Genome Medicine最新文献

{"title":"Developing a novel aging assessment model to uncover heterogeneity in organ aging and screening of aging-related drugs.","authors":"Yingqi Xu, Maohao Li, Congxue Hu, Yawen Luo, Xing Gao, Xinyu Li, Xia Li, Yunpeng Zhang","doi":"10.1186/s13073-025-01501-0","DOIUrl":"10.1186/s13073-025-01501-0","url":null,"abstract":"<p><strong>Background: </strong>The decline in organ function due to aging significantly impacts the health and quality of life of the elderly. Assessing and delaying aging has become a major societal concern. Previous studies have largely focused on differences between young and old individuals, often overlooking the complexity and gradual nature of aging.</p><p><strong>Methods: </strong>In this study, we constructed a comprehensive multi-organ aging atlas in mice and systematically analyzed the aging trajectories of 16 organs to elucidate their functional specificity and identify organ-specific aging trend genes. Cross-organ association analysis was employed to identify global aging regulatory genes, leading to the development of a multi-organ aging assessment model, hereafter referred to as the 2A model. The model's validity was confirmed using single-cell RNA sequencing data from aging mouse lungs, cross-species gene expression profiles, and pharmacogenomic data. Furthermore, a random walk algorithm and a weighted integration approach combining gene set enrichment analysis were implemented to systematically screen potential drugs for mitigating multi-organ aging.</p><p><strong>Results: </strong>The 2A model effectively assessed aging states in both human and mouse tissues and demonstrated predictive capability for senescent cell clearance rates. Compared to the sc-ImmuAging and SCALE clocks, the 2A model exhibited superior predictive accuracy at the single-cell level. Organ-specific analyses identified the lungs and kidneys as particularly susceptible to aging, with immune dysfunction and programmed cell death emerging as key contributors. Notably, single-cell data confirmed that plasma cell accumulation and naive-like cell reduction showed linear changes during organ aging. Aging trend genes identified in each organ were significantly enriched in aging-related functional pathways, enabling precise assessment of the aging process and determination of organ-specific aging milestones. Additionally, drug screening identified Fostamatinib, Ranolazine, and Metformin as potential modulators of multi-organ aging, with mechanisms involving key pathways such as longevity regulation and circadian rhythm.</p><p><strong>Conclusions: </strong>The 2A model represents a significant advancement in aging assessment by integrating multi-dimensional validation strategies, enhancing its accuracy and applicability. The identification of organ-specific aging pathways and candidate pharmacological interventions provides a theoretical foundation and translational framework for precision anti-aging therapies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"83"},"PeriodicalIF":10.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707323","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":"Epigenomic preconditioning of peripheral monocytes determines their transcriptional response to the tumor microenvironment.","authors":"Máté Kiss, Laszlo Halasz, Eva Hadadi, Wilhelm K Berger, Petros Tzerpos, Szilard Poliska, Daliya Kancheva, Aurélie Gabriel, Romina Mora Barthelmess, Ayla Debraekeleer, Jan Brughmans, Yvon Elkrim, Liesbet Martens, Yvan Saeys, Bence Daniel, Zsolt Czimmerer, Damya Laoui, Laszlo Nagy, Jo A Van Ginderachter","doi":"10.1186/s13073-025-01511-y","DOIUrl":"10.1186/s13073-025-01511-y","url":null,"abstract":"<p><strong>Background: </strong>Monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in controlling transcriptional responses to the tissue environment. It remains unknown whether systemic tumor-associated signals could alter the epigenomic landscape of peripheral monocytes before they reach the tumor, thus shaping their subsequent response to the tumor microenvironment.</p><p><strong>Methods: </strong>We used a combination of genome-wide assays for chromatin accessibility and multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) in a mouse tumor model to investigate changes in the epigenomic landscape of peripheral monocytes. We then integrated these epigenomic data with transcriptomic data to link altered regulatory elements to gene expression changes in monocytes occurring in the periphery or during tumor infiltration.