Genome Medicine最新文献

{"title":"SenPred: a single-cell RNA sequencing-based machine learning pipeline to classify deeply senescent dermal fibroblast cells for the detection of an in vivo senescent cell burden.","authors":"Bethany K Hughes, Andrew Davis, Deborah Milligan, Ryan Wallis, Federica Mossa, Michael P Philpott, Linda J Wainwright, David A Gunn, Cleo L Bishop","doi":"10.1186/s13073-024-01418-0","DOIUrl":"10.1186/s13073-024-01418-0","url":null,"abstract":"<p><strong>Background: </strong>Senescence classification is an acknowledged challenge within the field, as markers are cell-type and context dependent. Currently, multiple morphological and immunofluorescence markers are required. However, emerging scRNA-seq datasets have enabled an increased understanding of senescent cell heterogeneity.</p><p><strong>Methods: </strong>Here we present SenPred, a machine-learning pipeline which identifies fibroblast senescence based on single-cell transcriptomics from fibroblasts grown in 2D and 3D.</p><p><strong>Results: </strong>Using scRNA-seq of both 2D and 3D deeply senescent fibroblasts, the model predicts intra-experimental fibroblast senescence to a high degree of accuracy (> 99% true positives). Applying SenPred to in vivo whole skin scRNA-seq datasets reveals that cells grown in 2D cannot accurately detect fibroblast senescence in vivo. Importantly, utilising scRNA-seq from 3D deeply senescent fibroblasts refines our ML model leading to improved detection of senescent cells in vivo. This is context specific, with the SenPred pipeline proving effective when detecting senescent human dermal fibroblasts in vivo, but not the senescence of lung fibroblasts or whole skin.</p><p><strong>Conclusions: </strong>We position this as a proof-of-concept study based on currently available scRNA-seq datasets, with the intention to build a holistic model to detect multiple senescent triggers using future emerging datasets. The development of SenPred has allowed for the detection of an in vivo senescent fibroblast burden in human skin, which could have broader implications for the treatment of age-related morbidities. All code for the SenPred pipeline is available at the following URL: https://github.com/bethk-h/SenPred_HDF .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"2"},"PeriodicalIF":10.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983242","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":"TP53 germline testing and hereditary cancer: how somatic events and clinical criteria affect variant detection rate.","authors":"Paula Rofes, Carmen Castillo-Manzano, Mireia Menéndez, Álex Teulé, Sílvia Iglesias, Elisabet Munté, Mireia Ramos-Muntada, Carolina Gómez, Eva Tornero, Esther Darder, Eva Montes, Laura Valle, Gabriel Capellá, Marta Pineda, Joan Brunet, Lidia Feliubadaló, Jesús Del Valle, Conxi Lázaro","doi":"10.1186/s13073-025-01429-5","DOIUrl":"10.1186/s13073-025-01429-5","url":null,"abstract":"<p><strong>Background: </strong>Germline heterozygous pathogenic variants (PVs) in TP53 cause Li-Fraumeni syndrome (LFS), a condition associated with increased risk of multiple tumor types. As the associated cancer risks were refined over time, clinical criteria also evolved to optimize diagnostic yield. The implementation of multi-gene panel germline testing in different clinical settings has led to the identification of TP53 PV carriers outside the classic LFS-associated cancer phenotypes, leading to a broader cancer phenotypic redefinition and to the renaming of the condition as \"heritable TP53-related cancer syndrome\" (hTP53rc). Germline TP53 variant interpretation is challenging due to the diverse nature of TP53 PVs, variable penetrance of the syndrome, possible occurrence of TP53 somatic mosaicism, and TP53 involvement in clonal hematopoiesis of indeterminate potential (CHIP). Here we aim to assess the relevance and impact of these issues on the diagnostic routine, and to evaluate the sensitivity of the different LFS clinical criteria to identify hTP53rc.</p><p><strong>Methods: </strong>TP53 was analyzed in 6161 suspected hereditary cancer non-related patients categorized into three subgroups: (1) 495 patients fulfilling any LFS/Chompret clinical criteria; (2) 2481 patients diagnosed with early-onset breast/colorectal cancer; (3) 3185 patients without clinical criteria suggestive of hTP53rc. Ancillary tests were performed when TP53 PVs were identified in individuals not meeting LFS/Chompret criteria and/or when the variant was identified at low variant allele frequency (VAF).