Hum. Mutat. [JOURNAL]
Sun
200 papers
Single-Cell Transcriptomic Analysis Suggests That JUN May Regulate BAMBI to Promote Osteosarcoma Cell Migration and Invasion.
Song N, Zhang Q, Du J … +1 more , Jiang R
Hum Mutat · 2026 · PMID 42211757 · Full text
BACKGROUND: Distant metastasis of osteosarcoma (OS) is one of the major factors contributing to poor patient prognosis, and its underlying mechanisms remain incompletely understood. In this study, we employed single-cell...
BACKGROUND: Distant metastasis of osteosarcoma (OS) is one of the major factors contributing to poor patient prognosis, and its underlying mechanisms remain incompletely understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to assess intratumoral heterogeneity and identify immune diagnostic and therapeutic markers, providing novel insights to guide targeted therapy. METHODS: Key cell clusters were identified using InferCNV analysis and combined with differential gene expression analysis, pseudotime trajectory analysis, transcription factor regulatory network construction, and functional enrichment analysis; signaling pathways closely associated with OS metastasis were screened and subsequently validated through the GSE152048 dataset and in vitro functional experiments. RESULTS: In this study, a total of 10 cell clusters were identified. Immune cells exhibited higher infiltration levels in the metastatic group. Further dimensionality reduction and clustering of malignant osteoblastic cells revealed five subpopulations, among which the metastatic C1 and C3 subclusters exhibited more pronounced malignant features. The results showed that BAMBI was specifically downregulated during the transition from nonmetastatic to metastatic states. Further analysis indicated that JUN may maintain subcluster phenotypic stability by regulating BAMBI expression. Moreover, as a pseudoreceptor of the TGF- signaling pathway, the downregulation of BAMBI can promote pathway activation, thereby enhancing the migration and invasion potential of OS cells. Furthermore, the results were validated in the GSE152048 dataset and cell experiments. CONCLUSION: This study reveals that during the progression of OS from a nonmetastatic to a metastatic state, BAMBI expression is downregulated and may be regulated by JUN. The decreased expression of BAMBI leads to hyperactivation of the TGF- signaling pathway, thereby promoting the migration and invasion of OS cells. These findings provide potential immune-related and molecular targets that could inform single cell-guided strategies for targeted therapy and overcoming resistance.
Integrative Multiomics Analysis Reveals Tumor-Associated Macrophage Heterogeneity and a Prognostic Signature in Gastric Cancer.
Li Z, Xu M, Huang Y … +5 more , Huang C, Wu Y, Lu J, Zhang G, Zheng L
Hum Mutat · 2026 · PMID 42211756 · Full text
Gastric cancer (GC) is characterized by a complex tumor microenvironment (TME) with substantial cellular heterogeneity. Tumor-associated macrophages (TAMs) represent the most abundant immune cell population in the TME an...
Gastric cancer (GC) is characterized by a complex tumor microenvironment (TME) with substantial cellular heterogeneity. Tumor-associated macrophages (TAMs) represent the most abundant immune cell population in the TME and exhibit remarkable functional plasticity. This study integrated single-cell RNA-sequencing (scRNA-seq) data, bulk transcriptomics, and spatial transcriptomics to systematically characterize TAM heterogeneity and identify prognostic biomarkers in GC. ScRNA-seq analysis revealed nine major cell types (T cells, plasma cells, epithelial cells, fibroblasts, macrophages, endothelial cells, B cells, smooth muscle cells, and mast cells) and distinct macrophage subpopulations with tumor-specific expansion patterns. High-dimensional weighted gene coexpression network analysis identified coexpression modules enriched in GC-associated macrophages. Machine learning algorithms were employed to construct a prognostic signature, and the CoxBoost model demonstrated superior predictive performance across multiple cohorts. The seven-gene signature, including UPP1, VCAN, ELL2, ABCA1, TUBA1A, MX2, and TSPO, showed robust prognostic value in survival prediction. Spatial transcriptomic analysis further revealed distinct metabolic profiles and extensive cellular interaction networks mediated by UPP1-expressing TAMs. These findings provide a comprehensive atlas of TAM heterogeneity and establish novel prognostic biomarkers with potential therapeutic implications in GC.
Integrated Genomic and Single-Cell Analysis Reveals Heterogeneity, Prognosis, and Treatment Vulnerability in Urothelial Carcinoma.
Tang C, Liu Y, Wang TL … +6 more , Ma J, Chen W, Liu X, Xue J, Ye L, Yue F
Hum Mutat · 2026 · PMID 42211755 · Full text
At the transcriptomic level, several molecular subtyping schemes have been established to elucidate the intrinsic heterogeneity of urothelial carcinoma and to inform prognostic assessment and therapeutic guidance. Howeve...