</p><p><strong>Results: </strong>We found that tumor-induced systemic inflammation was associated with transcriptional and epigenomic preconditioning of peripheral monocytes. The distal tumor caused extensive remodeling of both H3K4me3⁺ promoters and H3K4me1⁺ enhancers. Specifically, this involved the repression of interferon-responsive regulatory elements as well as the establishment of enhancers harboring binding motifs for transcription factor families downstream of pro-inflammatory signaling, such as C/EBP, AP-1, and STAT. Reprogrammed enhancers in peripheral monocytes were linked to sustained gene expression changes that persisted after tumor infiltration. In addition, key pro-tumor genes upregulated in tumor-infiltrating monocytes showed epigenetic priming already in the circulation.</p><p><strong>Conclusions: </strong>These results suggest that cancer-associated remodeling of the epigenomic landscape in peripheral monocytes can shape the gene expression programs they acquire in the tumor, highlighting the role of the epigenome in redirecting monocyte function to support cancer progression.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"82"},"PeriodicalIF":10.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698306","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":"Impact of genetic risk and lifestyles on cardiovascular disease-free and total life expectancy: a cohort study.","authors":"Dong Sun, Qiufen Sun, Yinqi Ding, Canqing Yu, Dianjianyi Sun, Yuanjie Pang, Pei Pei, Ling Yang, Iona Y Millwood, Robin G Walters, Huaidong Du, Jun Zhang, Dan Schmidt, Junshi Chen, Zhengming Chen, Liming Li, Jun Lv","doi":"10.1186/s13073-025-01487-9","DOIUrl":"10.1186/s13073-025-01487-9","url":null,"abstract":"<p><strong>Background: </strong>Understanding the role of genetic risk and lifestyles on life expectancy (LE) without cardiovascular disease (CVD) and total LE may help optimize healthy aging strategies after taking genetic background into account.</p><p><strong>Methods: </strong>The China Kadoorie Biobank recruited participants from five urban and five rural areas across China during 2004-2008 and followed them up till December 31, 2018. A polygenic risk score (PRS) comprising 3.5 million genetic variants for overall CVD was constructed by combining multiple PRSs for CVD and CVD-related risk factors in 96,400 participants. Genetic risk was categorized into low, intermediate, and high according to the PRS, and lifestyles were categorized as favorable, intermediate, and unfavorable according to the number of unfavorable lifestyles. Using multistate life tables, we estimated CVD-free and total LE at age 40 for different genetic and lifestyle risk groups.</p><p><strong>Results: </strong>Genetic risk was more strongly associated with CVD onset than post-CVD mortality. As a result, the increase in LE without CVD associated with low genetic risk (4.9 years (95% CI 4.3-5.5) for women and 4.4 years (3.6-5.1) for men) was greater than the increase in total LE (2.9 years (1.8-3.8) for women and 2.6 years (1.5-3.5) for men) when compared to high genetic risk. In contrast, the association strengths of lifestyles with CVD onset and mortality after CVD were similar. Correspondingly, compared to those with unfavorable lifestyles, participants with favorable lifestyles had longer total LE and LE without CVD of 3.0 (1.5-4.3) and 4.0 (3.0-4.9) years in women and 5.7 (4.1-7.1) and 5.8 (4.7-6.9) years in men, respectively. Participants with high genetic risk benefited more from favorable lifestyles than those with low and intermediate genetic risk, gaining 5.9 (2.3-9.3) and 5.3 (3.0-7.6) years in women and 6.1 (0.8-10.6) and 6.2 (2.3-9.8) years in men for total and CVD-free LE, respectively.</p><p><strong>Conclusions: </strong>Improving lifestyles is critical for reducing CVD-related healthcare burden and promoting healthy aging, especially for individuals with high genetic risk.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"81"},"PeriodicalIF":10.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690008","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":"Microbiome-based prediction of allogeneic hematopoietic stem cell transplantation outcome.","authors":"Oshrit Shtossel, Adi Eshel, Shalev Fried, Mika Geva, Ivetta Danylesko, Ronit Yerushalmi, Noga Shem-Tov, Joshua A Fein, Marco Fabbrini, Avichai Shimoni, Sondra Turjeman, Yoram Louzoun, Arnon Nagler, Omry Koren, Roni Shouval","doi":"10.1186/s13073-025-01507-8","DOIUrl":"10.1186/s13073-025-01507-8","url":null,"abstract":"<p><strong>Background: </strong>Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative for hematologic malignancies but is frequently complicated by relapse and immune-mediated complications, such as graft-versus-host disease (GVHD). Emerging evidence suggests a role for the intestinal and oral microbiome in modulating HSCT outcomes, yet predictive models incorporating microbiome data remain limited.