Genome Medicine最新文献

{"title":"Distinct pathway-based effects of blood pressure and body mass index on cardiovascular traits: comparison of novel Mendelian randomization approaches.","authors":"Genevieve M Leyden, Maria K Sobczyk, Tom G Richardson, Tom R Gaunt","doi":"10.1186/s13073-025-01472-2","DOIUrl":"10.1186/s13073-025-01472-2","url":null,"abstract":"<p><strong>Background: </strong>Mendelian randomization (MR) leverages trait associated genetic variants as instrumental variables (IVs) to determine causal relationships in epidemiology. However, genetic IVs for complex traits are typically highly heterogeneous and, at a molecular level, exert effects on different biological processes. Exploration of the biological underpinnings of such heterogeneity can enhance our understanding of disease mechanisms and inform therapeutic strategies. Here, we introduce a new approach to instrument partitioning based on enrichment of Mendelian disease categories (pathway-partitioned) and compare it to an existing method based on genetic colocalization in contrasting tissues (tissue-partitioned).</p><p><strong>Methods: </strong>We employed individual- and summary-level MR methodologies using SNPs grouped by pathway informed by proximity to Mendelian disease genes affecting the renal system or vasculature (for blood pressure (BP)), or mental health and metabolic disorders (for body mass index (BMI)). We compared the causal effects of pathway-partitioned SNPs on cardiometabolic outcomes with those derived using tissue-partitioned SNPs informed by colocalization with gene expression in kidney, artery (BP), or adipose and brain tissues (BMI). Additionally, we assessed the likelihood that estimates observed for partitioned exposures could emerge by chance using random SNP sampling.</p><p><strong>Results: </strong>Our pathway-partitioned findings suggest the causal relationship between systolic BP and heart disease is predominantly driven by vessel over renal pathways. The stronger effect attributed to kidney over artery tissue in our tissue-partitioned MR hints at a multifaceted interplay between pathways in the disease aetiology. We consistently identified a dominant role for vessel (pathway) and artery (tissue) driving the negative directional effect of diastolic BP on left ventricular stroke volume and positive directional effect of systolic BP on type 2 diabetes. We also found when dissecting the BMI pathway contribution to atrial fibrillation that metabolic-pathway and brain-tissue IVs predominantly drove the causal effects relative to mental health and adipose in pathway- and tissue-partitioned MR analyses, respectively.</p><p><strong>Conclusions: </strong>This study presents a novel approach to dissecting heterogeneity in MR by integrating clinical phenotypes associated with Mendelian disease. Our findings emphasize the importance of understanding pathway-/tissue-specific contributions to complex exposures when interpreting causal relationships in MR. Importantly, we advocate caution and robust validation when interpreting pathway-partitioned effect size differences.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"54"},"PeriodicalIF":10.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077419","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 rights in precision oncology: right treatment, right time, right dose, right order, right place.","authors":"Elena Fountzilas, Apostolia-Maria Tsimberidou, Razelle Kurzrock","doi":"10.1186/s13073-025-01468-y","DOIUrl":"10.1186/s13073-025-01468-y","url":null,"abstract":"<p><p>Precision oncology has facilitated a transition from a one-size-fits-all to a precise individualized approach. This Comment discusses the broader challenges in the implementation of personalized treatments to further improve patients' outcomes, towards comprehensive strategies that address tumor complexity and patients' molecular portfolios, as well as quality of life and diversity considerations.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"53"},"PeriodicalIF":10.