Hum. Mutat. [JOURNAL]
Sun
200 papers
Variant-to-Biomarker Pathways in Peripheral Artery Disease: Multiomics Integration and Clinical Translation.
Wang W, Zhao G, Yang C … +1 more , Chang S
Hum Mutat · 2026 · PMID 42063615 · Full text
Peripheral artery disease (PAD) is a prevalent, disabling manifestation of systemic atherosclerosis that carries high risks of major adverse cardiovascular and limb events, yet remains incompletely explained by conventio...
Peripheral artery disease (PAD) is a prevalent, disabling manifestation of systemic atherosclerosis that carries high risks of major adverse cardiovascular and limb events, yet remains incompletely explained by conventional risk factors and haemodynamic indices. Although genome-wide association studies have nominated reproducible susceptibility loci and high-throughput profiling has expanded the landscape of circulating, imaging, vascular and skeletal muscle biomarkers, most signals are noncoding, mechanistic attribution is often uncertain and few biomarkers have demonstrated durable incremental utility for risk stratification or therapeutic guidance in routine care. In this review, we summarise PAD-relevant genetic architectures and multiomics modalities-fine-mapped GWAS with tissue- and cell-resolved functional genomics, proteogenomic and metabolomic profiling and network-based integration across vascular, muscle and circulating compartments-and we appraise translational opportunities that span variant-anchored protein and metabolite prioritisation, composite biomarker panels for limb-specific ischaemic burden and residual atherothrombotic risk and biomarker-informed selection of antithrombotic, lipid-lowering, anti-inflammatory and revascularisation strategies. We also discuss enduring challenges-including ancestry-sensitive transferability of genetic instruments, limited access to disease-relevant tissues, cross-platform standardisation, confounding by disease stage and therapy and the need for prospective validation and trial-ready pharmacodynamic endpoints-that temper implementation. The purpose of this review is to delineate variant-to-biomarker pathways in PAD and specify integrative, clinically actionable solutions for discovery, validation and translation. We further distinguish diagnostic, prognostic, predictive/theragnostic and pharmacodynamic biomarker contexts of use, and emphasise that phenotype definition, sex, diabetes, exposure measurement and treatment effects all condition the interpretation and transferability of PAD multiomic signals.
Targeting the Vim-PGI Pathway Enhances CD8 T Cell-Mediated Antitumor Immunity in Breast Cancer.
Quan H, Shao L, Li Q … +1 more , Dong C
Hum Mutat · 2026 · PMID 42058674 · Full text
Breast cancer is the most prevalent malignancy in women, and the limited effectiveness of current treatments highlights the need for novel immune regulatory mechanisms to improve long-term survival. This study investigat...
Breast cancer is the most prevalent malignancy in women, and the limited effectiveness of current treatments highlights the need for novel immune regulatory mechanisms to improve long-term survival. This study investigated the role of Vim in PGI synthesis and its impact on tumor immune regulation. Multiomics profiling revealed molecular alterations following Vim deletion, which were validated in murine breast cancer models using RT-qPCR, Western blot, ELISA, and flow cytometry, with rescue experiments involving exogenous PGI. The findings showed that Vim deletion downregulated arachidonic acid metabolism, reduced PTGIS expression, and significantly lowered PGI levels. Functional assays demonstrated that Vim deficiency enhanced T cell-mediated antitumor immunity, evidenced by an increased proportion of CD8 T cells, upregulation of cytotoxic genes (, , , and ), and activation of inflammation-related signaling pathways, as indicated by enhanced phosphorylation of ERK1/2 and p65. Both exogenous PGI supplementation and ozagrel treatment reversed these effects. In conclusion, the Vim-PGI axis is identified as a key regulator of CD8 T cell immunity in breast cancer, representing a potential therapeutic target and a critical consideration in anticoagulant management during cancer immunotherapy.
A Tertiary Lymphoid Structure-Derived Prognostic Signature Integrates Immune Microenvironment and Mutational Landscapes in Clear Cell Renal Cell Carcinoma.
Zhou X, Zhao Z, Huang K … +1 more , Ma G
Hum Mutat · 2026 · PMID 42058673 · Full text
Tertiary lymphoid structures (TLSs) are increasingly recognized as important components of the tumor immune microenvironment, yet their prognostic and immunological implications in clear cell renal cell carcinoma (ccRCC)...
