Genome Medicine最新文献

{"title":"Systemic multi-omics analysis reveals interferon response heterogeneity and links lipid metabolism to immune alterations in severe COVID-19.","authors":"Ronaldo Lira-Junior, Anoop T Ambikan, Axel Cederholm, Sefanit Rezene, Flora Mikaeloff, Sara Svensson Akusjärvi, Ahmet Yalcinkaya, Xi Chen, Maike Sperk, Maribel Aranda-Guillén, Hampus Nordqvist, Carl Johan Treutiger, Nils Landegren, Ujjwal Neogi, Soham Gupta","doi":"10.1186/s13073-026-01677-z","DOIUrl":"10.1186/s13073-026-01677-z","url":null,"abstract":"<p><strong>Background: </strong>Interferons play a central role in antiviral defense, but their dysregulation contributes to inflammation and immune dysfunction in respiratory viral infections, including COVID-19. While interferon-stimulated genes (ISGs) are essential effectors of this response, their expression patterns in patients are heterogeneous and not always predictive of disease severity. The immunometabolic consequences of this heterogeneity remain poorly understood.</p><p><strong>Methods: </strong>We analyzed hospitalized COVID-19 patients (n = 37) and uninfected controls (n = 31) using whole-blood transcriptomics, immune cell deconvolution, plasma proteomics, and standardized plasma metabolomics from a previously generated dataset within this cohort. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG score clusters. Plasma innate immune activation markers were measured by ELISA. Interferon-directed antibody reactivity was analyzed by multiplex bead-based assays measuring antigen reactivity. Functional immune responses were assessed via ex vivo stimulation of healthy donor immune cells with patient plasma, and correlations were performed between metabolites and immune activation markers.</p><p><strong>Results: </strong>HIS patients exhibited increased inflammatory mediators and innate immune cell expansion compared with LIS and MIS groups. However, within the HIS group, severe cases displayed distinct metabolic and immune dysregulation. Specifically, severe HIS cases showed reductions in phospholipids, sphingolipids, and tricarboxylic acid cycle intermediates, suggestive of disrupted mitochondrial and lipid metabolism. Plasma from severe HIS patients tended to impair neutrophil and monocyte activation, indicating functional attenuation of innate immune activation within a shared high-ISG background. Correlation analysis revealed that branched-chain lipids, tryptophan-derived metabolites, and a branched-chain dicarboxylic acid were positively associated with immune activation markers. Although type-I interferon neutralization was detected in a subset of patients with IFN antigen reactivity, these samples did not fully account for the observed ISG heterogeneity or disease severity.</p><p><strong>Conclusions: </strong>High ISG expression in COVID-19 defines a transcriptional endotype associated with systemic inflammation and innate immune activation. However, severe cases within this group exhibit metabolic constraints and reduced innate immune responsiveness, supporting an immune-metabolic axis in which inflammatory mediators and altered lipid/energy metabolism intersect with innate immune function. These findings motivate future studies to determine whether interferon-associated immune-metabolic states during acute infection relate to persistent inflammation or post-acute sequelae in selected patient subsets.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053919","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":"PAX4 R192H variant impairs β cell function by disrupting β cell identity and compensatory capacity in response to metabolic stress.","authors":"Jungsun Park, Kyun Hoo Kim, Hyunsuk Lee, Joon Ho Moon, Soo Heon Kwak, Jong Il Kim, Hail Kim, Kyong Soo Park","doi":"10.1186/s13073-026-01669-z","DOIUrl":"10.1186/s13073-026-01669-z","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes is characterized by progressive β cell dysfunction, yet the mechanisms by which genetic susceptibility contributes to β cell area and function remain poorly understood. PAX4 is a transcription factor critical for β cell development, and a nonsynonymous variant resulting in an arginine-to-histidine substitution at position 192 (R192H) has been associated with increased type 2 diabetes risk and identified only in individuals of East Asian ancestry.</p><p><strong>Methods: </strong>Here, we generated PAX4 R192H knock-in (Pax4^R192H/R192H) mouse and integrated metabolic phenotyping, bulk and single cell transcriptomics, and human cohort analyses to investigate how PAX4 R192H mutation increases the risk of type 2 diabetes.