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013270","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":"Effect of newborn genomic screening for lysosomal storage disorders: a cohort study in China.","authors":"Xin Wang, Yun Sun, Xian-Wei Guan, Yan-Yun Wang, Dong-Yang Hong, Zhi-Lei Zhang, Ya-Hong Li, Pei-Ying Yang, Tao Jiang, Zheng-Feng Xu","doi":"10.1186/s13073-025-01483-z","DOIUrl":"10.1186/s13073-025-01483-z","url":null,"abstract":"<p><strong>Background: </strong>Lysosomal storage disorders (LSDs) have a relatively high incidence among rare diseases and can lead to severe consequences if not treated promptly. However, many countries and regions have not included these disorders in their newborn screening programs, resulting in missed early detection, underdiagnosis, and delayed treatment. Newborn genomic screening (NBGS) has shown good screening effectiveness for traditional biochemical screening diseases; however, its effectiveness for LSDs has not yet been evaluated in the general newborn population.</p><p><strong>Methods: </strong>To evaluate the outcome of NBGS for LSDs, a cohort study was conducted involving newborns recruited from Nanjing Women and Children's Healthcare Hospital in China from March 18, 2022, to September 21, 2023. All participants underwent NBGS of 15 LSDs (18 genes) via dried blood spots, followed by enzyme activity testing for NBGS-positive individuals. The study calculated the incidence and carrier rates for each LSD though NBGS, as well as the positive screening rate, the false positive rate and the positive predictive value of the screening process.</p><p><strong>Results: </strong>Among 22,687 newborns (11,996 males [52.88%]), 1344 (6.0%) were identified as carriers, and 30 (0.13%) were initially positive for LSDs. Of these, 4 were excluded, 15 were diagnosed as LSD-presymptomatic individuals based on enzyme deficiency and pathogenic variants conforming to inheritance patterns, and 11 remain under follow-up. The estimated combined birth incidence of LSDs in Nanjing was 1/1512, primarily including Fabry disease, Krabbe disease, glycogen storage disease type II, Niemann-Pick disease, and mucopolysaccharidosis type II. Rather than directly comparing NBGS and enzyme activity screening, this study evaluated two sequential screening strategies: (1) NBGS-first with reflex enzyme testing and (2) enzyme activity-first with reflex genomic testing. The NBGS-first strategy demonstrated higher sensitivity and specificity, with a significantly lower false positive rate and higher positive predictive values compared to the enzyme-first strategy (P < 0.05).</p><p><strong>Conclusions: </strong>This study highlights the potential of NBGS to enhance early detection of presymptomatic LSD individuals, enabling timely interventions and improving newborn health outcomes. Integrating NBGS into routine newborn screening programs could provide an effective and proactive approach for LSD identification and management.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"52"},"PeriodicalIF":10.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991727","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 TyphiNET data visualisation dashboard: unlocking Salmonella Typhi genomics data to support public health.","authors":"Zoe A Dyson, Louise Cerdeira, Vandana Sharma, Megan E Carey, Kathryn E Holt","doi":"10.1186/s13073-025-01470-4","DOIUrl":"https://doi.org/10.1186/s13073-025-01470-4","url":null,"abstract":"<p><strong>Background: </strong>Salmonella enterica subspecies enterica serovar Typhi (abbreviated as 'Typhi') is the bacterial agent of typhoid fever. Effective antimicrobial therapy reduces complications and mortality; however, antimicrobial resistance (AMR) is a major problem in many endemic countries. Prevention through vaccination is possible through recently-licensed typhoid conjugate vaccines (TCVs). National immunisation programs are currently being considered or deployed in several countries where AMR prevalence is known to be high, and the Gavi vaccine alliance has provided financial support for their introduction. Pathogen whole genome sequence data are a rich source of information on Typhi variants (genotypes or lineages), AMR prevalence, and mechanisms. However, this information is currently not readily accessible to non-genomics experts, including those driving vaccine implementation or empirical therapy guidance.