal components 2-5, body mass index, and reproductive factors. Local ancestry-aware association analyses were conducted in 12 TNBC risk loci to identify ancestry-specific risk variants.</p><p><strong>Results: </strong>In case-control analyses, no statistically significant association was found between %AFR and TNBC risk after adjustment for potential confounders. However, TNBC cases had a significantly higher mean % AFR (mean = 0.811, standard deviation, SD = 0.104) compared to ER-positive cases (mean = 0.798, SD = 0.110, P < 0.001). Females with %AFR of ≥ 95% had 1.62 times higher odds (95% confidence interval, CI: 1.16-2.25) of having TNBC rather than ER-positive breast cancer, compared to those with %AFR of 55.0-64.9%. Local ancestry-aware association analyses identified seven subtype-informative variants in or near MDM4, RP11-19E11.1, TERT, MRPL36, TCF7L2, C11orf65, and ANKLE1. All of them were significantly associated with TNBC as compared with ER-positive cases, and six of them were also associated with TNBC risk in case-control analyses. Large allelic odds ratios of 1.25 or higher were found in association with TNBC risk or subtype classification. The risk allele frequency for five of them is substantially higher in haplotypes of African ancestry than those of European ancestry.</p><p><strong>Conclusions: </strong>These findings support a significant role of African-ancestry specific genetic factors in determining breast cancer subtypes and highlight the need for future research to uncover possible pathways driving TNBC susceptibility.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13321428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival Genie 2: a next-generation web server for targeted and single-cell-based survival analyses.","authors":"Chenbin Huang, Marina E Michaud, Hope Mumme, Swati S Bhasin, Manoj K Bhasin","doi":"10.1186/s13073-026-01651-9","DOIUrl":"10.1186/s13073-026-01651-9","url":null,"abstract":"<p><strong>Background: </strong>With the growing number of publicly available cancer genomics datasets, numerous web-based survival analysis tools have been developed to link gene expression data with patient outcomes, aiming to discover novel biomarkers and therapeutic targets. However, existing tools primarily support single-gene or gene-set analyses catered to targets derived from traditional sequencing approaches, limiting their applicability in the era of single-cell genomics.</p><p><strong>Results: </strong>Here, we introduce Survival Genie 2, the first web-based platform uniquely designed to facilitate survival analyses integrating user-generated single-cell data. Through this novel approach, our tool enables researchers to identify outcome-associated genes from single-cell cluster markers and weighted gene co-expression network modules. Furthermore, Survival Genie 2 offers specialized capabilities for parsing user inputs into biologically relevant categories, including long noncoding RNAs (lncRNAs), transcription factors, and ligand-receptor signaling genes, enhancing the robustness and interpretability of survival associations. Importantly, Survival Genie 2 also hosts the most comprehensive database to date, comprising 132 datasets from 53 cancer genome projects across 38 distinct malignancies, including both adult and pediatric cancers. The tool further provides versatile partitioning methods, generating analysis results through univariate Cox proportional hazards modeling, which are presented in publication-ready Kaplan-Meier and integrated forest plots. Additionally, Survival Genie 2 uniquely bridges the gap between publicly available bulk sequencing datasets and cell-type-specific targets derived from the user's single-cell sequencing data by correlating user input gene expression with predicted immune cell enrichment, estimated through deconvolution analysis on the selected cancer dataset.</p><p><strong>Conclusions: </strong>By integrating these innovative features, with specialized survival analyses on single-cell cluster markers, co-expression modules, regulatory networks, and ligand-receptor pairs, Survival Genie 2 represents a novel tool for expanding the translational impact of cancer research, enabling the precise identification of biomarkers and therapeutic targets. Survival Genie 2 is available at https://bhasinlab.bmi.emory.edu/SurvivalGenie2/home.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive molecular characterization identifies therapeutic vulnerabilities in ovarian clear cell carcinoma.","authors":"Yong Wu, Xinyi Guo, Tiantian Wang, Tianyi Zhao, Siyu Chen, Ying Su, Qin Li, Jun Zhu, Lingfang Xia, Xingzhu Ju, Xiaohua Wu, Shenglin Huang, Zhixiang Hu, Xiaojun Chen","doi":"10.1186/s13073-026-01663-5","DOIUrl":"10.1186/s13073-026-01663-5","url":null,"abstract":"<p><strong>Background: </strong>Ovarian clear cell carcinoma (OCCC) is a rare aggressive, and chemo-resistant subtype of epithelial ovarian cancer. Current limitations in precisely characterizing its molecular features have resulted in restricted availability of clinical targeted therapies and significant therapeutic challenges.