</p><p><strong>Results: </strong>TP53 PVs were identified in blood DNA of 45 probands. Variant origin was elucidated in 39 of these: 72% patients had a constitutional PV, 10% were mosaics, and 18% had CHIP-associated PVs. Notably, two of the seven CHIP-TP53 PVs identified were detected at high allelic frequencies (VAF > 35%). Twenty-nine percent of germline TP53 PV did not meet any of the LFS clinical criteria. Among the clinical criteria, Chompret 2009 showed the highest sensitivity in our cohort (68% vs. 54% for Chompret 2015), highlighting the relevance of considering lung cancer in the criteria.</p><p><strong>Conclusions: </strong>Our data supports performing TP53 ancillary testing for the identification of potential mosaicisms and CHIP-associated PVs, particularly in patients not meeting clinical criterial for LFS, irrespective of the VAF, and the application of clinical criteria that include lung cancer diagnosis.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"3"},"PeriodicalIF":10.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983288","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 evaluation of long-read sequencing-based episignature detection in developmental disorders.","authors":"Mathilde Geysens, Benjamin Huremagic, Erika Souche, Jeroen Breckpot, Koenraad Devriendt, Hilde Peeters, Griet Van Buggenhout, Hilde Van Esch, Kris Van Den Bogaert, Joris Robert Vermeesch","doi":"10.1186/s13073-024-01419-z","DOIUrl":"10.1186/s13073-024-01419-z","url":null,"abstract":"<p><strong>Background: </strong>A subset of developmental disorders (DD) is characterized by disease-specific genome-wide methylation changes. These episignatures inform on the underlying pathogenic mechanisms and can be used to assess the pathogenicity of genomic variants as well as confirm clinical diagnoses. Currently, the detection of these episignature requires the use of indirect methylation profiling methodologies. We hypothesized that long-read whole genome sequencing would not only enable the detection of single nucleotide variants and structural variants but also episignatures.</p><p><strong>Methods: </strong>Genome-wide nanopore sequencing was performed in 40 controls and 20 patients with confirmed or suspected episignature-associated DD, representing 13 distinct diseases. Following genomic variant and methylome calling, hierarchical clustering and dimensional reduction were used to determine the compatibility with microarray-based episignatures. Subsequently, we developed a support vector machine (SVM) for the detection of each DD.</p><p><strong>Results: </strong>Nanopore sequencing-based methylome patterns were concordant with microarray-based episignatures. Our SVM-based classifier identified the episignatures in 17/19 patients with a (likely) pathogenic variant and none of the controls. The remaining patients in which no episignature was identified were also classified as controls by a commercial microarray assay. In addition, we identified all underlying pathogenic single nucleotide and structural variants and showed haplotype-aware skewed X-inactivation evaluation directs clinical interpretation.</p><p><strong>Conclusion: </strong>This proof-of-concept study demonstrates nanopore sequencing enables episignature detection. In addition, concurrent haplotyped genomic and epigenomic analyses leverage simultaneous detection of single nucleotide/structural variants, X-inactivation, and imprinting, consolidating a multi-step sequential process into a single diagnostic assay.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"1"},"PeriodicalIF":10.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947596","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":"Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource's FBN1 variant curation expert panel.","authors":"A Drackley, C Somerville, P Arnaud, L M Baudhuin, N Hanna, M L Kluge, K Kotzer, C Boileau, L Bronicki, B Callewaert, A Cecchi, H Dietz, D Guo, S Harris, O Jarinova, M Lindsay, L Little, B Loeys, G MacCarrick, J Meester, D Milewicz, T Morisaki, H Morisaki, D Murdock, M Renard, J Richer, L Robert, M Ouzounian, L Van Laer, J De Backer, L Muiño-Mosquera","doi":"10.1186/s13073-024-01423-3","DOIUrl":"10.1186/s13073-024-01423-3","url":null,"abstract":"<p><strong>Background: </strong>In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clinical Genome Resource FBN1 variant curation expert panel (VCEP) was established in 2018 to develop adaptations to the ACMG/AMP criteria for FBN1 in association with Marfan syndrome.</p><p><strong>Methods: </strong>The specific recommendations were developed through literature review, surveys, online expert panel discussions, and pilot testing of a set of 60 different variants. Consensus among experts was considered reached if at least 75% of the members agreed with a given rule specification. The final set of rules received approval from the ClinGen Sequence Variant Interpretation Working Group.