</p><p><strong>Results: </strong>We developed TyphiNET ( https://www.typhi.net ), an interactive online dashboard for exploring Typhi genotype and AMR distributions derived from publicly available pathogen genome sequences. TyphiNET allows users to explore country-level summaries such as the frequency of pathogen lineages, temporal trends in resistance to clinically relevant antimicrobials, and the specific variants and mechanisms underlying emergent AMR trends. User-driven plots and session reports can be downloaded for ease of sharing. Importantly, TyphiNET is populated by high-quality genome data curated by the Global Typhoid Pathogen Genomics Consortium, analysed using the Pathogenwatch platform, and identified as coming from non-targeted sampling frames that are suitable for estimating AMR prevalence amongst Typhi infections (no personal data is included in the platform). As of February 2024, data from a total of n = 11,836 genomes from 101 countries are available in TyphiNET. We outline case studies illustrating how the dashboard can be used to explore these data and gain insights of relevance to both researchers and public health policy-makers.</p><p><strong>Conclusions: </strong>The TyphiNET dashboard provides an interactive platform for accessing genome-derived data on pathogen variant frequencies to inform typhoid control and intervention strategies. The platform is extensible in terms of both data and features, and provides a model for making complex bacterial genome-derived data accessible to a wide audience.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"51"},"PeriodicalIF":10.4,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013608","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":"Early-life and concurrent predictors of the healthy adolescent microbiome in a cohort study.","authors":"Hannah E Laue, Amy D Willis, Fang Wang, Melinda C MacDougall, Yingying Xu, Margaret R Karagas, Juliette C Madan, Abby F Fleisch, Bruce P Lanphear, Kim M Cecil, Kimberly Yolton, Aimin Chen, Jessie P Buckley, Joseph M Braun","doi":"10.1186/s13073-025-01481-1","DOIUrl":"https://doi.org/10.1186/s13073-025-01481-1","url":null,"abstract":"<p><strong>Background: </strong>The microbiome of adolescents is poorly understood, as are factors influencing its composition. We aimed to describe the healthy adolescent microbiome and identify early-life and concurrent predictors of its composition.</p><p><strong>Methods: </strong>We performed metagenomic sequencing of 247 fecal specimens from 167 adolescents aged 11-14 years participating in the Health Outcomes and Measures of the Environment (HOME) Study, a longitudinal pregnancy and birth cohort (Cincinnati, OH). We described common features of the adolescent gut microbiome and applied self-organizing maps (SOMs)-a machine-learning approach-to identify distinct microbial profiles (n = 4). Using prospectively collected data on sociodemographic characteristics, lifestyle, diet, and sexual maturation, we identified early-life and concurrent factors associated with microbial diversity and phylum relative abundance with linear regression models and composition with Kruskal-Wallis and Fisher's exact tests.</p><p><strong>Results: </strong>We found that household income and other sociodemographic factors were consistent predictors of the microbiome, with higher income associated with lower diversity and differential relative abundances of Firmicutes (increased) and Actinobacteria (decreased). Sexual maturation, distinct from chronological age, was related to higher diversity in females and differences in phylum relative abundances and compositional profiles in both males and females.</p><p><strong>Conclusions: </strong>Our study suggests that adolescence is a unique window for gut microbial composition and that it may be shaped by both early-life and concurrent exposures, highlighting its potential in future epidemiologic research.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"50"},"PeriodicalIF":10.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012337","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":"Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor.","authors":"Jenny Wegert, Silke Appenzeller, Taryn D Treger, Heike Streitenberger, Barbara Ziegler, Sabrina Bausenwein, Christian Vokuhl, Conor Parks, Eva Jüttner, Susanne Gramlich, Karen Ernestus, Steven W Warman, Jörg Fuchs, Jochen Hubertus, Dietrich von Schweinitz, Birgit Fröhlich, Norbert Jorch, Ralf Knöfler, Carsten Friedrich, Selim Corbacioglu, Michael C Frühwald, Arnulf Pekrun, Dominik T Schneider, Jörg Faber, Jana Stursberg, Markus Metzler, Nils Welter, Kathy Pritchard-Jones, Norbert Graf, Rhoikos Furtwängler, Sam Behjati, Manfred Gessler","doi":"10.1186/s13073-025-01482-0","DOIUrl":"https://doi.org/10.1186/s13073-025-01482-0","url":null,"abstract":"<p><strong>Background: </strong>Genetic predisposition is particularly common in children with the kidney cancer, Wilms tumor. In 10% of these children, this manifests as a family history of Wilms tumor or bilateral disease. The frequency and spectrum of underlying changes have not been systematically investigated.