At the transcriptomic level, several molecular subtyping schemes have been established to elucidate the intrinsic heterogeneity of urothelial carcinoma and to inform prognostic assessment and therapeutic guidance. However, a unified molecular classification scheme characterizing genomic alterations is lacking. Unsupervised and supervised clustering identified two distinct mutational signature subtypes. Kaplan-Meier analysis demonstrated that patients with the MUT2 subtype had a higher risk of death than those with the MUT1 subtype across multiple cohorts, including IMvigor210 (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.27-2.37; < 0.001), UC-GENOME (HR, 1.54; 95% CI, 0.93-2.54; = 0.091), The Cancer Genome Atlas (TCGA; HR, 1.45; 95% CI, 1.06-1.98; = 0.020), MSK2022 (HR, 1.34; 95% CI, 1.10-1.64; = 0.004), MSK2015 (HR, 3.43; 95% CI, 1.36-8.64; = 0.005), and the Tongji cohort (HR, 4.99; 95% CI, 0.57-43.69; = 0.11). Immunotherapy response rates were significantly higher in the MUT1 subtype than in the MUT2 subtype in IMvigor210 (31.8% vs. 13.1%; = 0.003) and UC-GENOME (42.3% vs. 29.0%; = 0.022). Consistent with these findings, single-cell analysis showed that MUT2 tumors were enriched in tumor-associated fibroblast subpopulations and had a lower abundance of immune effector cells. Overall, this genomic analysis identified two mutation-based subtypes of urothelial carcinoma associated with patient prognosis and immunotherapy response.
A Spatially Constrained Fibroblast-Myeloid Program Associates With Immune Exclusion and Poor Prognosis in Lung Adenocarcinoma.
Zhou Y, Ren X, Li R … +8 more , Chen S, Wei B, Shen Y, Wang X, Xia Y, Cao S, Sun P, Ding N
Hum Mutat · 2026 · PMID 42206269 · Full text
BACKGROUND: Although immune checkpoint blockade (ICB) therapy has improved clinical outcomes for some patients with lung adenocarcinoma (LUAD), only a subset of cases can achieve durable benefits, and primary resistance...
BACKGROUND: Although immune checkpoint blockade (ICB) therapy has improved clinical outcomes for some patients with lung adenocarcinoma (LUAD), only a subset of cases can achieve durable benefits, and primary resistance is often associated with an immune-excluded tumor microenvironment (TME). Existing studies indicate that cancer-associated fibroblasts (CAFs) are increasingly recognized as important participants in extracellular matrix (ECM) remodeling and stroma-immune crosstalk. However, in LUAD, it is still unclear which CAFs-related programs are involved in immune exclusion, particularly in relation to their spatial interactions with myeloid cell states. METHODS: We integrated eight publicly available LUAD single-cell RNA-seq cohorts (164 samples; 471,501 cells) using Harmony and annotated major lineages and stromal subsets. CAFs were reclustered to resolve subtype heterogeneity, followed by pathway activity scoring, weighted gene coexpression network analysis (WGCNA), pseudotime trajectory inference (Slingshot), and regulon analysis. Bulk TCGA-LUAD data were used for immune-exclusion correlation and survival analyses. Spatial transcriptomics was applied for in situ validation, and ligand-receptor analysis together with NicheNet was used to prioritize CAFs-derived signaling interactions and downstream targets. RESULTS: The integrated atlas identified 10 major cell lineages and revealed tumor-associated expansion of stromal and myeloid compartments. We further resolved six CAFs subtypes with distinct molecular and functional features. Tumor-enriched CAFs subsets showed stronger activation of ECM remodeling, focal adhesion, TGF- signaling, hypoxia-related pathways, and inflammatory programs. Bulk-level analyses in TCGA-LUAD demonstrated that CAFs-related signatures were associated with a T-cell exclusion index and increased expression of the immune checkpoint-related molecule CD276 (B7-H3). Spatial transcriptomic mapping further showed that selected CAFs signatures were enriched in hypoxic, nonepithelial regions and colocalized with myeloid-associated signals, supporting the presence of a spatially constrained fibro-myeloid niche. Cell-cell communication analysis revealed extensive ligand-receptor interactions between CAFs subtypes and myeloid populations, whereas survival and immunotherapy cohort analyses showed that specific CAFs-related programs were associated with worse clinical outcomes and less favorable treatment responses. CONCLUSIONS: Multicohort single-cell integration and spatial validation define a CAFs-centered, immune-excluded niche in LUAD characterized by coordinated stromal and myeloid programs. These findings improve current understanding of CAFs heterogeneity and fibroblast-myeloid coupling in LUAD and provide a framework for future strategies aimed at targeting stromal barriers and remodeling the immune microenvironment to enhance ICB responsiveness.
CENPA as a Genome Stability-Associated Biomarker in Hepatocellular Carcinoma: Multiomics Analysis and Experimental Validation.
Shi H, Sun L, Zhang P … +3 more , Ye R, Lai M, Du M
Hum Mutat · 2026 · PMID 42206268 · Full text
Genomic instability is closely involved in hepatocellular carcinoma (HCC) progression, but biomarkers that reflect genome stability-related tumor biology and functional vulnerability remain incompletely defined. In this...
Genomic instability is closely involved in hepatocellular carcinoma (HCC) progression, but biomarkers that reflect genome stability-related tumor biology and functional vulnerability remain incompletely defined. In this study, we performed an integrative multiomics analysis to identify genome stability-associated candidates in HCC and experimentally evaluated the functional relevance of CENPA. By intersecting genome stability-related genes with differentially expressed and survival-associated genes in TCGA-LIHC, we identified a candidate gene set enriched in mitotic regulation, DNA maintenance, and cell-cycle pathways. A LASSO Cox model was then constructed to derive a 10-gene prognostic signature. Among these genes, CENPA was selected for focused analysis because of its contribution to the model and its established role in centromere identity and chromosome segregation. CENPA was significantly upregulated in HCC tissues, associated with advanced clinicopathological features, and correlated with unfavorable survival outcomes. Copy-number and cell-cycle analyses further linked high CENPA expression to proliferative and genome instability-related molecular states. Functional-state scoring showed strong associations between CENPA expression and cell-cycle activity, DNA repair, and DNA damage-related programs. In vitro, CENPA knockdown suppressed HCC cell proliferation, clonogenic growth, and migration. Moreover, CENPA depletion increased cisplatin sensitivity, reduced IC50 values, and induced G2/M accumulation in HCC cell line models. Collectively, these findings suggest that CENPA is a genome stability-associated biomarker and functional contributor to malignant phenotypes in HCC. The cisplatin-related results further indicate a potential association between CENPA-dependent mitotic regulation and genotoxic stress response, although in vivo and clinical validation are required to determine its translational significance.
