Genome Medicine最新文献

{"title":"Whole genome sequencing of 378 prostate cancer metastases reveals tissue selectivity for mismatch deficiency with potential therapeutic implications.","authors":"Daniel J Vis, Sander A L Palit, Marie Corradi, Edwin Cuppen, Niven Mehra, Martijn P Lolkema, Lodewyk F A Wessels, Michiel S van der Heijden, Wilbert Zwart, Andries M Bergman","doi":"10.1186/s13073-025-01445-5","DOIUrl":"10.1186/s13073-025-01445-5","url":null,"abstract":"<p><strong>Background: </strong>Survival of patients with metastatic castration-resistant prostate cancer (mCRPC) depends on the site of metastatic dissemination.</p><p><strong>Methods: </strong>Patients with mCRPC were prospectively included in the CPCT-02 metastatic site biopsy study. We evaluated whole genome sequencing (WGS) of 378 mCRPC metastases to understand the genetic traits that affect metastatic site distribution.</p><p><strong>Results: </strong>Our findings revealed that RB1, PIK3CA, JAK1, RNF43, and TP53 mutations are the most frequent genetic determinants associated with site selectivity for metastatic outgrowth. Furthermore, we explored mutations in the non-coding genome and found that androgen receptor (AR) chromatin binding sites implicated in metastatic prostate cancer differ in mutation frequencies between metastatic sites, converging on pathways that impact DNA repair. Notably, liver and visceral metastases have a higher tumor mutational load (TML) than bone and lymph node metastases, independent of genetic traits associated with neuroendocrine differentiation. We found that TML is strongly associated with DNA mismatch repair (MMR)-deficiency features in these organs.</p><p><strong>Conclusions: </strong>Our results revealed gene mutations that are significantly associated with metastatic site selectivity and that frequencies of non-coding mutations at AR chromatin binding sites differ between metastatic sites. Immunotherapeutics are thus far unsuccessful in unselected mCRPC patients. We found a higher TML in liver and visceral metastases compared to bone and lymph node metastases. As immunotherapeutics response is associated with mutational burden, these findings may assist in selecting mCRPC patients for immunotherapy treatment based on organs affected by metastatic disease.</p><p><strong>Trial registration number: </strong>NCT01855477.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"24"},"PeriodicalIF":10.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669540","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":"A polygenic score for height identifies an unmeasured genetic predisposition among pediatric patients with idiopathic short stature.","authors":"John P Shelley, Mingjian Shi, Josh F Peterson, Sara L Van Driest, Jill H Simmons, Jonathan D Mosley","doi":"10.1186/s13073-025-01455-3","DOIUrl":"10.1186/s13073-025-01455-3","url":null,"abstract":"<p><strong>Background: </strong>A subset of children with short stature do not have an identified clinical explanation after extensive diagnostic evaluation. We hypothesized that a polygenic score for height (PGS_height) could identify children with non-familial idiopathic short stature (ISS-NF) who carry a polygenic predisposition to shorter height that is not accounted for by existing measures.</p><p><strong>Methods: </strong>We studied 534 pediatric participants in an electronic health record (EHR)-linked DNA biobank (BioVU) who had been evaluated for short stature by an endocrinologist. Participants were classified as having one of five short stature subtypes: primary growth disorders, secondary growth disorders, idiopathic short stature (ISS), which was sub-classified into familial (ISS-F) and non-familial (ISS-NF), and constitutional delay of puberty (ISS-DP). Differences in polygenic predisposition between subtypes were analyzed using a validated PGS_height which was standardized to a standard deviation score (SDS). Adult height predictions were generated using the PGS_height and mid-parental height (MPH). Within-child differences in height predictions were compared across subtypes. Logistic regression models and AUC analyses were used to test the ability of the PGS_height to differentiate ISS-NF from growth disorders. The incremental improvement (ΔAUC) of adding the PGS_height to prediction models with MPH was also estimated.</p><p><strong>Results: </strong>Among the 534 participants, 29.0% had secondary growth disorders, 24.9% had ISS-F, 20.2% had ISS-NF, 17.2% had ISS-DP, and 8.6% had primary growth disorders. Participants with ISS-NF had similar PGS_height values to those with ISS-F (difference [Δ] in PGS_height SDS [95% CI] = 0.19 [- 0.31 to 0.70], p = 0.75). Predicted heights generated by the PGS_height were lower than the MPH estimate for children with ISS-NF (Δ[PGS_height - MPH] =  - 0.37 SDS; p = 3.2 × 10^-9) but not for children with ISS-F (Δ =  - 0.07; p = 0.56). Children with ISS-NF also had lower PGS_height than children with primary growth disorders (ΔPGS_height =  - 0.53 [- 1.03 to - 0.04], p = 0.03) and secondary growth disorders (Δ =  - 0.45 [- 0.80 to - 0.10], p = 0.005). The PGS_height improved model discrimination between ISS-NF and children with primary (ΔAUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (ΔAUC, + 0.03 [95% CI, 0.01 to 0.10]).