</p><p><strong>Methods: </strong>To address this unmet need, we conducted an integrative multi-omics study of 82 OCCC cases, incorporating whole-exome sequencing (WES), bulk RNA sequencing, and single-cell RNA sequencing (scRNA-seq).</p><p><strong>Results: </strong>Our analysis uncovered recurrent mutations in multiple epigenetic regulators including ARID1A, EP300, and SETD2B, reinforcing chromatin remodeling as a hallmark of OCCC pathogenesis. Strikingly, FOXA2 mutations were absent in early-stage tumors but specifically enriched in advanced-stage cases (19% frequency), with functional validation demonstrating their role in driving malignant progression. Copy number alteration profiling revealed frequent amplifications in chromosomal arms such as 17q, which contains the ERBB2 oncogene that potentially regulates OCCC progression. Chromosomal translocations were detected in 35.59% of cases, including a novel FGFR2/RPAP3 fusion with therapeutic implications. Notably, scRNA-seq delineated immune-rich subsets characterized by abundant cytotoxic T-cell and B-cell infiltration, suggesting immunotherapeutic opportunities in a patient subset. Moreover, molecular subtyping identified ERBB2 amplification/overexpression as a high-risk feature strongly associated with poor survival. Patient-derived xenograft (PDX) models and a retrospective analysis of two clinical cases demonstrated that HER2-targeted antibody-drug conjugates (HER2-ADCs) significantly suppressed tumor growth and progression in OCCC patients with HER2 expression.</p><p><strong>Conclusions: </strong>In summary, our study establishes the comprehensive molecular atlas and a targeted therapeutic subtyping framework, revealing therapeutic vulnerabilities and providing novel insights for advancing precision oncology in OCCC management.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13312614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Twelve years of genomic surveillance of vancomycin-resistant Enterococcus faecium: emergence of linear vanA and bacteriocin-carrying plasmids challenging infection control.","authors":"Ana C Almeida-Santos, Ana P Tedim, Bárbara Duarte, Ana P Pereira, Luís M Silva, Júlio Teixeira, Ana P Castro, Louise Roer, Anette M Hammerum, Henrik Hasman, Teresa M Coque, Carla Novais, Ana R Freitas, Luísa Peixe","doi":"10.1186/s13073-026-01656-4","DOIUrl":"10.1186/s13073-026-01656-4","url":null,"abstract":"<p><strong>Background: </strong>The epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) varies across different countries, with a steady global increase. In Portugal, however, epidemiological data on clinical VREfm have been scarce since the early 2000s. This long-term study investigates VREfm isolates from human infections collected at a Porto hospital between 2010 and 2021.</p><p><strong>Methods: </strong>Two hundred VREfm isolates, mostly urinary (39%) were characterized by antimicrobial susceptibility testing to 8 antibiotics, chlorhexidine susceptibility, and PCR-based detection of vancomycin-resistance genes, virulence markers, plasmid replicases, and the bac43/T8 gene. Whole-genome sequencing, by Illumina, was used to assess clonal diversity (MLST, cgMLST, SNP phylogeny) and genomic content of antimicrobial resistance (AMR) genes, bacteriocins (76 genes) and putative virulence markers (35 genes). The plasmidome size and replicase initiation proteins of selected isolates was further improved by incorporating nanopore sequencing which enabled hybrid assemblies.</p><p><strong>Results: </strong>All isolates were multidrug resistant; 98% carried vanA, while two (1%) were resistant to linezolid (G2576T mutation). Chlorhexidine susceptibility remained stably low over time (MICs: 2-4 mg/L). The population was polyclonal, with a shift from ST18-like lineages to ST80 and ST117 dominance. While ARGs and virulence markers showed no clear association with clonal waves, bacteriocin profiles did, with bac43 becoming increasingly prevalent. ST117-CT24 emerged as the most persistent clone. The plasmidome comprised stable Rep3-like mobilizable plasmids carrying bacteriocins (bac43, bacAS5), RepA_N mega-plasmids harboring virulence/AMR/bacteriocins, and highly plastic medium-to-large vanA plasmids with diverse replicase initiation proteins. Strikingly, linear vanA plasmids (repUS78_pZY2) appeared in the most recent isolates, paralleling findings in vancomycin-variable E. faecium from the same hospital and VREfm from other countries.</p><p><strong>Conclusions: </strong>Our findings reveal dynamic clonal shifts, novel plasmid architectures, and the key role of bacteriocins in shaping clonal success in a WHO priority pathogen. Furthermore, we highlight the need for AMR surveillance frameworks to consider factors beyond conventional prevalence metrics and core-genome comparisons. Integrating intra-species genomic heterogeneity and non-traditional evolutionary indicators will be essential to more accurately predict, track, and ultimately mitigate the dissemination of multidrug-resistant human pathogens.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}