PLSCR3 Deficiency Triggers mtDNA-Driven cGAS-STING Activation to Potentiate Antitumor Immunity in Colorectal Cancer.
Ling L, Wu J, Bao L … +8 more , Liu Z, Deng Q, Ji X, Yu S, Yu F, Zhu A, Xiao Q, Zheng W
Hum Mutat · 2026 · PMID 42206267 · Full text
BACKGROUND: Immunotherapy efficacy in colorectal cancer (CRC) is largely restricted to microsatellite instability-high (MSI-H) tumors, highlighting an urgent need to overcome resistance in microsatellite-stable (MSS) CRC...
BACKGROUND: Immunotherapy efficacy in colorectal cancer (CRC) is largely restricted to microsatellite instability-high (MSI-H) tumors, highlighting an urgent need to overcome resistance in microsatellite-stable (MSS) CRC. Mitochondrial DNA (mtDNA) leakage activates the cGAS-STING pathway, a potent inducer of antitumor immunity. However, endogenous regulators constraining mtDNA release in CRC, particularly within the inner mitochondrial membrane (IMM), remain poorly defined. METHODS: In CRC cohorts from TCGA, integrated bioinformatics analysis identified dysregulated mitochondria-associated genes exhibiting significant differential expression and survival outcomes. Phospholipid Scramblase 3 (PLSCR3) emerged as the prime candidate. Functional validation employed siRNA knockdown and CRISPR/Cas9 knockout in human (HT29) and mouse (CT26) CRC cell lines. Mitochondrial integrity was evaluated via JC-1 membrane potential assay, oxygen consumption rate (OCR) measurement, and cytosolic mtDNA quantification. cGAS-STING activation was measured by 2 3 -cGAMP ELISA, cytokine (IFN and CXCL10) secretion, immunoblotting (p-STING and ISGs), and RT-qPCR. Immune cell cytotoxicity was assessed using ex vivo NK cell killing assays. In vivo antitumor immunity and response to anti-PD-1 therapy were evaluated in syngeneic CT26 graft models in BALB/c mice, with tumor-infiltrating lymphocytes analyzed by flow cytometry. RESULTS: PLSCR3 was selected for further study because it fulfilled three criteria simultaneously: differential expression in CRC, significant association with survival in univariate analysis, and established mitochondrial localization. PLSCR3 deficiency disrupted mitochondrial integrity, causing membrane depolarization, impaired respiration, and significant cytosolic mtDNA accumulation. This mtDNA leakage robustly activated the cGAS-STING pathway, evidenced by increased 2 3 -cGAMP, IFN/CXCL10 secretion, STING phosphorylation (Ser366), and ISG upregulation. Functionally, PLSCR3 knockdown enhanced NK cell-mediated killing of CRC cells in vitro. Critically, PLSCR3 knockout in CT26 tumors significantly potentiated the efficacy of anti-PD-1 therapy in vivo, overcoming inherent resistance in this MSS-CRC model. This was associated with increased intratumoral infiltration of CD8+ and CD4+ T cells, elevated Granzyme B levels, and enhanced activation markers on CD8+ T cells within the tumor microenvironment. CONCLUSION: Our study identifies PLSCR3 as a previously unrecognized negative regulator of mtDNA-associated cGAS-STING activation in CRC. By maintaining mitochondrial homeostasis and limiting mtDNA leakage, PLSCR3 constrains innate immune signaling and reduces sensitivity to anti-PD-1 therapy in the CT26 model. These findings establish PLSCR3 as a promising therapeutic target to enhance immunotherapy responses in CRC.
Clinically Translatable Mutation-Based Biomarkers in Ascending Aortic Aneurysm: A Bibliometric Study.
Yang F, Yang T, Xie X … +2 more , Yang Q, Wang F
Hum Mutat · 2026 · PMID 42199299 · Full text
Ascending aortic aneurysm is often clinically silent until rupture or acute dissection, and reliance on diameter-based thresholds leaves substantial risk heterogeneity that may be reduced by genetic variant-informed biom...