</p><p><strong>Conclusions: </strong>Some children with ISS-NF have an unrecognized polygenic predisposition to shorter height, similar to children with ISS-F and greater than those with growth disorders. A PGS_height could aid clinicians in identifying children with a benign, polygenic predisposition to shorter height.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"23"},"PeriodicalIF":10.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662670","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":"Metatranscriptomic profiling reveals pathogen and host response signatures of pediatric acute sinusitis and upper respiratory infection.","authors":"Andrew C Doxey, Nooran Abu Mazen, Max Homm, Vivian Chu, Manjot Hunjan, Briallen Lobb, Sojin Lee, Marcia Kurs-Lasky, John V Williams, William MacDonald, Monika Johnson, Jeremy A Hirota, Nader Shaikh","doi":"10.1186/s13073-025-01447-3","DOIUrl":"10.1186/s13073-025-01447-3","url":null,"abstract":"<p><strong>Background: </strong>Acute sinusitis (AS) is a frequent cause of antibiotic prescriptions in children. Distinguishing bacterial AS from common viral upper respiratory infections (URIs) is crucial to prevent unnecessary antibiotic use but is challenging with current diagnostic methods. Despite its speed and cost, untargeted RNA sequencing of clinical samples from children with suspected AS has the potential to overcome several limitations of other methods. In addition, RNA-seq may reveal novel host-response biomarkers for development of future diagnostic assays that distinguish bacterial from viral infections. There are however no available RNA-seq datasets of pediatric AS that provide a comprehensive view of both pathogen etiology and host immune response.</p><p><strong>Methods: </strong>Here, we performed untargeted RNA-seq (metatranscriptomics) of nasopharyngeal samples from 221 children with AS and performed a comprehensive analysis of pathogen etiology and the impact of bacterial and viral infections on host immune responses. Accuracy of RNA-seq-based pathogen detection was evaluated by comparison with culture tests for three common bacterial pathogens and qRT-PCR tests for 12 respiratory viruses. Host gene expression patterns were explored to identify potential host responses that distinguish bacterial from viral infections.</p><p><strong>Results: </strong>RNA-seq-based pathogen detection showed high concordance with culture or qRT-PCR, showing 87%/81% sensitivity (sens) / specificity (spec) for detecting three AS-associated bacterial pathogens, and 86%/92% (sens/spec) for detecting 12 URI-associated viruses, respectively. RNA-seq also detected an additional 22 pathogens not tested for clinically and identified plausible pathogens in 11/19 (58%) of cases where no organism was detected by culture or qRT-PCR. We reconstructed genomes of 196 viruses across the samples including novel strains of coronaviruses, respiratory syncytial virus, and enterovirus D68, which provide useful genomic data for ongoing pathogen surveillance programs. By analyzing host gene expression, we identified host-response signatures that differentiate bacterial and viral infections, revealing hundreds of candidate gene biomarkers for future diagnostic assays.</p><p><strong>Conclusions: </strong>Our study provides a one-of-kind dataset that profiles the interplay between pathogen infection and host responses in pediatric AS and URI. It reveals bacterial and viral-specific host responses that could enable new diagnostic approaches and demonstrates the potential of untargeted RNA-seq in diagnostic analysis of AS and URI.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"22"},"PeriodicalIF":10.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648274","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":"MuCST: restoring and integrating heterogeneous morphology images and spatial transcriptomics data with contrastive learning.","authors":"Yu Wang, Zaiyi Liu, Xiaoke Ma","doi":"10.1186/s13073-025-01449-1","DOIUrl":"10.1186/s13073-025-01449-1","url":null,"abstract":"<p><p>Spatially resolved transcriptomics (SRT) simultaneously measure spatial location, histology images, and transcriptional profiles of cells or regions in undissociated tissues. Integrative analysis of multi-modal SRT data holds immense potential for understanding biological mechanisms. Here, we present a flexible multi-modal contrastive learning for the integration of SRT data (MuCST), which joins denoising, heterogeneity elimination, and compatible feature learning. MuCST accurately identifies spatial domains and is applicable to diverse datasets platforms. Overall, MuCST provides an alternative for integrative analysis of multi-modal SRT data ( https://github.com/xkmaxidian/MuCST ).