Tertiary lymphoid structures (TLSs) are increasingly recognized as important components of the tumor immune microenvironment, yet their prognostic and immunological implications in clear cell renal cell carcinoma (ccRCC) remain incompletely characterized. In this study, we performed an integrated bioinformatic and translational analysis to investigate TLS-associated molecular features in ccRCC. Using TCGA-KIRC transcriptomic data, we identified three TLS-related molecular subtypes with distinct survival outcomes and immune microenvironment characteristics. Based on prognostic TLS-associated genes, we developed a four-gene TLS-derived score (CSF2, CXCL13, IL1R2, and SGPP2) that stratified patients into groups with significantly different overall survival. The TLS score remained an independent prognostic factor after adjustment for clinical variables. Interestingly, higher TLS scores were associated with increased immune infiltration but poorer survival outcomes, suggesting that TLS-associated transcriptional patterns may reflect heterogeneous immune functional states rather than uniformly effective antitumor immunity. Computational analyses indicated potential differences in predicted immunotherapy response and mutation landscapes between TLS score groups. Limited experimental validation using fresh ccRCC specimens supported the feasibility of TLS score assessment and provided preliminary histopathological context for TLS-associated immune features. Overall, this study proposes a TLS-derived transcriptional signature that may help capture immune heterogeneity in ccRCC and may provide a complementary framework for prognostic assessment. Further studies are required to validate its biological and clinical relevance.
De Novo Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus.
Mehta NH, Dennis E, Allington G … +10 more , Mekbib KY, Hale AT, Davalan WC, Duy PQ, Zilla E, Fan B, Kasper EM, Alper SL, Haider S, Kahle KT
Hum Mutat · 2026 · PMID 42051466 · Full text
Congenital hydrocephalus (CH), characterized by congenital ventriculomegaly (CV), affects approximately 0.5-1 per 1000 live births and is a common cause of pediatric neurosurgical intervention, yet its genetic architectu...
Congenital hydrocephalus (CH), characterized by congenital ventriculomegaly (CV), affects approximately 0.5-1 per 1000 live births and is a common cause of pediatric neurosurgical intervention, yet its genetic architecture remains incompletely defined. We report a child with syndromic CH requiring cerebrospinal fluid diversion who harbored a pathogenic de novo missense variant in (c.3232C > T; p.(Arg1078Trp)), a gene previously associated with autosomal dominant neurodevelopmental disorders featuring variable head circumference. This case prompted systematic evaluation of variation in our CV/CH cohort (2,697 patient-parent trios) using exome sequencing. We identified five additional unrelated probands with de novo variants, including two novel substitutions affecting the same residue within the Ras-GEF1 domain (p.(Glu1299Lys) and p.(Glu1299Gly)), yielding significant gene-level enrichment for protein-damaging de novo variants (adjusted = 6.12 × 10). All affected individuals exhibited CV, frequently accompanied by developmental delay and additional structural brain abnormalities. In silico structural modeling predicted that associated variants destabilize critical Ras-GEF domains required for Rho GTPase activation. Analysis of single-nucleus transcriptomic data from the developing human neocortex revealed enrichment of expression in multipotent progenitor populations. A systematic literature review identified six additional individuals with de novo variants and reported CV or CH, including an unrelated patient with the same p.(Arg1078Trp) substitution. Together, these findings expand the phenotypic spectrum associated with pathogenic variation to include CV/CH and support as a clinically relevant gene in the genetic evaluation of syndromic CV/CH patients.
Identification of a Novel VLDLR Variant in the First Report of CAMRQ1 From Africa: Expanding the Spectrum of Cerebellar Ataxia Syndromes.
Jawabri AA, Salazar-Villacorta A, Senghor H … +6 more , Ndiaye R, Al-Mehrzi A, Diop AG, Ndiaye M, Ali BR, Rodriguez Cruz PM
Hum Mutat · 2026 · PMID 42051465 · Full text
Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ)-related disorders are rare, nonprogressive, autosomal recessive conditions primarily characterized by cerebellar ataxia, hypotonia, intellectual...
Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ)-related disorders are rare, nonprogressive, autosomal recessive conditions primarily characterized by cerebellar ataxia, hypotonia, intellectual disability, delayed ambulation, and, in some cases, quadrupedal locomotion. Pathogenic variants in four disease genes, , , , and have been linked to these disorders, with cases reported across various ethnic groups and geographic regions. However, no reports of CAMRQ1 (OMIM #224050) have been previously made from Africa. In this study, we report the first African family with four affected siblings exhibiting typical CAMRQ1 clinical features with varying levels of phenotypic severity. Genetic analysis revealed a novel missense homozygous variant (c.1694C > A; p.P565Q) in the gene in all the affected individuals, with the parents being heterozygous. Biochemical analysis, including immunofluorescence and confocal laser microscopy, western blot, and endoglycosidase H sensitivity and resistance assay, demonstrated the retention of the p.(P565Q) VLDLR protein in the endoplasmic reticulum (ER), impairing its trafficking to the plasma membrane and thus confirming its pathogenic impact. This ER retention is expected to disrupt VLDLR-mediated signaling pathways, including reelin signaling, thereby affecting neuronal migration. Furthermore, due to its ER retention, the p.(P565Q) is expected to induce ER stress and activate the endoplasmic reticulum-associated degradation (ERAD) pathway. Our findings expand the genetic and geographical spectrum of CAMRQ1 and provide further functional insights into its underlying pathogenesis.
Single-Cell Transcriptomic Profiling and Machine Learning Integration Unveil Stromal Cell Heterogeneity in Endometriosis.
Zhang H, Luo Y
Hum Mutat · 2026 · PMID 42040898 · Full text
BACKGROUND: Endometriosis (EMs) affects approximately 10% of reproductive-age women worldwide, yet its pathogenesis remains incompletely understood. Abnormal cell differentiation and somatic mutations in the ectopic endo...
BACKGROUND: Endometriosis (EMs) affects approximately 10% of reproductive-age women worldwide, yet its pathogenesis remains incompletely understood. Abnormal cell differentiation and somatic mutations in the ectopic endometrial microenvironment play critical roles in disease progression and treatment response heterogeneity. This study is aimed at elucidating the molecular mechanisms underlying ectopic endometrial cell differentiation using machine learning (ML) approaches and single-cell RNA sequencing (scRNA-seq), and identifying novel prognostic biomarkers and therapeutic targets, with particular attention to mutation-driven transcriptional alterations. METHODS: We analyzed comprehensive transcriptomic data from the Gene Expression Omnibus (GEO) and Human Endometrium Database (HED), including scRNA-seq data from 162,485 cells across 46 EMs patients. Through systematic comparative analysis, we identified 298 genes associated with ectopic endometrial cell differentiation, including genes harboring recurrent somatic mutations reported in endometriotic lesions. We evaluated 10 distinct ML algorithms and 101 hybrid combinations to develop predictive models for patient stratification. Unsupervised clustering analysis identified distinct patient phenotypes. Functional enrichment analysis, pathway analysis, and cell-cell communication networks were constructed to characterize the ectopic microenvironment. Four key genes (HOXA10, ESR1, MMP9, and SPP1) were validated by quantitative real-time PCR in normal endometrial stromal cells (NESCs) and ectopic endometrial stromal cells (EESCs). RESULTS: Unsupervised clustering revealed two distinct patient subgroups characterized as high- and low-invasive ectopic endometrium phenotypes with significantly different disease progression trajectories. Single-cell analysis unveiled extensive cellular heterogeneity within the ectopic endometrial microenvironment, identifying multiple cell types including epithelial, stromal, endothelial, and immune cells. Gene ontology and pathway enrichment analyses demonstrated significant activation of extracellular matrix organization, cell adhesion, cell migration, and angiogenesis pathways. Cell-cell communication analysis revealed macrophages as central mediators forming extensive connections with stromal, epithelial, and endothelial cells, with SPP1 emerging as a key signaling molecule. Trajectory analysis of stromal cells identified at least two major differentiation branches, indicating divergent differentiation programs. Notably, several of the 298 differentiation-associated genes overlapped with loci frequently mutated in ectopic lesions, suggesting that somatic mutations may contribute to aberrant gene regulation. qRT-PCR validation confirmed significant differential expression of key genes: HOXA10 showed 62% downregulation (0.38 ± 0.06 vs. 1.00 ± 0.09, < 0.001), whereas ESR1, MMP9, and SPP1 demonstrated 108%, 252%, and 189% upregulation, respectively, in EESCs compared with NESCs (all < 0.001). CONCLUSIONS: This study provides a comprehensive molecular characterization of ectopic endometrial cell differentiation through integrative ML-based analysis and single-cell sequencing. The identification of distinct patient phenotypes, key regulatory genes, and macrophage-centric communication networks advances our understanding of EMs pathogenesis. HOXA10, ESR1, MMP9, and SPP1 represent potential diagnostic biomarkers and therapeutic targets for personalized treatment strategies. The convergence of mutation-associated transcriptional changes and differentiation abnormalities underscores the need for mutation-aware therapeutic strategies. These findings pave the way for developing more effective and targeted interventions to improve patient outcomes in EMs management.