</p><p><strong>Methods: </strong>We applied the RATIO (suRvival Analysis lefT barrIer lOss) model to longitudinal stool and saliva microbiome data from 204 adult HSCT recipients to predict the timing of seven outcomes: overall survival (OS), non-relapse mortality (NRM), relapse, acute GVHD (grades II-IV and III-IV), chronic GVHD, and oral chronic GVHD. A total of 514 stool and 1291 saliva samples were collected over 70 weeks post-HSCT. Model performance was evaluated using the concordance index (CI) and Spearman correlation coefficient (SCC), with SHAP (SHapley Additive exPlanations) analysis used for model interpretability.</p><p><strong>Results: </strong>Oral and stool microbial dysbiosis peaked within the first 2 weeks post-HSCT, followed by partial recovery. Using the RATIO model, we found that microbiome features from early time points (weeks 1-2) were most predictive of short-term complications such as acute GVHD, while later samples (weeks 36-70) were more informative for long-term outcomes, including overall survival. RATIO outperformed traditional survival models (Cox and Random Survival Forest) across most outcomes (median CI > 0.65), with stool microbiota showing greater predictive power than saliva. SHAP analysis identified specific stool genera, including Collinsella and Eggerthella, associated with shorter time to various complications. External validation using a pediatric GVHD cohort confirmed the model's generalizability and reproducibility. External validation using a pediatric HSCT cohort (n = 90) confirmed the reproducibility and generalizability of these microbiome-based predictions.</p><p><strong>Conclusions: </strong>Microbiome profiling of stool and saliva samples offers robust, time-sensitive prediction of post-HSCT complications. The RATIO model enables interpretable, time-to-event prediction across multiple outcomes and may inform microbiome-guided interventions to improve transplant success.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"80"},"PeriodicalIF":10.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659072","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 dynamics of the gut microbiota in prediabetes during a four-year follow-up among European patients-an IMI-DIRECT prospective study.","authors":"Liwei Lyu, Yong Fan, Josef Korbinian Vogt, Marc Clos-Garcia, Amelie Bonnefond, Helle Krogh Pedersen, Avirup Dutta, Robert Koivula, Sapna Sharma, Kristine Højgaard Allin, Caroline Brorsson, Henna Cederberg, Elizaveta Chabanova, Federico De Masi, Emmanouil Dermitzakis, Petra J Elders, Marieke T Blom, Monika Hollander, Rebeca Eriksen, Ian Forgie, Gary Frost, Giuseppe N Giordano, Harald Grallert, Mark Haid, Tue Haldor Hansen, Bernd Jablonka, Tarja Kokkola, Anubha Mahajan, Andrea Mari, Timothy J McDonald, Petra B Musholt, Imre Pavo, Cornelia Prehn, Martin Ridderstråle, Hartmut Ruetten, Leen M 't Hart, Jochen M Schwenk, Evelina Stankevic, Henrik S Thomsen, Jagadish Vangipurapu, Henrik Vestergaard, Ana Viñuela, Mark Walker, Torben Hansen, Allan Linneberg, Henrik Bjørn Nielsen, Søren Brunak, Mark I McCarthy, Philippe Froguel, Jerzy Adamski, Paul W Franks, Marku Laakso, Joline W J Beulens, Ewan Pearson, Oluf Pedersen","doi":"10.1186/s13073-025-01508-7","DOIUrl":"10.1186/s13073-025-01508-7","url":null,"abstract":"<p><strong>Background: </strong>Previous case-control studies have reported aberrations of the gut microbiota in individuals with prediabetes. The primary objective of the present study was to explore the dynamics of the gut microbiota of individuals with prediabetes over 4 years with a secondary aim of relating microbiota dynamics to temporal changes of metabolic phenotypes.</p><p><strong>Methods: </strong>The study included 486 European patients with prediabetes. Gut microbiota profiling was conducted using shotgun metagenomic sequencing and the same bioinformatics pipelines at study baseline and after 4 years. The same phenotyping protocols and core laboratory analyses were applied at the two timepoints. Phenotyping included anthropometrics and measurement of fasting plasma glucose and insulin levels, mean plasma glucose and insulin under an oral glucose tolerance test (OGTT), 2-h plasma glucose after an OGTT, oral glucose insulin sensitivity index, Matsuda insulin sensitivity index, body mass index, waist circumference, and systolic and diastolic blood pressure. Measures of the dynamics of bacterial microbiota were related to concomitant changes in markers of host metabolism.