</p><p><strong>Methods: </strong>We analyzed 129 children with suspected Wilms tumor predisposition, 20 familial cases, and 109 children with bilateral disease, enrolled over 30 years in the German SIOP93-01/GPOH and SIOP2001 studies. We used whole exome, whole genome, and targeted DNA sequencing, together with MLPA and targeted methylation assays on tumor, blood, and normal kidney to determine predisposing changes.</p><p><strong>Results: </strong>Predisposing variants were identified in 117/129 children, comprising DNA variants (57%) and epigenetic changes (34%). Most children had predisposition variants in genes previously implicated in Wilms tumor: most prominently WT1 (n = 35) and less frequently TRIM28, REST, DIS3L2, CTR9, DICER1, CDC73, and NONO. Nine children carried germline mutations in cancer predisposition genes not considered Wilms tumor predisposition genes, such as CHEK2, CDKN2A, BLM, BRCA2, STK11, and FMN2. Predisposition via epigenetic BWS-IC1 alterations occurred as early somatic events, reflected by partial (mosaic) loss of imprinting or loss of heterozygosity at the IGF2/H19 locus in normal kidney or blood. These patients rarely had a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS). Especially WT1-driven tumors follow a stereotypical pathway of germline WT1 mutations becoming homozygous in renal precursor lesions through 11p LOH, which concomitantly activates imprinted IGF2 expression, with subsequent WNT pathway activation leading to tumor growth. There is a high rate of multicentric tumors, which may have previously been missed in unilateral tumors. While Wilms tumor predisposition genes relied on somatic inactivation of the second allele, this was different for general cancer predisposition genes. The latter cases were often associated with additional oncogenic alterations, similar to tumors with epigenetic predisposition.</p><p><strong>Conclusions: </strong>We identified two main mechanisms of Wilms tumor predisposition: either germline genetic alterations of Wilms tumor and, less frequently, general cancer genes; or postzygotic mosaic imprinting defects activating IGF2. These findings inform future genetic screening and risk assessment of affected children and lend support to liquid biopsy screening for enhanced therapeutic stratification.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"49"},"PeriodicalIF":10.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967523","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":"Combining chromosome conformation capture and exome sequencing for simultaneous detection of structural and single-nucleotide variants.","authors":"Maria Gridina, Timofey Lagunov, Polina Belokopytova, Nikita Torgunakov, Miroslav Nuriddinov, Artem Nurislamov, Lyudmila P Nazarenko, Anna A Kashevarova, Maria E Lopatkina, Stanislav Vasilyev, Andrey Zuev, Elena O Belyaeva, Olga A Salyukova, Aleksandr D Cheremnykh, Natalia N Sukhanova, Marina E Minzhenkova, Zhanna G Markova, Nina A Demina, Yana Stepanchuk, Anna Khabarova, Alexandra Yan, Emil Valeev, Galina Koksharova, Elena V Grigor'eva, Natalia Kokh, Tatiana Lukjanova, Yulia Maximova, Elizaveta Musatova, Elena Shabanova, Andrey Kechin, Evgeniy Khrapov, Uliana Boyarskih, Oxana Ryzhkova, Maria Suntsova, Alina Matrosova, Mikhail Karoli, Andrey Manakhov, Maxim Filipenko, Evgeny Rogaev, Nadezhda V Shilova, Igor N Lebedev, Veniamin Fishman","doi":"10.1186/s13073-025-01471-3","DOIUrl":"https://doi.org/10.1186/s13073-025-01471-3","url":null,"abstract":"<p><strong>Background: </strong>Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type-whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs).</p><p><strong>Methods: </strong>We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy.</p><p><strong>Results: </strong>Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases.</p><p><strong>Conclusions: </strong>Through several case studies, we demonstrate how Exo-C's multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"47"},"PeriodicalIF":10.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002206","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":"Retroelement co-option disrupts the cancer transcriptional programme.","authors":"Jane Loong, Rachael Thompson, Callum Hall, Laura Doglio, Judith Pape, Tobias Plowman, George Kassiotis","doi":"10.1186/s13073-025-01479-9","DOIUrl":"https://doi.org/10.1186/s13073-025-01479-9","url":null,"abstract":"<p><strong>Background: </strong>Transcriptional activation of otherwise repressed retrotransposable elements (RTEs) is a hallmark of cancer, shaping tumour progression and immunogenicity by multifaceted, yet incompletely understood, mechanisms.</p><p><strong>Methods: </strong>We used an extended pan-cancer transcriptome assembly to identify potential effects of RTEs on the genes within which they have integrated or those in proximity. These were subsequently verified in test cases by further analysis of transcriptional profiles in cancer patient data, and by in vitro studies involving restoration of gene activity, and proliferation and migration assays in cancer cell lines.</p><p><strong>Results: </strong>We report that cancer-specific transcriptional activation of RTEs causes frequent reduction or loss of gene function. Exonisation and alternative splicing of RTEs creates non-functional RNA and protein isoforms and derepressed RTE promoter activity initiates antisense transcription, both at the expense of the canonical isoforms. Contrary to theoretical expectation, transcriptionally activated RTEs affect genes with established tumour-promoting functions, including the common essential RNGTT and the lung cancer-promoting CHRNA5 genes. Furthermore, the disruptive effect of RTE activation on adjacent tumour-promoting genes is associated with slower disease progression in clinical data, whereas experimental restoration of gene activity enhances tumour cell growth and invasiveness in vitro.</p><p><strong>Conclusions: </strong>These findings underscore the gene-disruptive potential of seemingly innocuous germline RTE integrations, unleashed only by their transcriptional utilisation in cancer. They further suggest that such metastable RTE integrations are co-opted as sensors of the epigenetic and transcriptional changes occurring during cellular transformation and as executors that disrupt the function of tumour-promoting genes.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"48"},"PeriodicalIF":10.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019006","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":"Simultaneous detection of pathogens and antimicrobial resistance genes with the open source, cloud-based, CZ ID platform.","authors":"Dan Lu, Katrina L Kalantar, Abigail L Glascock, Victoria T Chu, Estella S Guerrero, Nina Bernick, Xochitl Butcher, Kirsty Ewing, Elizabeth Fahsbender, Olivia Holmes, Erin Hoops, Ann E Jones, Ryan Lim, Suzette McCanny, Lucia Reynoso, Karyna Rosario, Jennifer Tang, Omar Valenzuela, Peter M Mourani, Amy J Pickering, Amogelang R Raphenya, Brian P Alcock, Andrew G McArthur, Charles R Langelier","doi":"10.1186/s13073-025-01480-2","DOIUrl":"https://doi.org/10.1186/s13073-025-01480-2","url":null,"abstract":"<p><strong>Background: </strong>Antimicrobial resistant (AMR) pathogens represent urgent threats to human health, and their surveillance is of paramount importance. Metagenomic next-generation sequencing (mNGS) has revolutionized such efforts, but remains challenging due to the lack of open-access bioinformatics tools capable of simultaneously analyzing both microbial and AMR gene sequences.