Ascending aortic aneurysm is often clinically silent until rupture or acute dissection, and reliance on diameter-based thresholds leaves substantial risk heterogeneity that may be reduced by genetic variant-informed biomarkers. In plain language, clinically translatable variant biomarkers are genetic findings that can change diagnosis, family screening, surveillance intensity, or prophylactic surgical timing. We performed a cross-database bibliometric study to delineate the intellectual structure and thematic evolution of clinically translatable variant-based biomarker research in ascending aortic aneurysm. Web of Science Core Collection, Scopus, and PubMed were queried using concept-driven terms spanning thoracic/ascending aneurysm phenotypes, genomic variation, and biomarker/clinical translation; searches and exports were executed on January 10, 2026, for publications from 1997 to 2025. After harmonization, deduplication, and adjudicated screening of titles/abstracts and metadata, 1346 eligible journal articles and reviews were analyzed using bibliometrix and VOSviewer to compute productivity/impact indicators and construct co-authorship, co-citation, and keyword co-occurrence networks with temporal overlays. The literature exhibited rapid growth (15.35% annual growth rate) across 478 sources, with a mean of 8.94 co-authors per document, 24.67% international co-authorship, an average article age of 9.28 years, and 30.68 citations per article. The United States was the dominant hub (405 articles and 17,383 citations), with a densely connected Western European cluster and accelerating output from China (155 articles) but lower citation intensity. Conceptual cores were anchored in syndromic and heritable thoracic aortic disease genetics (e.g., Marfan and Loeys-Dietz syndromes; FBN1 and TGF-beta signaling), increasingly linked to diagnosis, variant interpretation, risk stratification, guidelines, and management. Life cycle modeling suggested an approach to publication peak around 2028, implying a shift from gene discovery toward variant interpretation, implementation, and equity-conscious validation. Notably, peripheral participation from low-resource regions remained sparse overall.
Spectrum and Classification of CFTR and ADGRG2 Variants in Chinese Patients With Isolated CAVD: A Large Cohort Study and Risk Assessment of CFTR Variant Carriage in Couples.
Yuan P, Liang Z, Zhou L … +9 more , Ji X, Wang S, Zhang J, Li J, Xie S, Li Y, Yalikun T, Sun Q, Chen H
Hum Mutat · 2026 · PMID 42199298 · Full text
Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia and male infertility, with its genetic etiology primarily associated with CFTR (autosomal recessive) and ADGRG2 (X-linked) mutatio...
Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia and male infertility, with its genetic etiology primarily associated with CFTR (autosomal recessive) and ADGRG2 (X-linked) mutations. However, the genetic spectrum and classification of variants in isolated congenital absence of the vas deferens (iCAVD), as well as the risk of CFTR variant carriage in affected couples, remain incompletely understood. In this cross-sectional study, we enrolled 199 Chinese iCAVD patients and 148 female partners between 2012 and 2024. CFTR and ADGRG2 variants were identified in 74.87% of iCAVD patients, with CFTR being the predominant pathogenic gene. Notably, 10.14% of couples carried shared pathogenic or likely pathogenic CFTR variants, highlighting the potential reproductive risks. The most common pathogenic variants were CFTR c.1210-12T (Yu et al., 2012) (5T) and c.4056G > C (p.Gln1352His), whereas c.1666A > G (p.Ile556Val) was classified as likely benign. The c.4056G > C variant exhibited significant regional ethnic characteristics. Furthermore, genotype-phenotype correlation analysis revealed significant differences in semen volume, pH, and fructose levels among different variant subgroups in CBAVD patients. Collectively, these findings provide a comprehensive overview of the genotype-phenotype landscape in a large iCAVD cohort, emphasizing variant classification and reproductive risks associated with CFTR and ADGRG2. This study offers valuable insights for genetic counseling and reproductive planning in affected couples.
From Variant to Biomarker in NSCLC Immunotherapy Resistance: Multiomics Evidence Chains and Accountable AI Integration.
Jiang Y, Wang N, Zeng Q … +3 more , Liu J, Liu X, Cao G
Hum Mutat · 2026 · PMID 42181742 · Full text
Immune checkpoint inhibitors have become integral to the management of non-small cell lung cancer (NSCLC), yet both primary and acquired resistance remain frequent and are only partially captured by routine biomarkers su...
Immune checkpoint inhibitors have become integral to the management of non-small cell lung cancer (NSCLC), yet both primary and acquired resistance remain frequent and are only partially captured by routine biomarkers such as programmed death-ligand 1 (PD-L1) immunohistochemistry and tumor mutational burden (TMB). Resistance is increasingly viewed as a multiaxis functional phenotype shaped by antigenicity and neoantigen quality, antigen processing and presentation competence, interferon signaling and adaptive resistance programs, tumor-immune spatial organization, suppressive myeloid/stromal ecosystems, and metabolic constraints that limit effector function. Multiomics profiling provides a practical route to translate genomic event anchors into reproducible, mechanistically interpretable biomarker outputs by assembling coherent evidence chains across genomics, transcriptomics, epigenomics, proteomics, and metabolomics, complemented by spatial assays, digital pathology, and imaging-derived surrogates.
NDUFA4 Deletion Upregulates VDAC1 to Promote Mitochondrial Damage, Endoplasmic Reticulum Expansion, and Neuronal Apoptosis.
Li L, Fu F, Li R … +11 more , Zhou H, Huang R, Lu J, Guo F, Chen H, Lei T, Han J, Zhen L, Pan M, Li D, Liao C
Hum Mutat · 2026 · PMID 42181741 · Full text
BACKGROUND: Dandy-Walker malformation (DWM) is a rare congenital brain defect whose mechanism is still not fully understood. Genetic studies have suggested that NADH Dehydrogenase 1 alpha Subcomplex 4 (NDUFA4) may be ass...