</p><p><strong>Results: </strong>Over 4 years, significant declines in richness were observed in gut bacterial and viral species and microbial pathways accompanied by significant changes in the relative abundance and the genetic composition of multiple bacterial species. Additionally, bacterial-viral interactions diminished over time. Despite the overall reduction in bacterial richness and microbial pathway richness, 80 dominant core bacterial species and 78 core microbial pathways were identified at both timepoints in 99% of the individuals, representing a resilient component of the gut microbiota. Over the same period, individuals with prediabetes exhibited a significant increase in glycemia and insulinemia alongside a significant decline in insulin sensitivity. Estimates of the gut bacterial microbiota dynamics were significantly correlated with temporal impairments in host metabolic health.</p><p><strong>Conclusions: </strong>In this 4-year prospective study of European patients with prediabetes, the gut microbiota exhibited major changes in taxonomic composition, bacterial species genetics, and microbial functional potentials, many of which paralleled an aggravation of host metabolism. Whether the temporal gut microbiota changes represent an adaptation to the progression of metabolic abnormalities or actively contribute to these in prediabetes cases remains unsettled.</p><p><strong>Trial registration: </strong>The Diabetes Research on Patient Stratification (DIRECT) study, an exploratory observational study initiated on October 15, 2012, was registered on ClinicalTrials.gov under the number NCT03814915.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"78"},"PeriodicalIF":10.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642452","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":"Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups.","authors":"Enze Liu, Oumaima Jaouadi, Riya Sharma, Nathan Becker, Travis S Johnson, Parvathi Sudha, Vivek S Chopra, Faiza Zafar, Habib Hamidi, Charlotte Pawlyn, Attaya Suvannasankha, Rafat Abonour, Brian A Walker","doi":"10.1186/s13073-025-01503-y","DOIUrl":"10.1186/s13073-025-01503-y","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy is now standard of care for multiple myeloma (MM), where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D (GPRC5D). However, additional novel targets are needed to counter tumor heterogeneity, therefore new strategies to identify additional targets are also required.</p><p><strong>Methods: </strong>We utilized multi-omics data from two large datasets A framework that utilized prior knowledge of cell surface potential, expression in healthy organs, and expression level in MM cells was established to define novel immunotherapeutic targets. High confidence targets were prioritized for myeloma populations and subgroups, validated with flow cytometry and immunoblotting.</p><p><strong>Results: </strong>Novel population-level candidate targets such as ITGA4 and LAX1, as well as subtype-specific targets including ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), CD180 in hyperdiploidy, GPRC5D in 1q gain, and ADAM28 in biallelic TP53 samples were identified. Candidate target surface expression was validated by flow cytometry and CRISPR-Cas9 knock-out models. Sub-clonal differences in expression were noted, using single-cell RNA-seq data. Additionally, alternative splicing of existing immunotherapy targets, such as FCRL5, was noted as a potential mechanism of antigen loss.</p><p><strong>Conclusions: </strong>Our study presents a methodology to identify novel candidate immunotherapy targets. We also use known genomic data to identify subtype-specific targets that could be used either as complementary or alternative targets to existing treatments. We show that immunotherapy targets can have heterogenous expression within a patient, which can affect treatment efficacy. Taken together, our study establishes a robust methodology to identify novel therapeutic targets in MM, revealing critical insights that will inform the development of current and next-generation immunotherapies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"79"},"PeriodicalIF":10.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642453","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":"PGSFusion streamlines polygenic score construction and epidemiological applications in biobank-scale cohorts.","authors":"Sheng Yang, Xiangyu Ye, Xiaolong Ji, Zhenghui Li, Min Tian, Peng Huang, Chen Cao","doi":"10.1186/s13073-025-01505-w","DOIUrl":"10.1186/s13073-025-01505-w","url":null,"abstract":"<p><strong>Background: </strong>The polygenic score (PGS) is an estimate of an individual's genetic susceptibility to a specific complex trait and has been instrumental to the development of precision medicine. As an increasing number of genome-wide association studies (GWAS) have emerged, numerous sophisticated statistical and computational methods have been developed to facilitate the PGS construction. However, both the complex statistical estimation procedure and the various data formats of summary statistics and reference panel make the PGS calculation challenging and not easily accessible to researchers with limited statistical and computational backgrounds.