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"21"},"PeriodicalIF":10.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624377","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":"Genomic insights into the plasmidome of non-tuberculous mycobacteria.","authors":"Margo Diricks, Florian P Maurer, Viola Dreyer, Ivan Barilar, Christian Utpatel, Matthias Merker, Nils Wetzstein, Stefan Niemann","doi":"10.1186/s13073-025-01443-7","DOIUrl":"10.1186/s13073-025-01443-7","url":null,"abstract":"<p><strong>Background: </strong>Non-tuberculous mycobacteria (NTM) are a diverse group of environmental bacteria that are increasingly associated with human infections and difficult to treat. Plasmids, which might carry resistance and virulence factors, remain largely unexplored in NTM.</p><p><strong>Methods: </strong>We used publicly available complete genome sequence data of 328 NTM isolates belonging to 125 species to study gene content, genomic diversity, and clusters of 196 annotated NTM plasmids. Furthermore, we analyzed 3755 draft genome assemblies from over 200 NTM species and 5415 short-read sequence datasets from six clinically relevant NTM species or complexes including M. abscessus, M. avium complex, M. ulcerans complex and M. kansasii complex, for the presence of these plasmids.</p><p><strong>Results: </strong>Between one and five plasmids were present in approximately one-third of the complete NTM genomes. The annotated plasmids varied widely in length (most between 10 and 400 kbp) and gene content, with many genes having an unknown function. Predicted gene functions primarily involved plasmid replication, segregation, maintenance, and mobility. Only a few plasmids contained predicted genes that are known to confer resistance to antibiotics commonly used to treat NTM infections. Out of 196 annotated plasmid sequences, 116 could be grouped into 31 clusters of closely related sequences, and about one-third were found across multiple NTM species. Among clinically relevant NTM, the presence of NTM plasmids showed significant variation between species, within (sub)species, and even among strains within (sub)lineages, such as dominant circulating clones of Mycobacterium abscessus.</p><p><strong>Conclusions: </strong>Our analysis demonstrates that plasmids are a diverse and heterogeneously distributed feature in NTM bacteria. The frequent occurrence of closely related putative plasmid sequences across different NTM species suggests they may play a significant role in NTM evolution through horizontal gene transfer at least in some groups of NTM. However, further in vitro investigations and access to more complete genomes are necessary to validate our findings, elucidate gene functions, identify novel plasmids, and comprehensively assess the role of plasmids in NTM.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"19"},"PeriodicalIF":10.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556626","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":"Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits.","authors":"Ricardo A Vialle, Katia de Paiva Lopes, Yan Li, Bernard Ng, Julie A Schneider, Aron S Buchman, Yanling Wang, Jose M Farfel, Lisa L Barnes, Aliza P Wingo, Thomas S Wingo, Nicholas T Seyfried, Philip L De Jager, Chris Gaiteri, Shinya Tasaki, David A Bennett","doi":"10.1186/s13073-025-01444-6","DOIUrl":"10.1186/s13073-025-01444-6","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci.</p><p><strong>Methods: </strong>By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's disease and other common age-related clinical and neuropathologic traits were examined.</p><p><strong>Results: </strong>First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10^-4).</p><p><strong>Conclusions: </strong>While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"20"},"PeriodicalIF":10.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556628","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":"STModule: identifying tissue modules to uncover spatial components and characteristics of transcriptomic landscapes.","authors":"Ran Wang, Yan Qian, Xiaojing Guo, Fangda Song, Zhiqiang Xiong, Shirong Cai, Xiuwu Bian, Man Hon Wong, Qin Cao, Lixin Cheng, Gang Lu, Kwong Sak Leung","doi":"10.1186/s13073-025-01441-9","DOIUrl":"10.1186/s13073-025-01441-9","url":null,"abstract":"<p><p>Here we present STModule, a Bayesian method developed to identify tissue modules from spatially resolved transcriptomics that reveal spatial components and essential characteristics of tissues. STModule uncovers diverse expression signals in transcriptomic landscapes such as cancer, intraepithelial neoplasia, immune infiltration, outcome-related molecular features and various cell types, which facilitate downstream analysis and provide insights into tumor microenvironments, disease mechanisms, treatment development, and histological organization of tissues. STModule captures a broader spectrum of biological signals compared to other methods and detects novel spatial components. The tissue modules characterized by gene sets demonstrate greater robustness and transferability across different biopsies. STModule: https://github.com/rwang-z/STModule.git .