BACKGROUND: Dandy-Walker malformation (DWM) is a rare congenital brain defect whose mechanism is still not fully understood. Genetic studies have suggested that NADH Dehydrogenase 1 alpha Subcomplex 4 (NDUFA4) may be associated with DWM; however, the functional consequences of NDUFA4 dysregulation in experimental neural models remain unclear. In this study, we investigated the cellular effects of NDUFA4 deficiency, rather than aiming to establish a causal mechanism for DWM. METHODS: NDUFA4-related differentially expressed proteins were analyzed using iTRAQ tandem mass spectrometry, followed by functional, pathway, and protein interaction network analyses. Then, voltage-dependent anion Channel 1 (VDAC1), apoptosis-, endoplasmic reticulum (ER) stress-related proteins, and ETC Complex IV activity were assessed in NDUFA4 knockout mice. After NDUFA4 and VDAC1 knockdown, cell proliferation, apoptosis, mitochondrial status, and ER function were evaluated by CCK-8, Edu staining, flow cytometry, and Western blot in C8-D1A cells. In addition, the interaction between NDUFA4 and VDAC1 was evaluated using immunofluorescence and coimmunoprecipitation. RESULTS: NDUFA4 knockout upregulated VDAC1, ER stress- and apoptosis-related proteins, and inhibited ETC complex IV activity in mice. NDUFA4 knockdown inhibited proliferation and promoted apoptosis, ER stress, and mitochondrial damage in C8-D1A cells, and these changes were partially reversed by VDAC1 knockdown. Moreover, NDUFA4 and VDAC1 colocalized in C8-D1A cells and mouse cerebellar tissue, and NDUFA4 was found to interact with VDAC1. CONCLUSIONS: NDUFA4 deletion was associated with VDAC1 upregulation, mitochondrial damage, ER stress, and apoptosis-related changes in our experimental models. These findings may provide insight into cellular changes potentially relevant to DWM; however, they do not establish a direct causal relationship.
A New Mutant Rat Model of Osteogenesis Imperfecta and Its Application in AAV9-Mediated Gene Therapy.
Li S, Chen X, Cao Y … +7 more , Han M, Guan F, Ren X, Mi H, Yang T, Li M, Zhao X
Hum Mutat · 2026 · PMID 42181740 · Full text
Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous bone disorder, with more than 20 genes contributing to OI development. Previously, we identified c.620G > A (p.Arg207His) mutation among Chinese...
Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous bone disorder, with more than 20 genes contributing to OI development. Previously, we identified c.620G > A (p.Arg207His) mutation among Chinese patients with autosomal recessive OI (AR-OI). This study aims at investigating the causative role of deficiency in OI and evaluate whether AAV-based gene therapy could ameliorate bone abnormalities. We generated and analyzed the Wnt1 rat model. The AAV9-Wnt1 virus was delivered via direct intraosseous injection into the femoral marrow cavity of the OI rats to evaluate its therapeutic potential. The homozygous Wnt1 rat recapitulated key features of AR-OI, including fractures, reduced bone mass, growth retardation, decreased survival rate, increased osteoclast numbers, diminished osteoblast function and mineralization capacity, compared with heterozygous and wild-type littermates. In vitro, overexpression in osteoblasts promoted osteoblast activity and bone mineralization. Furthermore, AAV9-Wnt1 treatment in OI rats resulted in significant recovery of bone density and mechanical strength, stimulation of osteoblast activity, suppression of osteoclast activity, and upregulation of Type I collagen expression. Our study demonstrates that c.620G > A (p.Arg207His) is pathogenic, and confirms that AAV-mediated Wnt1 gene therapy represents a promising strategy for treating OI caused by mutations.
Causal Mediation of Immune Cells and Fatty Acids in Coronary Atherosclerosis: Insights From Mendelian Randomization Analysis.
Zhang Y, Xu J, Deng Z … +7 more , Long X, Liu J, Jiang L, Liu N, Zhang D, Zhou W, Zhu P
Hum Mutat · 2026 · PMID 42181739 · Full text
Observational studies have suggested a link between total fatty acid levels and the development of coronary atherosclerosis. While the involvement of immune cells in the pathogenesis of this condition is well-established...
Observational studies have suggested a link between total fatty acid levels and the development of coronary atherosclerosis. While the involvement of immune cells in the pathogenesis of this condition is well-established, the precise causal mechanisms by which fatty acids influence immune cell function and subsequently affect coronary atherosclerosis remain unclear. To address this, we systematically assessed the causal relationships among 731 immune cell traits, circulating fatty acid levels, and coronary atherosclerosis using a two-sample Mendelian randomization (MR) approach. Multivariable Mendelian randomization (MVMR) was further employed to investigate the potential mediating role of dendritic cells in the pathway linking fatty acids to coronary atherosclerosis. Our analysis identified significant causal associations between 30 immune cell traits and coronary atherosclerosis. Furthermore, circulating fatty acid levels were causally linked to an increased risk of coronary atherosclerosis. MVMR analysis revealed that dendritic cells, specifically the CD62L- CD86+ myeloid subset, partially mediate the causal effect of fatty acid levels on coronary atherosclerosis. This study provides genetic evidence supporting the causal roles of multiple immune cell traits and fatty acid levels in coronary atherosclerosis. Importantly, dendritic cells were identified as a key mediator in the pathway through which fatty acids influence disease risk. These findings offer new insights into the interplay between nutrition and immunity in atherosclerosis and highlight potential targets for future therapeutic and preventive strategies.
-Related Neurodevelopmental Disorder Without Metabolic Findings.