</p><p><strong>Results: </strong>Here, we propose PGSFusion, a webserver designed to carry out PGS construction for targeting variety of analytic requirements while requiring minimal prior computational knowledge. Implemented with well-established web development technologies, PGSFusion streamlines the construction of PGS using 17 PGS methods in four categories: 11 single-trait, one multiple-trait, two annotation-based and three cross-ancestry based methods. In addition, PGSFusion also utilizes UK Biobank data to provide two kinds of in-depth analyses for 201 complex traits: i) prediction performance evaluation to display the consistency between PGS and specific traits and the effect size of PGS in different genetic risk groups; ii) joint effect analysis to investigate the interaction between PGS and covariates, as well as the effect size of covariates in different genetic subgroups. PGSFusion benchmarks the prediction performances for different methods in one summary statistics. PGSFusion automatically identifies the required parameters in different data formats of uploaded GWAS summary statistics files, provides a selection of suitable methods, and outputs calculated PGSs and their corresponding epidemiological results. Finally, we showcase three case studies in different application scenarios, highlighting its versatility and values to researchers.</p><p><strong>Conclusions: </strong>Overall, PGSFusion presents an easy-to-use, effective, and extensible platform for PGS construction, promoting the accessibility and utility of PGS for researchers in the field of precision medicine. PGSFusion is freely available at http://www.pgsfusion.net/ .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"77"},"PeriodicalIF":10.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626060","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":"Joint inference of mutational signatures from indels and single-nucleotide substitutions reveals prognostic impact of DNA repair deficiencies.","authors":"Patricia Ferrer-Torres, Iván Galván-Femenía, Fran Supek","doi":"10.1186/s13073-025-01497-7","DOIUrl":"10.1186/s13073-025-01497-7","url":null,"abstract":"<p><strong>Background: </strong>Mutational signatures are increasingly used to understand the mechanisms causing cancer. However, their important applications in predicting prognosis and stratifying patients for therapy are hampered by inaccurate inference of the various featureless, dense trinucleotide mutational spectra, which are often confounded with one another. One of them is the homologous recombination deficiency (HRd)-associated signature SBS3, relevant because of its association with prognosis in ovarian and breast cancer and because of its potential as a biomarker for synthetic lethality therapies.</p><p><strong>Methods: </strong>Here, we highlight strong benefits of a multimodal approach for mutational signature extraction, applied on top of standard bioinformatic pipelines. By jointly operating on single-base substitution (SBS) and indel (ID) spectra, this method enables accurate identification of various DNA repair deficiency signatures and patient survival prediction.</p><p><strong>Results: </strong>Across four different cohorts of whole-genome sequenced high-grade serous ovarian cancers (HGSOC), the multimodal SBS + ID approach correctly distinguished the commonly confused signatures SBS3, SBS5, SBS8, SBS39, and SBS40. Importantly, we robustly identified two different multimodal SBS3 signatures, m-SBS3a and m-SBS3b, with distinct patterns in the indel spectrum. Multimodal SBS3b signature was strongly predictive of longer survival in ovarian cancer patients, replicating across four cohorts, with effect sizes greatly exceeding other genetic markers. Our m-SBS3 also predicted survival in platinum-treated patients with various cancer types, and moreover, the SBS + ID joint inference was successfully applied to mismatch repair-deficient colorectal cancer and immunotherapy response, supporting a general utility of the multimodal mutational signatures approach.</p><p><strong>Conclusions: </strong>Overall, combining SBS and ID mutations improves detection of HR deficiency-associated signatures and reveals distinct SBS3 subtypes with prognostic value. This multimodal approach outperforms existing markers and is readily applicable to therapy stratification.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"76"},"PeriodicalIF":10.