</p><p><strong>Results: </strong>Homozygote knock-in mice (Pax4 R192H) exhibited normal pancreatic endocrine development but developed glucose intolerance and impaired insulin secretion when fed a high-fat diet. Bulk and single-cell RNA-seq of islets from Pax4 R192H mice fed high-fat diet revealed impaired β cell adaptation to metabolic stress characterized by enhanced endoplasmic reticulum stress and impaired β cell maturity, with upregulation of dedifferentiation and α cell markers and downregulation of β cell identity genes. Pax4 deletion in β cells resulted in similar phenotypic and transcriptomic profiles to Pax4 R192H mice. In humans, the trajectories of β cell function were evaluated over a 14-year period using biennial oral glucose tolerance tests from 4,242 participants, where PAX4 R192H carriers showed 1.4-fold accelerated decline in disposition index, with increasing body mass index further exacerbating their type 2 diabetes risk.</p><p><strong>Conclusions: </strong>Overall, PAX4 is essential for maintaining β cell identity and compensatory function under metabolic stress, and the R192H variant predisposes to type 2 diabetes by impairing this adaptive capacity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053786","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":"Epigenetic indicators of body mass predict survival outcomes in colorectal cancer patients: patient cohort analysis.","authors":"Tanwei Yuan, Marko Mandic, Xianzhe Li, Melanie Bewerunge-Hudler, Hermann Brenner, Michael Hoffmeister","doi":"10.1186/s13073-026-01678-y","DOIUrl":"10.1186/s13073-026-01678-y","url":null,"abstract":"<p><strong>Background: </strong>The prognostic relevance of body mass index (BMI) in colorectal cancer (CRC) remains controversial, partly due to disease-related weight loss. DNA methylation (DNAm)-based BMI scores may be a more stable prognostic indicator than a single BMI measurement. This study evaluated the associations between blood-derived DNAm-BMI scores and mortality in CRC patients, compared with self-reported BMI.</p><p><strong>Methods: </strong>We analyzed data from 2,126 newly diagnosed CRC patients (41.2% women, median age 69) in the German DACHS study. Self-reported BMI at diagnosis and up to 14 years earlier and pre-diagnostic weight loss was recorded. Five externally developed and validated DNAm-BMI scores were calculated from blood DNAm. Outcomes included all-cause, CRC-specific, and non-CRC-specific mortality. Associations were estimated using Cox proportional hazards models adjusted for demographic, lifestyle, clinical, and treatment factors.</p><p><strong>Results: </strong>All DNAm-BMI scores showed consistent correlations with self-reported BMI at CRC diagnosis and up to14 years prior (Spearman r = 0.15-0.41). Underweight at diagnosis was linked to increased all-cause mortality (adjusted hazard ratio [aHR]: 1.42, 95% confidence interval [CI]: 1.07-1.88), whereas obesity was associated with decreased risk (0.83, 95%CI: 0.70-0.99). In contrast, four of the five DNAm-BMI scores (mBMI-135, mBMI-379, mBMI-435, mBMI-1109) showed consistent, positive linear associations with mortality risk. The 135-CpG score was most predictive (1.57, 95%CI: 1.23-1.99). Most of these associations were confined to the subgroup with blood samples collected before chemo-/radiotherapy.</p><p><strong>Conclusions: </strong>Blood-based DNAm-BMI scores, reflecting the biological effects of adiposity exposure, were positively associated with CRC mortality, and might be useful to improve risk stratification beyond self-reported BMI.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13218036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053973","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":"Preservation and clonal behavior of extrachromosomal DNA in patient-derived xenograft models of childhood cancers.","authors":"Rishaan Kenkre, Owen S Chapman, Eugene Yui-Ching Chow, Jens Luebeck, Yan Yuen Lo, Megan Paul, Wenshu Zhang, Jill Mesirov, Vineet Bafna, Kevin Yip, Jon D Larson, Robert J Wechsler-Reya, Lukas Chavez","doi":"10.1186/s13073-026-01676-0","DOIUrl":"10.1186/s13073-026-01676-0","url":null,"abstract":"<p><strong>Background: </strong>Extrachromosomal DNA (ecDNA) is a structural variant linked to poor prognosis in pediatric cancers. Patient-derived xenograft (PDX) models are crucial tools for cancer research, as they are believed to recapitulate the molecular features and intratumoral heterogeneity in patient tumors. However, ecDNA demonstrates unique evolutionary dynamics under selective pressure, and its behavior during PDX development remains largely uncharacterized. This study investigates the fidelity of PDX models in representing ecDNA from primary tumors. By analyzing ecDNA sequence composition and copy number conservation across pediatric solid cancers, we assess how well PDX models recapitulate the ecDNA landscape observed in human tumors.