Ülker Üstebay D, Aksu Şahin İ, Üstebay S … +2 more , Ünsel Bolat G, Bolat H
Hum Mutat · 2026 · PMID 42181738 · Full text
is a tRNA methyltransferase gene associated with a rare autosomal recessive disorder characterized by microcephaly, intellectual disability, epilepsy, short stature, and abnormalities in glucose metabolism. Although an i...
is a tRNA methyltransferase gene associated with a rare autosomal recessive disorder characterized by microcephaly, intellectual disability, epilepsy, short stature, and abnormalities in glucose metabolism. Although an increasing number of patients have been reported, the extent of phenotypic variability and genotype-phenotype correlations remains incompletely understood. We report a 15-year-old male presenting with microcephaly, intellectual disability, epilepsy, and short stature, without evidence of diabetes or other metabolic abnormalities at the time of evaluation. Neurodevelopmental delay was evident from early childhood, and electroencephalography revealed generalized epileptiform activity requiring treatment, whereas brain magnetic resonance imaging was normal. Exome sequencing identified a homozygous stop-gained pathogenic (PVS1, PM2, and PM3) variant in (c.127C>T; p.Arg43Ter), which was confirmed by Sanger sequencing and showed segregation consistent with autosomal recessive inheritance. This case represents one of the rare reported -related syndrome patients in whom diabetes has not yet been documented. This observation highlights the clinical importance of establishing the diagnosis prior to the onset of diabetes, enabling anticipatory monitoring and timely intervention for potential metabolic complications. These findings underscore the importance of considering in the differential diagnosis of patients with microcephaly, intellectual disability, epilepsy, and growth abnormalities, and emphasize the need for longitudinal follow-up to monitor for the possible later development of endocrine and metabolic manifestations.
ENPP2 Dysregulation Defines a Candidate Biomarker Axis Coupling Tumor-Intrinsic cAMP Signaling to Macrophage Polarization in Hepatocellular Carcinoma.
Chen S, Zheng J, Long J … +3 more , Ou P, Tong J, Lin F
Hum Mutat · 2026 · PMID 42181737 · Full text
Hepatocellular carcinoma (HCC) shows substantial biological heterogeneity and commonly develops within an immunosuppressive microenvironment. Tumor-associated macrophages (TAMs), particularly M2-skewed subsets, are repea...
Hepatocellular carcinoma (HCC) shows substantial biological heterogeneity and commonly develops within an immunosuppressive microenvironment. Tumor-associated macrophages (TAMs), particularly M2-skewed subsets, are repeatedly associated with aggressive disease and may represent a biologically meaningful phenotype for biomarker development. Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been implicated in malignant behavior, but its linkage to TAM polarization and its potential as a laboratory-interpretable translational readout in HCC remain insufficiently clarified. ENPP2 expression was examined in paired HCC and adjacent tissues and referenced to public cohorts to provide clinical context. ENPP2 was overexpressed or silenced in HCC cells, followed by assays of proliferation, apoptosis, migration, and invasion. Macrophage polarization was evaluated using a noncontact Transwell coculture system with marker assessment and flow-cytometric readouts. Intracellular cyclic adenosine monophosphate (cAMP) was quantified, and forskolin was used to interrogate pathway involvement. Xenograft experiments were conducted to examine in vivo tumor growth. ENPP2 was upregulated in HCC and showed an association with unfavorable outcomes in public datasets. ENPP2 increased malignant phenotypes in HCC cells and shifted cocultured macrophages toward an M2-skewed state, whereas ENPP2 suppression produced the opposite pattern. ENPP2 modulation coincided with changes in intracellular cAMP signaling, and forskolin partially attenuated phenotypes observed after ENPP2 knockdown. These findings delineate a novel ENPP2/cAMP signaling axis that directly links tumor-intrinsic ENPP2 overexpression in HCC cells to the induction of M2-skewed TAM polarization, a mechanism that has not been previously characterized in HCC. This work not only identifies ENPP2 as a dual regulator of HCC cell malignancy and TAM polarization but also establishes cAMP as the critical intracellular mediator of this crosstalk, thereby strengthening the logical connection between these elements and advancing the understanding of HCC tumor-immune microenvironment interactions beyond existing literature.
Multiomics Identification of Radioresistance-Associated Biomarkers and Prognostic Model Construction in Rectal Cancer.
Deng Z, Lu C, Wang Z
Hum Mutat · 2026 · PMID 42181736 · Full text
BACKGROUND: Radiotherapy remains a cornerstone in the local management of rectal cancer (RC); however, resistance to radiation significantly compromises therapeutic efficacy and adversely affects patient prognosis. Ident...