</p><p><strong>Results: </strong>The developed specifications introduce modifications to 14 of the 28 ACMG/AMP evidence criteria and deem 6 criteria non-applicable. Some of these specifications include refining the minor allele frequency thresholds, creating a FBN1-specific flowchart for PVS1, defining functional domains of the protein, developing a point-based system of counting probands and instances of de novo occurrences, recommending a points-based method of accounting for family segregation data, and clarifying the applicable functional assays that should be considered. To date, this VCEP has curated 120 variants which have been deposited to ClinVar with the 3-star review status.</p><p><strong>Conclusions: </strong>Establishing specific adaptations for FBN1 has provided a framework to foster greater classification concordance among clinical laboratories, ultimately improving clinical care for patients with Marfan syndrome.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"154"},"PeriodicalIF":10.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909524","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 role of gut microbiota in the pathogenesis of diverticular disease: where are we now?","authors":"Antonio Tursi, Alfredo Papa","doi":"10.1186/s13073-024-01426-0","DOIUrl":"10.1186/s13073-024-01426-0","url":null,"abstract":"<p><p>Diverticular disease (DD) is widespread worldwide. The role of gut microbiota (GM) in DD is not entirely understood.  Here we discuss the significance of the current knowledge on GM in the different stages of DD and how crucial these acquisitions are for designing diagnostic and therapeutic trials in this field.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"153"},"PeriodicalIF":10.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906911","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 tool for CRISPR-Cas9 sgRNA evaluation based on computational models of gene expression.","authors":"Shai Cohen, Shaked Bergman, Nicolas Lynn, Tamir Tuller","doi":"10.1186/s13073-024-01420-6","DOIUrl":"10.1186/s13073-024-01420-6","url":null,"abstract":"<p><strong>Background: </strong>CRISPR is widely used to silence genes by inducing mutations expected to nullify their expression. While numerous computational tools have been developed to design single-guide RNAs (sgRNAs) with high cutting efficiency and minimal off-target effects, only a few tools focus specifically on predicting gene knockouts following CRISPR. These tools consider factors like conservation, amino acid composition, and frameshift likelihood. However, they neglect the impact of CRISPR on gene expression, which can dramatically affect the success of CRISPR-induced gene silencing attempts. Furthermore, information regarding gene expression can be useful even when the objective is not to silence a gene. Therefore, a tool that considers gene expression when predicting CRISPR outcomes is lacking.</p><p><strong>Results: </strong>We developed EXPosition, the first computational tool that combines models predicting gene knockouts after CRISPR with models that forecast gene expression, offering more accurate predictions of gene knockout outcomes. EXPosition leverages deep-learning models to predict key steps in gene expression: transcription, splicing, and translation initiation. We showed our tool performs better at predicting gene knockout than existing tools across 6 datasets, 4 cell types and ~207k sgRNAs. We also validated our gene expression models using the ClinVar dataset by showing enrichment of pathogenic mutations in high-scoring mutations according to our models.</p><p><strong>Conclusions: </strong>We believe EXPosition will enhance both the efficiency and accuracy of genome editing projects, by directly predicting CRISPR's effect on various aspects of gene expression. EXPosition is available at http://www.cs.tau.ac.il/~tamirtul/EXPosition . The source code is available at https://github.com/shaicoh3n/EXPosition .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"152"},"PeriodicalIF":10.