</p><p><strong>Methods: </strong>AmpliconArchitect was used to analyze whole-genome sequencing (WGS) of 338 PDX models and 127 corresponding primary tumors. ecDNA status, sequence, copy number, and associated genes were compared between PDX models and their matched human tumors. Additionally, multiome RNA and ATAC single-cell sequencing of a PDX tumor enabled comparison of ecDNA intratumoral heterogeneity relative to similar data from the primary tumor.</p><p><strong>Results: </strong>ecDNA in PDX models largely recapitulated oncogene amplifications observed in human tumors, with MYCN being the most frequently amplified. ecDNA status remained unchanged for a majority of the PDX models (105/127, 83%) compared to primary tumors, with 20% of previously ecDNA-negative cases acquiring ecDNA during PDX development. Consequently, ecDNA was more prevalent in the PDX models than in their corresponding human tumors (McNemar's test, p = 0.00086). Detailed examination of ecDNA sequences in tumor-PDX pairs showed substantial conservation (67% with > 90% sequence overlap) but variable breakpoint concordance. Single-cell analysis demonstrated that rare ecDNA-positive cells from the primary tumor preferentially drive PDX tumor development.</p><p><strong>Conclusion: </strong>This study highlights the prevalence, oncogenic content, and conservation of ecDNA in PDX models relative to pediatric patient tumors. We observed that ecDNA frequently recapitulates oncogene amplifications found in human cancers, is generally preserved during PDX establishment, and reflects subtype-specific patterns across tumor types. These findings support the utility of PDX models in studying ecDNA biology in pediatric cancer progression and therapy. Longitudinal sampling during PDX tumor growth and under therapeutic pressure could provide insights into molecular evolution, clonal selection, and ecDNA-driven therapy resistance.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association study reveals a novel tuberculosis susceptibility locus in multiple East Asian and European populations.","authors":"Xuling Chang, Zheng Li, Phan Vuong Khac Thai, Dang Thi Minh Ha, Nguyen Thuy Thuong Thuong, Denise Wee, Alya Sufiyah Binte Mohamed Subhan, Matthew Silcocks, Cynthia Bin Eng Chee, Nguyen Thi Quynh Nhu, Chew-Kiat Heng, Yik Ying Teo, Amit Singhal, Stefan H Oehlers, Jian-Min Yuan, Woon-Puay Koh, Maxine Caws, Chiea Chuen Khor, Rajkumar Dorajoo, Sarah J Dunstan","doi":"10.1186/s13073-026-01670-6","DOIUrl":"10.1186/s13073-026-01670-6","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Although numerous genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, multi-population replication of findings has been very limited, particularly outside the HLA region, and a significant portion of TB heritability remains unexplained.</p><p><strong>Methods: </strong>We conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating 4 independent East Asian datasets (N = 11,841 cases; N = 197,373 controls). The transferability of any identified association was assessed using summary statistics from independent European populations. Potential candidate genes were prioritized using gene-based association testing and integrative bioinformatic database mining, followed by functional validation through assessment of Mycobacterium marinum (M.marinum) infection burden in CRISPR-Cas9-edited zebrafish embryos.</p><p><strong>Results: </strong>We identified a novel susceptibility locus for pulmonary TB (PTB) at 22q12.2 in East Asians [rs6006426, OR (95%Cl) = 1.097(1.066, 1.130), P_meta=3.31 × 10^- 10]. The association was further validated in Europeans [OR (95%Cl) = 1.101(1.002, 1.211), P = 0.046] and was strengthened in the combined meta-analysis including a total of 12,736 PTB cases and 673,864 controls [OR (95%Cl) = 1.098 (1.068, 1.129); P_meta=4.33 × 10^- 11]. Gene-based association test identified Oncostatin M (OSM) to be significantly associated with PTB (ZSTAT = 5.013; P = 2.68 × 10^- 7; P_adj=0.005). The lead SNP rs6006426 affected Splicing factor 3a subunit 1 (SF3A1) expression in various immune cells (P from 0.003 to 6.17 × 10^- 18) and OSM expression in monocytes post lipopolysaccharide stimulation (P = 5.57 × 10^- 4) as reported in the eQTL Catalogue. CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of M.marinum in infected embryos (P = 0.047).