Variant-to-Biomarker Integration and Mechanistic Validation Identify CES1 as a Copy Number-Linked Predictor of Radiotherapy Response in Rectal Cancer.
Yang X, Zheng M, Lu X … +1 more , Li Y
Hum Mutat · 2026 · PMID 42040897 · Full text
BACKGROUND: Radiotherapy is a fundamental component of rectal cancer treatment, yet patient responses remain highly heterogeneous due to the lack of reliable biomarkers supported by genomic variation evidence. Integratin...
BACKGROUND: Radiotherapy is a fundamental component of rectal cancer treatment, yet patient responses remain highly heterogeneous due to the lack of reliable biomarkers supported by genomic variation evidence. Integrating multi-cohort transcriptomic data with machine-learning approaches enables systematic identification of genes with both predictive and therapeutic relevance. This study aimed to develop a robust model for predicting radiotherapy response and to functionally characterize CES1 as a key regulator of radiosensitivity and a potential therapeutic target. METHODS: Three independent GEO cohorts were standardized and integrated, followed by a comprehensive machine-learning pipeline incorporating LASSO, Elastic Net, Random Forest, XGBoost, and information gain. A consensus-ranked five-gene model was constructed using nested cross-validation. CES1, identified as the top-ranked contributor to model performance, was selected for biological validation. To connect transcriptomic findings with genetic variation, copy number alteration (GISTIC2) and somatic mutation analyses were performed in TCGA-READ. Functional assays-including quantitative PCR, CCK-8 viability assays, colony formation, wound-healing migration assays, Annexin V/PI flow cytometry, and rescue by CES1 overexpression-were performed in HT-29 and SW480 cells to evaluate its mechanistic role in radiotherapy response. RESULTS: The machine-learning model demonstrated high discriminative accuracy across datasets and consistently highlighted CES1 as a dominant contributor to radiosensitivity prediction. CES1 expression increased after clinical chemoradiotherapy and showed dose-dependent induction following irradiation in vitro. CES1 knockdown significantly reduced radiation-induced apoptosis, enhanced clonogenic survival, and promoted migratory capacity, collectively indicating a radioresistant and more aggressive phenotype. Restoration of CES1 expression in CES1-silenced cells reversed radioresistance and re-established irradiation sensitivity. Genomic analysis in TCGA-READ further demonstrated that CES1 expression was positively associated with copy number status, whereas coding-sequence mutations in CES1 were infrequent, suggesting dysregulation primarily through copy-number and transcriptional mechanisms. CONCLUSION: This integrative computational and experimental study identifies CES1 as a predictive biomarker and copy number-linked regulator of radiosensitivity in rectal cancer. Modulation of CES1 directly alters cellular responses to irradiation, supporting its role as a mechanistically interpretable biomarker for response stratification. These findings align with the emerging concept that integrating genetic variation profiling with functional validation can accelerate variant-to-biomarker translation in precision oncology.
Cholesterol Reprograms Oxysterol Metabolism via the LOX1/CH25H/CYP7B1 Signaling Axis to Drive Multidrug Resistance in Colorectal Cancer.
Cheng H, Huang L, Huang J … +4 more , Feng J, Huang K, Liu M, Li J
Hum Mutat · 2026 · PMID 42040896 · Full text
Chemotherapeutic resistance remains a major contributor to tumor recurrence and unfavorable clinical outcomes in colorectal cancer (CRC). Although cholesterol metabolic reprogramming has been implicated in tumorigenesis,...