BACKGROUND: Radiotherapy remains a cornerstone in the local management of rectal cancer (RC); however, resistance to radiation significantly compromises therapeutic efficacy and adversely affects patient prognosis. Identification of biomarkers associated with radioresistance and the development of a prognostic model based on radiotherapy-related genes in RC remain critical for enhancing treatment outcomes. METHODS: Data related to RC were obtained from public repositories, including bulk RNA-seq data from 993 patients across four Gene Expression Omnibus (GEO) and one The Cancer Genome Atlas (TCGA) cohort, as well as single-cell RNA-seq data from six samples. A prognostic model was developed using differential expression analysis, functional enrichment analysis, and least absolute shrinkage and selection operator regression analysis. Associations between risk score and prognosis were assessed through gene set variation analysis, gene set enrichment analysis, and construction of a nomogram to identify potential therapeutic targets for RC. RESULTS: Prognosis-related genes were determined through analysis of clinical data from patients with RC in the GEO and TCGA datasets, leading to the development of a risk score model. The risk score demonstrated significant associations with immune cell infiltration, chemotherapy drug sensitivity, and multiple signaling pathways. Protein expression levels of the key genes in patients with RC were verified using the Human Protein Atlas database. Furthermore, immunohistochemical evaluation in animal models provided additional validation. CONCLUSION: Molecular characteristics and mechanisms underlying radiotherapy response in RC were clarified through multiomics analysis. Five key genes were identified as potentially related to radiotherapy sensitivity in RC. These prognostic genes may serve as novel biomarkers and potential targets for diagnosis, prognostic evaluation, and clinical management of RC.
Bioinformatics Combined With Biological Experiments to Explore the Promotion of Lung Metastasis by CCL18 in the Immune Microenvironment of Colorectal Cancer.
Xia Q, Yin S, Chen J … +9 more , Wang H, Shi Y, Li J, Yuan Z, Wang Z, Lu M, Zhao Q, Wei W, Ma X
Hum Mutat · 2026 · PMID 42170304 · Full text
BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms. Tumor metastasis represents a significant contributor to unfavorable prognosis, and lung metastasis is the most common extra-abdominal...
BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms. Tumor metastasis represents a significant contributor to unfavorable prognosis, and lung metastasis is the most common extra-abdominal metastasis of CRC. However, pulmonary metastatic CRC has not received significant attention. Therefore, in this study, our main aim was to discover the key genes for lung metastasis and improve the prognosis of CRC. METHODS: Differentially expressed genes (DEGs) between primary tumors and patients with pulmonary metastatic CRC were obtained by analysis of a comprehensive database of gene expression (GEO). DEGs were screened by prognostic survival analysis, TCGA differential expression analysis, and single gene GSEA. RESULTS: Combining the differences in patient prognosis and expression, we found that CCL18 is a key gene in CRC lung metastasis. Macrophage coculture and transwell assay verified the potential of CCL18 in promoting the invasive metastatic ability of CRC cells, as well as the proliferation of CRC cells.
A Mitoxyperilysis-Related Single-Cell and Machine-Learning Framework Defines an Immune-Cold Melanoma Phenotype and a Robust Prognostic Signature.
Zhou Y, Fang J, Fei L … +4 more , Li H, Xu X, Xie J, Qi M
Hum Mutat · 2026 · PMID 42170303 · Full text
Mitoxyperilysis is a mitochondria-dependent membrane lysis process driven by innate immune and metabolic cues, yet its clinical relevance in melanoma remains unclear. We analyzed single-cell RNA-seq data (GSE215120) to q...
Mitoxyperilysis is a mitochondria-dependent membrane lysis process driven by innate immune and metabolic cues, yet its clinical relevance in melanoma remains unclear. We analyzed single-cell RNA-seq data (GSE215120) to quantify a mitoxyperilysis-related score (MRS), resolve cell-type heterogeneity, and compare predicted cell-cell communication between MRS-high and MRS-low tumor states. MRS was robust across alternative scoring approaches and varied markedly across cell types and malignant subpopulations. Compared with MRS-low tumors, the MRS-high state exhibited increased predicted intercellular communication (740 vs. 448 interactions) and higher global interaction strength (18,989 vs. 10,652), suggesting a rewired tumor ecosystem. To translate these programs to bulk melanoma, we selected the top 150 genes most correlated with MRS and benchmarked 101 machine-learning strategies in TCGA-SKCM to derive prognostic models, followed by external validation in six independent GEO cohorts. A gradient boosting machine (GBM)-based signature showed the most consistent cross-cohort performance and reliably stratified overall survival. High riskScore was associated with reduced immune and stromal signals, higher tumor purity, and an immune-cold tumor microenvironment as estimated by multialgorithm deconvolution and ESTIMATE. As a representative model gene, GPR143 was upregulated in melanoma, was associated with worse survival, and its functional knockdown suppressed colony formation in melanoma cells. Collectively, this work establishes a novel integrative framework that-for the first time-connects single-cell-resolved mitoxyperilysis-associated transcriptional programs with large-scale multicohort machine-learning validation, thereby enabling both mechanistic interpretation of immunometabolic heterogeneity and clinically applicable risk stratification in melanoma.
Promotes the Pathogenesis of IBS by Downregulating the Expression of Ferroptosis-Related Molecule ERBB1: A Mendelian Randomization Mediation Analysis.
Mo L, Wu Y, Zhou Y … +5 more , He Y, Wei L, Zhou C, Cai S, Yuan J
Hum Mutat · 2026 · PMID 42170302 · Full text
OBJECTIVE: Although gut microbiota dysbiosis has been associated with irritable bowel syndrome (IBS), the specific roles of individual bacterial strains in the pathogenesis of IBS remain incompletely elucidated. Addition...