</p><p><strong>Conclusions: </strong>Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029281","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":"High-fidelity genome and prime editing enabled by the AI-designed openCRISPR-1.","authors":"Hye-Yeon Hwang, Hwalin Yi, Yuju Gwon, Eunju Jeon, Daesik Kim","doi":"10.1186/s13073-026-01682-2","DOIUrl":"10.1186/s13073-026-01682-2","url":null,"abstract":"<p><strong>Background: </strong>RNA-guided nucleases such as CRISPR-Cas9 systems have revolutionized genome engineering by enabling programmable DNA modifications. Although structure-guided and evolution-derived high-fidelity Cas9 variants improve target specificity, they often compromise on-target activity or constrain guide RNA (gRNA) design.</p><p><strong>Methods: </strong>We performed head-to-head comparisons of OpenCRISPR-1 and Cas9 in human cells using amplicon sequencing, multiplex Digenome-seq, and off-target validation by targeted sequencing. Editing activity was assessed across 28 endogenous loci in HEK293T cells and further evaluated in human induced pluripotent stem cells (iPSCs) and MRC-5 fibroblasts. To test clinically relevant delivery, Cas9 and OpenCRISPR-1 ribonucleoproteins were delivered using engineered virus-like particles (eVLPs). We also generated OpenCRISPR-based prime editors, OpenCRISPR-PE2 and OpenCRISPR-PE7, and compared them with PE2max and PE7 using pegRNAs and engineered epegRNAs.</p><p><strong>Results: </strong>Here, we show that OpenCRISPR-1, an AI-designed, Cas9-like nuclease, retains Cas9-level editing efficiency across multiple genomic loci while significantly reducing off-target mutations. Using multiplex Digenome-seq and targeted deep sequencing, OpenCRISPR-1 exhibits up to a 553-fold reduction in off-target mutations compared to Cas9 and achieves off-target indices that match or surpass those of high-fidelity Cas9 variants. OpenCRISPR-1 also sustains robust editing across diverse gRNA formats (GX₁₉, gX₁₉, and gX₂₀), highlighting its enhanced versatility. Furthermore, converting OpenCRISPR-1 into a prime editor yields comparable editing efficiencies while lowering the relative specificity ratio by up to 97%.</p><p><strong>Conclusions: </strong>These findings establish generative AI-guided protein design as a powerful strategy to overcome the specificity-efficiency trade-off, expanding the genome editing toolkit for both research and therapeutic use, and ushering in a new era of rational protein design.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029347","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":"Enhanced measures of neoantigenicity capture unique tumor-immune interactions across primary melanoma subtypes.","authors":"Eva R Shteinman, Grace H Attrill, Nigel G Maher, Kiran Gnana, Venkateswar Addala, Yizhe Mao, Umaimainthan Palendira, Jordan W Conway, Andrew J Colebatch, Nicola Waddell, Nicholas K Hayward, John V Pearson, Georgina V Long, Richard A Scolyer, James S Wilmott, Ismael A Vergara","doi":"10.1186/s13073-026-01673-3","DOIUrl":"10.1186/s13073-026-01673-3","url":null,"abstract":"<p><strong>Background: </strong>As immune checkpoint inhibitor therapies move toward treatment of clinically high-risk localized primary melanoma, there is an increasing need for clear understanding of the tumor-immune interaction across primary melanoma subtypes. Tumor genomic properties play a crucial role in the interaction with the immune system and have been widely explored in metastatic melanoma, but are less understood in the primary context across melanoma subtypes. Persistent tumor mutational burden (pTMB) has been proposed as an enhanced proxy of neoantigenicity in metastatic melanoma compared to standard TMB, but its role in primary disease is not known.</p><p><strong>Methods: </strong>This study utilised a cohort of 178 predominantly primary melanomas (cutaneous non-acral: n = 69, acral: n = 36, mucosal: n = 73) with available whole-genome sequencing (WGS, n = 127) to measure TMB, pTMB, aneuploidy and loss of heterozygosity, as well as multiplexed immunohistochemistry (mIHC, n = 140) to identify intratumoral T cells (CD3 + , CD8 + , CD45RO + & CD103 +), B cells (CD20 +), dendritic cells (CD11c +), macrophages (CD68 +) and PD-L1 + cells.</p><p><strong>Results: </strong>Whilst pTMB is mostly contributed by mutations present in multiple copies across primary melanoma subtypes, distinct families of clonal pTMB capture relationships with CD8 + T cells and CD8 + CD103 + T cells across subtypes not captured by clonal standard TMB. Clonal single-copy pTMB was positively associated with elevated CD8 + T cell (p = 0.003) and CD8 + CD103 + T cell infiltration (p = 0.008) in cutaneous melanomas. In contrast, clonal multiple-copy pTMB was positively associated with elevated CD8 + CD103 + T cell infiltration in acral (p = 0.048) and mucosal (p = 0.049) melanomas. Cutaneous primary melanomas had greater proportions of CD8 + T cells (p = 0.009) and CD8 + CD103 + T cells (p = 0.0002) compared to mucosal melanomas. In turn, CD8 + T cell infiltration was associated with absence of lymphatic invasion (p = 0.003), and negatively associated with tumor mitotic rate (p = 0.049) in cutaneous melanomas, indicative of less aggressive disease.