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"18"},"PeriodicalIF":10.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541180","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":"Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity.","authors":"Jasmin J Bennett, Cécile Saint-Martin, Bianca Neumann, Jonna M E Männistö, Jayne A L Houghton, Susann Empting, Matthew B Johnson, Thomas W Laver, Jonathan M Locke, Benjamin Spurrier, Matthew N Wakeling, Indraneel Banerjee, Antonia Dastamani, Hüseyin Demirbilek, John Mitchell, Markus Stange, Klaus Mohnike, Jean-Baptiste Arnoux, Nick D L Owens, Martin Zenker, Christine Bellanné-Chantelot, Sarah E Flanagan","doi":"10.1186/s13073-025-01440-w","DOIUrl":"10.1186/s13073-025-01440-w","url":null,"abstract":"<p><strong>Background: </strong>We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1-hyperinsulinism by screening a large international cohort of patients living with the condition.</p><p><strong>Methods: </strong>We screened the HK1 cis-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories.</p><p><strong>Results: </strong>We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses (n = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis-regulatory region from 42 to 46 bp.</p><p><strong>Conclusions: </strong>Non-coding variants within the HK1 cis-regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"17"},"PeriodicalIF":10.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541178","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":"LETSmix: a spatially informed and learning-based domain adaptation method for cell-type deconvolution in spatial transcriptomics.","authors":"Yangen Zhan, Yongbing Zhang, Zheqi Hu, Yifeng Wang, Zirui Zhu, Sijing Du, Xiangming Yan, Xiu Li","doi":"10.1186/s13073-025-01442-8","DOIUrl":"10.1186/s13073-025-01442-8","url":null,"abstract":"<p><p>Spatial transcriptomics (ST) enables the study of gene expression in spatial context, but many ST technologies face challenges due to limited resolution, leading to cell mixtures at each spot. We present LETSmix to deconvolve cell types by integrating spatial correlations through a tailored LETS filter, which leverages layer annotations, expression similarities, image texture features, and spatial coordinates to refine ST data. Additionally, LETSmix employs a mixup-augmented domain adaptation strategy to address discrepancies between ST and reference single-cell RNA sequencing data. Comprehensive evaluations across diverse ST platforms and tissue types demonstrate its high accuracy in estimating cell-type proportions and spatial patterns, surpassing existing methods (URL: https://github.com/ZhanYangen/LETSmix ).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"16"},"PeriodicalIF":10.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531239","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":"Genomic alterations and transcriptional phenotypes in circulating free DNA and matched metastatic tumor.","authors":"Nobuyuki Takahashi, Lorinc Pongor, Shivam P Agrawal, Mariya Shtumpf, Ankita Gurjar, Vinodh N Rajapakse, Ahmad Shafiei, Christopher W Schultz, Sehyun Kim, Diana Roame, Paula Carter, Rasa Vilimas, Samantha Nichols, Parth Desai, William Douglas Figg, Mohammad Bagheri, Vladimir B Teif, Anish Thomas","doi":"10.1186/s13073-025-01438-4","DOIUrl":"10.1186/s13073-025-01438-4","url":null,"abstract":"<p><strong>Background: </strong>Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), due to the aggressive clinical course of this cancer, which makes obtaining tumor biopsies exceedingly challenging.</p><p><strong>Methods: </strong>In this study, we analyzed a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC. We conducted cfDNA low-pass whole genome sequencing (0.1X coverage), comparing it with time-point matched tumor characterized using whole-exome (130X) and transcriptome sequencing.</p><p><strong>Results: </strong>A direct comparison of cfDNA and tumor biopsy revealed that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not detected in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Sequencing coverage of plasma DNA fragments around transcription start sites showed distinct treatment-related changes and captured the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors. This allowed for the prediction of SCLC neuroendocrine phenotypes and treatment responses.</p><p><strong>Conclusions: </strong>cfDNA captures a comprehensive view of tumor heterogeneity and evolution. These findings have significant implications for the non-invasive stratification of SCLC, a disease currently treated as a single entity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"15"},"PeriodicalIF":10.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500581","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}