OBJECTIVE: Although gut microbiota dysbiosis has been associated with irritable bowel syndrome (IBS), the specific roles of individual bacterial strains in the pathogenesis of IBS remain incompletely elucidated. Additionally, whether these bacterial strains exert their effects through the ferroptosis pathway remains unclear. Therefore, this study is aimed at investigating the impact of ferroptosis-related molecules regulated by gut microbiota on IBS development using Mendelian randomization (MR) mediation analysis. METHODS: Genome-wide association study (GWAS) data for gut microbiota were acquired from the FINRISK study, and protein quantitative trait loci (pQTL) data were retrieved from the deCODE database. Ferroptosis-related genes and their downstream molecules were identified using the FerrDb V2 database; these molecules were then intersected with pQTL data to obtain ferroptosis-related pQTLs. IBS datasets were derived from the FinnGen R12 database. A two-step MR mediation analysis was performed, with the inverse-variance weighted (IVW) method designated as the primary analytical approach. Eligible results were defined by three criteria: value < 0.05, mediation proportion > 10%, and consistency between mediation effects and total effects. Heterogeneity analysis, pleiotropy testing, and sensitivity analysis were further conducted to verify the robustness of the results. RESULTS: exhibited a negative correlation with v-erb-b2 avian erythroblastic leukemia viral oncogene Homolog 1 (ERBB1) (beta1 = -0.125). In turn, ERBB1 was negatively correlated with IBS (beta2 = -0.223), whereas showed a positive total effect on IBS (beta_all = 0.168). The mediation proportion of this pathway was 16.57% ( < 0.05). CONCLUSION: may promote the pathogenesis of IBS by downregulating ERBB1, suggesting that increased ferroptosis susceptibility in intestinal epithelial cells may play a role in this pathway. This finding provides novel insights into the underlying mechanisms of IBS and may offer a potential target for IBS intervention.
Type B Aortic Dissection Following Abdominal Aortic Aneurysm Repair in Loeys-Dietz Syndrome: A Novel Variant.
Zhang Y, Qiu S, Hu C … +4 more , Zhang L, Guo W, Fu W, Wang L
Hum Mutat · 2026 · PMID 42164325 · Full text
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by aggressive aortic pathology, primarily caused by pathogenic variants in genes such as . We report a 44-year-old female with...
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by aggressive aortic pathology, primarily caused by pathogenic variants in genes such as . We report a 44-year-old female with a known LDS diagnosis who presented with a symptomatic, rapidly expanding abdominal aortic aneurysm (44.8 mm) with concurrent iliac and renal artery involvement. Given the high rupture risk, she underwent open abdominal aortic reconstruction. However, she subsequently developed a Type B aortic dissection nearly 2 months after the initial repair, necessitating a second open thoracic surgery. Whole-exome sequencing confirmed a novel, de novo heterozygous missense variant in the gene: c.1051G>T (p.Asp351Tyr), located within the highly conserved kinase domain and classified as likely pathogenic. Structural modeling suggested that this variant enhances binding affinity to SMAD2, and immunohistochemistry of the patient's aortic tissue confirmed hyperactivation of the TGF- pathway via increased SMAD2/SMAD3 phosphorylation. This case expands the pathogenic variant spectrum of -related LDS. Furthermore, it provides valuable clinical insights into the management of abdominal aortic aneurysms in LDS, suggesting that symptoms and rapid growth may warrant surgical intervention before conventional diameter thresholds are met. It also serves as a stark reminder of the residual vascular fragility, reinforcing the need for lifelong, whole-body vascular surveillance.
Frequent Detection of -G12C and -Q546K Mutations in MAP Tumors Highlights their Role in Variants of Uncertain Significance Reclassification.
Medeiros ABD, Kozak VN, Picanço-Albuquerque CG … +6 more , Neto FGKV, Dos Santos GO, Junior SA, Casali-da-Rocha JC, Carraro DM, Torrezan GT
Hum Mutat · 2026 · PMID 42164324 · Full text
Biallelic pathogenic variants in cause -associated polyposis (MAP), a rare recessive colorectal cancer (CRC) predisposition syndrome characterized by somatic G:C > T:A transversions. The hotspot somatic mutations -G12C...
Biallelic pathogenic variants in cause -associated polyposis (MAP), a rare recessive colorectal cancer (CRC) predisposition syndrome characterized by somatic G:C > T:A transversions. The hotspot somatic mutations -G12C and -Q546K are highly enriched in MAP CRCs, and are rarely observed in sporadic cases, suggesting their potential utility in supporting the reclassification of variants of uncertain significance (VUS) in . This study is aimed at evaluating the frequency of -G12C and -Q546K in adenomas and CRC from MAP patients and to demonstrate their relevance to reclassify VUS. These hotspot mutations were evaluated using targeted NGS in adenomas and CRC tissues from 16 previously diagnosed MAP patients and three patients suspected of MAP, who harbored a VUS in either homozygosity or compound heterozygosity with a germline pathogenic variant. -G12C and -Q546K were identified in 92.3% and 38.4% of 13 MAP adenocarcinomas, respectively. -G12C was also present in 47% of 17 MAP adenomas, whereas none of them harbored -Q546K. The detection of either mutation in CRC showed 100% sensitivity and 97% specificity for MAP ( = 0.00001). Among the three-suspected MAP cases with VUS, two harbored somatic -G12C and/or -Q546K, providing sufficient evidence to reclassify VUS p.Pro301Arg and p.Trp113Arg as likely pathogenic based on ACMG/AMP criteria. These findings support the use of -G12C and -Q546K as cost-effective, accessible tumor biomarkers for aiding in MAP diagnosis and VUS reclassification, particularly in settings with limited access to whole-exome/genome mutational signature analysis.
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