</p><p><strong>Results: </strong>To address this need, we developed the Chan Zuckerberg ID (CZ ID) AMR module, an open-access, cloud-based workflow designed to integrate detection of both microbes and AMR genes in mNGS and single-isolate whole-genome sequencing (WGS) data. It leverages the Comprehensive Antibiotic Resistance Database and associated Resistance Gene Identifier software, and works synergistically with the CZ ID short-read mNGS module to enable broad detection of both microbes and AMR genes from Illumina data. We highlight diverse applications of the AMR module through analysis of both publicly available and newly generated mNGS and single-isolate WGS data from four clinical cohort studies and an environmental surveillance project. Through genomic investigations of bacterial sepsis and pneumonia cases, hospital outbreaks, and wastewater surveillance data, we gain a deeper understanding of infectious agents and their resistomes, highlighting the value of integrating microbial identification and AMR profiling for both research and public health. We leverage additional functionalities of the CZ ID mNGS platform to couple resistome profiling with the assessment of phylogenetic relationships between nosocomial pathogens, and further demonstrate the potential to capture the longitudinal dynamics of pathogen and AMR genes in hospital acquired bacterial infections.</p><p><strong>Conclusions: </strong>In sum, the new AMR module advances the capabilities of the open-access CZ ID microbial bioinformatics platform by integrating pathogen detection and AMR profiling from mNGS and single-isolate WGS data. Its development represents an important step toward democratizing pathogen genomic analysis and supporting collaborative efforts to combat the growing threat of AMR.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"46"},"PeriodicalIF":10.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018936","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 analysis reveals immunosuppression in oesophageal squamous cell carcinoma induced by creatine accumulation and HK3 deficiency.","authors":"Yingzhen Gao, Siyu He, Xiaoyan Meng, Kun Zheng, Heyang Cui, Yikun Cheng, Xinyuan Shen, Yuanfang Zhai, Binbin Zou, Fang Wang, Hongyi Li, Pengzhou Kong, Yanqiang Wang, Xuefei Feng, Bin Yang, Ruifang Sun, Yongsheng Meng, Enwei Xu, Yanlin Guo, Ning Ding, Weimin Zhang, Xiaolong Cheng, Lunzhi Dai, Yongping Cui, Ling Zhang","doi":"10.1186/s13073-025-01465-1","DOIUrl":"https://doi.org/10.1186/s13073-025-01465-1","url":null,"abstract":"<p><strong>Background: </strong>Deep insights into the metabolic remodelling effects on the immune microenvironment of oesophageal squamous cell carcinoma (ESCC) are crucial for advancing precision immunotherapies and targeted therapies. This study aimed to provide novel insights into the molecular landscape of ESCC and identify clinically actionable targets associated with immunosuppression driven by metabolic changes.</p><p><strong>Methods: </strong>We performed metabolomic and proteomic analyses combined with previous genomic and transcriptomic data, identified multi-omics-linked molecular features, and constructed metabolic-immune interaction-based ESCC classifiers in a discovery cohort and an independent validation cohort. We further verified the molecular characteristics and related mechanisms of ESCC subtypes.</p><p><strong>Results: </strong>Our integrated multi-omics analysis revealed dysregulated proteins and metabolic imbalances characterizing ESCC, with significant alterations in metabolites and proteins linked to genetic traits. Importantly, ESCC patients were stratified into three subtypes (S1, S2, and S3) on the basis of integrated metabolomic and proteomic data. A robust subtype prediction model was developed and validated across two independent cohorts. Notably, patients classified under the poorest prognosis subtype (S3 subtype) exhibited a significant immunosuppressive microenvironment. We identified key metabolism-related biomarkers for the S3 subtype, specifically creatine and hexokinase 3 (HK3). Creatine accumulation and HK3 protein deficiency synergistically reprogrammed macrophage metabolism, driving M2-like TAM polarization. This metabolic shift fostered an immunosuppressive microenvironment that accelerated tumour progression. These results highlight the potential of targeting creatine metabolism to improve the efficacy of immunotherapy and targeted therapy for ESCC.</p><p><strong>Conclusions: </strong>Our analysis reveals molecular variation in multi-omics linkages and identifies targets that reverse the immunosuppressive microenvironment through metabolic remodelling improving immunotherapy and targeted therapy for ESCC.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"44"},"PeriodicalIF":10.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992555","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}