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559956","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":"Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.","authors":"Jamie C Stark, Neta Pipko, Yijing Liang, Anna Szuto, Chung Ting Tsoi, Megan A Dickson, Kyoko E Yuki, Huayun Hou, Sydney Scholten, Kenzie Pulsifer, Meryl Acker, Meredith Laver, Harsha Murthy, Olivia M Moran, Emily Bonnell, Nicole Liang, Jashanpreet Sidhu, Lucie Dupuis, Mohammad M Ghahramani Seno, Marisa Chard, Rebekah K Jobling, Jessie Cameron, Rose Chami, Michal Inbar-Feigenberg, Michael D Wilson, David A Chitayat, Kym M Boycott, Lianna Kyriakopoulou, Roberto Mendoza-Londono, Christian R Marshall, James J Dowling, Gregory Costain, Ashish R Deshwar","doi":"10.1186/s13073-025-01494-w","DOIUrl":"10.1186/s13073-025-01494-w","url":null,"abstract":"<p><strong>Background: </strong>RNA sequencing (RNA-seq) is emerging as a valuable tool for identifying disease-causing RNA transcript aberrations that cannot be identified by DNA-based testing alone. Previous studies demonstrated some success in utilizing RNA-seq as a first-line test for rare inborn genetic conditions. However, DNA-based testing (increasingly, whole genome sequencing) remains the standard initial testing approach in clinical practice. The indications for RNA-seq after a patient has undergone DNA-based sequencing remain poorly defined, which hinders broad implementation and funding/reimbursement.</p><p><strong>Methods: </strong>In this study, we identified four specific and familiar clinical scenarios, and investigated in each the diagnostic utility of RNA-seq on clinically accessible tissues: (i) clarifying the impact of putative intronic or exonic splice variants (outside of the canonical splice sites), (ii) evaluating canonical splice site variants in patients with atypical phenotypes, (iii) defining the impact of an intragenic copy number variation on gene expression, and (iv) assessing variants within regulatory elements and genic untranslated regions.</p><p><strong>Results: </strong>These hypothesis-driven RNA-seq analyses confirmed a molecular diagnosis and pathomechanism for 45% of participants with a candidate variant, provided supportive evidence for a DNA finding for another 21%, and allowed us to exclude a candidate DNA variant for an additional 24%. We generated evidence that supports two novel Mendelian gene-disease associations (caused by variants in PPP1R2 and MED14) and several new disease mechanisms, including the following: (1) a splice isoform switch due to a non-coding variant in NFU1, (2) complete allele skew from a transcriptional start site variant in IDUA, and (3) evidence of a germline gene fusion of MAMLD1-BEND2. In contrast, RNA-seq in individuals with suspected rare inborn genetic conditions and negative whole genome sequencing yielded only a single new potential diagnostic finding.</p><p><strong>Conclusions: </strong>In summary, RNA-seq had high diagnostic utility as an ancillary test across specific real-world clinical scenarios. The findings also underscore the ability of RNA-seq to reveal novel disease mechanisms relevant to diagnostics and treatment.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"72"},"PeriodicalIF":10.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539927","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":"Microbiome-based therapeutics towards healthier aging and longevity.","authors":"Saurabh Kadyan, Gwoncheol Park, Tejinder P Singh, Cole Patoine, Saiful Singar, Teresa Heise, Christin Domeier, Chester Ray, Manoj Kumar, Pradip V Behare, Paramita Chakrabarty, Philip Efron, Julia Sheffler, Ravinder Nagpal","doi":"10.1186/s13073-025-01493-x","DOIUrl":"10.1186/s13073-025-01493-x","url":null,"abstract":"<p><p>The gut microbiome is our lifetime companion, regulating our health from birth throughout the lifespan. The gut microbiome composition changes continually with age, influencing both physiological and immunological development. Emerging evidence highlights the close association, and thus implication, of the microbiome with healthy disease-free aging and longevity. Accordingly, targeting the gut microbiome is emerging as a promising avenue to prevent, alleviate, and ameliorate aging-related disorders. Herein, we provide a prospective and inclusive framework of the close connection of the gut microbiome with human aging, while contemplating how this association is intertwined with age-related diseases. We delve into recently emerging and potential microbiome-based therapeutics that are projected to aid in alleviating myriad aging-related diseases, thereby enhancing the health and well-being of the aging population. Finally, we present a foundation and perspective underlining the prospects of microbiome-based therapeutics developed and tailored precisely for the elderly, with the overarching goal of promoting health and longevity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"75"},"PeriodicalIF":10.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539929","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}