</p><p><strong>Conclusions: </strong>Primary melanoma subtypes present significant differences in their immune and genomic landscapes, as well as their interactions. Distinct measures of pTMB carry added value compared to standard TMB for identification of tumour-immune associations across primary melanoma subtypes. Our findings indicate that pTMB is a relevant neoantigenicity marker in primary melanoma with the potential to modulate immune infiltration, leading to more aggressive disease.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148014804","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":"Pervasive chromosomal instability drives the karyotypic evolution of hypodiploid tumours.","authors":"Elle Loughran, Aoife McLysaght, Máire Ní Leathlobhair","doi":"10.1186/s13073-026-01632-y","DOIUrl":"10.1186/s13073-026-01632-y","url":null,"abstract":"<p><strong>Background: </strong>Tumours frequently exhibit extreme levels of aneuploidy. While increases in ploidy are well-characterised, the opposite phenomenon-extensive chromosome loss leading to hypodiploidy-remains underexplored.</p><p><strong>Methods: </strong>Here, we analyse over 17,000 cancer genomes from 34 cancer types and perform a pan-cancer analysis of karyotypic evolution in hypodiploid tumours. We develop methods to identify current and former hypodiploid tumours, analyse predictors of chromosome loss patterns across tissues, and characterise the relationship between hypodiploidy and other forms of chromosomal instability.</p><p><strong>Results: </strong>We find that hypodiploidy is widespread and associated with a generalised chromosomal instability phenotype, marked by significantly elevated rates of genome doubling, intrachromosomal copy number alterations, chromoanagenesis, and intra-tumour heterogeneity. These tumours are hypoxic and strongly enriched for TP53 mutations. However, we also identify a subset of cancers-acute lymphoblastic leukaemia (ALL), kidney chromophobe, and adrenocortical carcinoma-that exhibit stable hypodiploidy, with stereotyped chromosome loss patterns, low chromosomal instability, and distinct evolutionary origins. We exploit this stability to develop a simple method of distinguishing poor-prognosis masked hypodiploid from good-prognosis hyperdiploid ALL using only cytogenetic data, enabling more precise risk stratification. Finally, we show that unstable hypodiploidy predicts poor prognosis across cancers. Genome doubling does not confer a fitness advantage in hypodiploid tumours, nor do these tumours evolve to avoid loss of dosage-sensitive genes.</p><p><strong>Conclusions: </strong>Together, these findings provide the first pan-cancer characterization of hypodiploidy as a widespread and clinically relevant phenomenon often driven by pervasive chromosomal instability, and illustrate the remarkable ability of cancer cells to tolerate and evolve under extreme dosage imbalance.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13195901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005206","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":"GWAS-by-subtraction reveals new genetic architecture and health implications of type 2 diabetes-independent gestational diabetes mellitus.","authors":"Siquan Zhou, Zhichang Ran, Yanliu Li, Jiayuan He, Xin Yuan, Yuanqi Hu, Xiaoyu Wang, Ruirui Li, Yujie Xu, Ciling Yan, Jingyuan Xiong, Guo Cheng","doi":"10.1186/s13073-026-01674-2","DOIUrl":"10.1186/s13073-026-01674-2","url":null,"abstract":"<p><strong>Background: </strong>The etiology of gestational diabetes mellitus (GDM) is constituted by both type 2 diabetes (T2D)-dependent and T2D-independent mechanisms. However, existing studies have evaluated the impact of T2D-dependent loci only for GDM, which limits the power to assess to what extent genetic variants or biological pathways are specific to GDM.</p><p><strong>Methods: </strong>We subtracted the genetic effects of a genome-wide association study (GWAS) data for T2D from a GWAS data for GDM to reveal loci linked with T2D-independent components of GDM using genomic structural equation model (SEM). In the discovery stage of GWAS-by-subtraction, we used GWAS summary statistics of GDM and T2D from the FinnGen study as input latent variables (16,802 GDM cases and 237,816 controls; 71,728 T2D cases and 369,007 controls). In the replication stage, we adopted the summary statistics from a previously reported GWAS for GDM and T2D as input (21,263 GDM cases and 301,918 controls; 50,409 T2D cases and 523,897 controls). We functionally annotated variants with genome-wide significance, and performed comprehensive analyses including transcriptome-wide and proteome-wide associations, summary-data-based mendelian randomization, linkage disequilibrium score regression, and Mendelian randomization, to explore genetic patterns for T2D-dependent and -independent components of GDM.