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881888","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":"Tracing carriage, acquisition, and transmission of ESBL-producing Escherichia coli over two years in a tertiary care hospital.","authors":"Minh Ngoc Nguyen, Beryl Primrose Gladstone, Giulia De Angelis, Michael Biggel, Basil Britto Xavier, Christine Lammens, Qiang Lin, Sandra Van Puyvelde, Herman Goossens, Samir Kumar-Singh, Youri Glupczynski, Yehuda Carmeli, Evelina Tacconelli, Surbhi Malhotra-Kumar","doi":"10.1186/s13073-024-01424-2","DOIUrl":"10.1186/s13073-024-01424-2","url":null,"abstract":"<p><strong>Background: </strong>The impact of community carriage on the influx of extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) into hospitals remains understudied. In this prospective 2-year single-centre study, we investigate the community ESBL-E influx and trace the colonisation, nosocomial acquisition, transmission, and infection dynamics of ESBL-producing Escherichia coli (ESBL-Ec) in non-ICU wards at a tertiary care hospital.</p><p><strong>Methods: </strong>This study reports primary and post hoc outcomes of the clinical trial NCT01208519 in which hospitalised patients were screened for rectal carriage of ESBL-E. ESBL-Ec isolates from ≈50% of carriers, including all patients who developed infections, were sequenced and genotyped. Endogenous infection was defined as infection by the same strain (< 10 SNPs distance) as colonizing strain.</p><p><strong>Results: </strong>Of 3703 screened patients, 456 (12.3%) were ESBL-positive-at-admission (PA-ESBL). Of the 2268 ESBL-negative-at-admission (NA-ESBL) patients with follow-up samples, 240 (10.6%) acquired ESBL-E (HA-ESBL), with an incidence density rate of 7.96 cases/1000 patient-day, notably higher in patients receiving antibiotics (P < 0.001). PA- and HA-ESBL patients developed significantly more ESBL-E infections than ESBL-free patients (P < 0.001). Sequenced ESBL-Ec showed high clonal diversity dominated by the multidrug-resistant and highly virulent ST131 clade, C2/H30-Rx. Among ESBL-Ec infections, 60% (18/30) were endogenous. Direct between-patients transmission clusters (n = 21) involved 23.9% (48/201) of patients and 23.0% (84/366) of ESBL-Ec isolates.</p><p><strong>Conclusions: </strong>Our data show a high prevalence of nosocomial acquisition of ESBL-E in a non-ICU setting. The study provides genomic evidence that the endogenous reservoir is the main driver of ESBL-Ec infections underscoring the need for wide implementation of antibiotic stewardship programmes to reduce antibiotic pressure.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"151"},"PeriodicalIF":10.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871889","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":"HGVS Nomenclature 2024: improvements to community engagement, usability, and computability.","authors":"Reece K Hart, Ivo F A C Fokkema, Marina DiStefano, Ros Hastings, Jeroen F J Laros, Rachel Taylor, Alex H Wagner, Johan T den Dunnen","doi":"10.1186/s13073-024-01421-5","DOIUrl":"10.1186/s13073-024-01421-5","url":null,"abstract":"<p><strong>Background: </strong>The Human Genome Variation Society (HGVS) Nomenclature is the global standard for describing and communicating variants in DNA, RNA, and protein sequences in clinical and research genomics. This manuscript details recent updates to the HGVS Nomenclature, highlighting improvements in governance, community engagement, website functionality, and underlying implementation of the standard.</p><p><strong>Methods: </strong>The HGVS Variant Nomenclature Committee (HVNC) now operates under the Human Genome Organization (HUGO), facilitating broader community feedback and collaboration with related standards organizations. The website has been redesigned using modern documentation tools and practices. The specification was updated to include guidance for transcript selection and to align with recent cross-consortia recommendations for the representation of gene fusions. A formal computational grammar was introduced to improve the precision and consistency of variant descriptions.</p><p><strong>Results: </strong>Major improvements in HGVS Nomenclature v. 21.1 include a redesigned website with enhanced navigation, search functionality, and mobile responsiveness; a new versioning policy aligned with software management practices; formal mechanisms for community feedback and change proposals; and adoption of Extended Backus-Naur Form (EBNF) for defining syntax. The specification now recommends MANE Select transcripts where appropriate and includes updated guidance for representing adjoined transcripts and gene fusions. All content is freely available under permissive licenses at hgvs-nomenclature.org.</p><p><strong>Conclusions: </strong>These advancements establish a more sustainable foundation for maintaining and evolving the HGVS Nomenclature while improving its accessibility and utility. The introduction of formal computational grammar marks a crucial step toward unambiguous variant descriptions that can be reliably processed by both humans and machines. Combined with enhanced community engagement mechanisms and improved guidance, these changes position the HGVS Nomenclature to better serve the evolving needs of clinical and research genomics while maintaining the stability that users require.