</p><p><strong>Results: </strong>We found 69 independent genome-wide significant loci associated with the T2D-independent components of GDM for discovery stage, of which 49 SNPs are not significant in the GWAS for GDM used as input. T2D-independent components of GDM showed only genetic correlation with birth weight dependent on maternal genetic effect (rg = 0.19; P = 0.01), whilst T2D-dependent components of GDM showed genetic correlation with birth weight dependent on fetal genetic effect (rg = -0.22; P = 4.76 × 10^- 7). Loci of T2D-independent components of GDM effects map to genes related to islets of Langerhans, neural stem cells, blood levels of mannose, abundance of Streptococcus thermophilus and Bacteroides vulgatus, glucose and carbohydrate homeostasis, and the MAPK cascade and adenylate cyclase-activating G protein-coupled receptor signaling pathway.</p><p><strong>Conclusions: </strong>We identified independent genetic components, loci and genes of GDM that may have been previously masked by T2D, providing more accurate targets for early detection and management of GDM.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005229","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":"From text to translation: using language models to prioritize variants for clinical review.","authors":"Weijiang Li, Xiaomin Li, Ethan Lavallee, Alice Saparov, Marinka Zitnik, Christopher Cassa","doi":"10.1186/s13073-026-01661-7","DOIUrl":"10.1186/s13073-026-01661-7","url":null,"abstract":"<p><strong>Background: </strong>Despite rapid advances in genomic sequencing, most rare coding variants remain insufficiently characterized for clinical use, limiting the potential of personalized medicine. When classifying whether a variant is pathogenic, clinical labs adhere to diagnostic guidelines that integrate many forms of evidence, including case data, computational predictions, and functional screening data. While a great deal of clinical evidence has been curated for many variants, the majority still cannot be definitively classified as 'pathogenic' or 'benign', and thus persist as 'Variants of Uncertain Significance' (VUS). Variant Curation Expert Panels (VCEPs) are tasked with analyzing the available evidence for each variant to reach a classification.</p><p><strong>Methods: </strong>To make use of previously curated evidence, we processed over 2.3 million free-text variant summaries from ClinVar, employing sentence-level classification to restrict to sentences that contain different forms of evidence, and removing uninformative or similar summaries. We then used labeled text summaries to train ClinVar-BERT, a model that can discern evidence of pathogenicity or benignity within variant text summaries.</p><p><strong>Results: </strong>We validated ClinVar-BERT model predictions for variant summaries that are classified as uncertain using variants curated by expert panels, orthogonal functional screening data, and computational predictions. ClinVar-BERT model predictions of VUS had significantly different estimates of functional impact in clinically actionable genes, including BRCA1 (p = [Formula: see text]), TP53 (p = [Formula: see text]), and PTEN (p = [Formula: see text]) with an AUROC = 0.927 when classifying whether variants are damaging or are expected to retain function. Similarly, ClinVar-BERT model predictions of VUS had significantly different AlphaMissense computational scores: BRCA1 (p = [Formula: see text]), TP53 (p = [Formula: see text]), and PTEN (p = [Formula: see text]). In genes screened for secondary findings or included on ClinGen expert panels, ClinVar-BERT prioritizes 7,644 variants for expert review, where 2 or more clinical summaries related to the same VUS were model-predicted to contain pathogenic evidence, and 7,042 variants with 2 or more summaries predicted to contain benign evidence. This would result in the average VCEP having 143 variants prioritized for review, ranging from 8 to 907 variants across VCEPs.</p><p><strong>Conclusions: </strong>These findings suggest that ClinVar-BERT can discern evidence from diagnostic reports, useful for prioritizing variants for re-assessment by expert curation panels.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971901","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}