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"149"},"PeriodicalIF":10.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864021","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":"SARS-CoV-2 introductions to the island of Ireland: a phylogenetic and geospatiotemporal study of infection dynamics.","authors":"Alan M Rice, Evan P Troendle, Stephen J Bridgett, Behnam Firoozi Nejad, Jennifer M McKinley, Declan T Bradley, Derek J Fairley, Connor G G Bamford, Timofey Skvortsov, David A Simpson","doi":"10.1186/s13073-024-01409-1","DOIUrl":"10.1186/s13073-024-01409-1","url":null,"abstract":"<p><strong>Background: </strong>Ireland's COVID-19 response combined extensive SARS-CoV-2 testing to estimate incidence, with whole genome sequencing (WGS) for genome surveillance. As an island with two political jurisdictions-Northern Ireland (NI) and Republic of Ireland (RoI)-and access to detailed passenger travel data, Ireland provides a unique setting to study virus introductions and evaluate public health measures. Using a substantial Irish genomic dataset alongside global data from GISAID, this study aimed to trace the introduction and spread of SARS-CoV-2 across the island.</p><p><strong>Methods: </strong>We recursively searched for 29,518 SARS-CoV-2 genome sequences collected in Ireland from March 2020 to June 2022 within the global SARS-CoV-2 phylogenetic tree and identified clusters based on shared last common non-Irish ancestors. A maximum parsimony approach was used to assign a likely country of origin to each cluster. The geographic locations and collection dates of the samples in each introduction cluster were used to map the spread of the virus across Ireland. Downsampling was used to model the impact of varying levels of sequencing and normalisation for population permitted comparison between jurisdictions.</p><p><strong>Results: </strong>Six periods spanning the early introductions and the emergence of Alpha, Delta, and Omicron variants were studied in detail. Among 4439 SARS-CoV-2 introductions to Ireland, 2535 originated in England, with additional cases largely from the rest of Great Britain, United States of America, and Northwestern Europe. Introduction clusters ranged in size from a single to thousands of cases. Introductions were concentrated in the densely populated Dublin and Belfast areas, with many clusters spreading islandwide. Genetic phylogeny was able to effectively trace localised transmission patterns. Introduction rates were similar in NI and RoI for most variants, except for Delta, which was more frequently introduced to NI.</p><p><strong>Conclusions: </strong>Tracking individual introduction events enables detailed modelling of virus spread patterns and clearer assessment of the effectiveness of control measures. Stricter travel restrictions in RoI likely reduced Delta introductions but not infection rates, which were similar across jurisdictions. Local and global sequencing levels influence the information available from phylogenomic analyses and we describe an approach to assess the ability of a chosen WGS level to detect virus introductions.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"150"},"PeriodicalIF":10.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864023","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":"Spatial transcriptome profiling identifies DTX3L and BST2 as key biomarkers in esophageal squamous cell carcinoma tumorigenesis.","authors":"Rutao Li, Na Li, Qianqian Yang, Xing Tong, Wei Wang, Chang Li, Jun Zhao, Dong Jiang, Haitao Huang, Chen Fang, Kai Xie, Jiamin Yuan, Shaomu Chen, Guangbin Li, Haitao Luo, Zhibo Gao, Dongfang Wu, Xiaoli Cui, Wei Jiang, Lingchuan Guo, Haitao Ma, Yu Feng","doi":"10.1186/s13073-024-01422-4","DOIUrl":"10.1186/s13073-024-01422-4","url":null,"abstract":"<p><strong>Background: </strong>Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC.</p><p><strong>Methods: </strong>Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted.</p><p><strong>Results: </strong>Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell-cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages.</p><p><strong>Conclusions: </strong>Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"148"},"PeriodicalIF":10.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853912","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}