Chemotherapeutic resistance remains a major contributor to tumor recurrence and unfavorable clinical outcomes in colorectal cancer (CRC). Although cholesterol metabolic reprogramming has been implicated in tumorigenesis, metastasis, and drug resistance across multiple malignancies, its specific role in CRC chemoresistance requires systematic investigation. We analyzed RNA-seq data from GEO dataset GSE196900 to identify differentially expressed genes (|Log2FC| ≥ 1.5, adjusted < 0.05). Functional enrichment analysis (GO/KEGG), protein-protein interaction (PPI) network construction, and gene set enrichment analysis (GSEA) were performed. Experimental validation using 5-fluorouracil (5-FU)-resistant CRC cell lines (HCT8/HCT15) included cholesterol/25-hydroxycholesterol (25-HC) treatments, assessed through CCK-8 proliferation assays, wound healing migration tests, quantitative real-time PCR (qRT-PCR), Western blotting, and cholesterol metabolite quantification. Integrative bioinformatics and experimental evidence revealed that 5-FU-resistant CRC cells demonstrate significant upregulation of cholesterol metabolism regulators, including lectin-type oxidized LDL Receptor 1 (LOX1), cholesterol 25-hydroxylase (CH25H), and Cytochrome P450 Family 7 Subfamily B Member 1 (CYP7B1). These cells exhibited impaired cholesterol efflux capacity and consequent intracellular cholesterol accumulation. Exogenous supplementation with cholesterol or 25-HC promoted proliferation, migration, and chemoresistance in both parental and resistant cells. Conversely, CH25H knockdown in resistant cells significantly attenuated malignant phenotypes and restored drug sensitivity. Our findings establish cholesterol metabolic dysregulation as a novel mechanistic contributor to 5-FU resistance in CRC, mediated through the LOX1-CH25H-CYP7B1 regulatory axis. These results propose that therapeutic targeting of cholesterol homeostasis may overcome chemoresistance and improve clinical management of refractory CRC patients.
Visualization and Cluster Analysis of Peroxisome Proliferator-Activated Receptors in Colorectal Cancer: Research Trends and Future Directions.
Dong B, Zhou B, Zhang H … +6 more , Wang T, Xu Z, Zhu L, Li Q, Niu B, Sun X
Hum Mutat · 2026 · PMID 42040895 · Full text
OBJECTIVE: Peroxisome proliferator-activated receptors (PPARs) are essential regulators in the development and progression of colorectal cancer (CRC). However, a comprehensive bibliometric analysis of PPAR-related CRC re...
OBJECTIVE: Peroxisome proliferator-activated receptors (PPARs) are essential regulators in the development and progression of colorectal cancer (CRC). However, a comprehensive bibliometric analysis of PPAR-related CRC research is lacking. METHODS: Publications on PPARs in CRC from 1998 to 2024 were retrieved from the Web of Science Core Collection. VOSviewer, CiteSpace, and the R package bibliometrix were used to analyze publication trends, hotspots, and collaboration networks. Contributions from countries, institutions, authors, and journals were systematically evaluated. RESULTS: A total of 1380 publications were analyzed, with an annual growth rate of 8.33%. The United States led with the highest number of publications (386) and citations (28,461), followed by China and Japan. The University of Texas System was the most productive institution (125 publications). Gonzalez, Frank J. and Peters, Jeffrey M. were the most prolific authors (16 publications each). was the leading journal. Cluster analysis of keywords identified three major themes: regulatory mechanisms of PPARs in CRC, the association with obesity, and therapeutic applications. Current research hotspots included proliferation, inflammation, oxidative stress, and ulcerative colitis. CONCLUSION: This study highlights three key research focuses: molecular mechanisms of PPARs in CRC, the link between obesity and CRC, and therapeutic potential. These findings underscore the growing interest in PPAR-mediated metabolic regulation, inflammation, and targeted interventions, offering valuable guidance for future research directions.
A Novel Variant Causing Loss of Function Identified in a Family With Cardiospondylocarpofacial Syndrome: Functional Validation and Molecular Insights.
Zhu T, Shi J, Li J … +9 more , Zhou T, Fu X, Xu F, Gu C, Wang D, Wu R, Liu L, Shen J, Wang D
Hum Mutat · 2026 · PMID 42040894 · Full text
Mitogen-activated protein kinase kinase kinase 7 (), also known as transforming growth factor--activated kinase 1 (TAK1), is a widely expressed kinase that plays a crucial role in various cellular processes variants in t...
Mitogen-activated protein kinase kinase kinase 7 (), also known as transforming growth factor--activated kinase 1 (TAK1), is a widely expressed kinase that plays a crucial role in various cellular processes variants in the gene have been implicated in two distinct genetic disorders: frontometaphyseal dysplasia Type 2 (FMD2) and cardiofaciocutaneous syndrome (CSCF). To elucidate the consequences of the variant, we investigated a Chinese family with CSCF harboring a novel heterozygous variant and examined the genotype-phenotype correlation. Functional validation was performed using clinical evaluations, whole-exome sequencing (WES), and biochemical assays, including western blotting to assess TAK1 phosphorylation levels and downstream signaling pathways. Clinical data and genomic DNA were collected from the proband and family members. WES identified a novel heterozygous variant in (NM_145331.3: c.149 T > C, p.Val50Ala) inherited from the affected mother. Sequence conservation analysis revealed that the Val50 residue is highly conserved among vertebrates and is critical for ATP binding. Protein 3D modeling predicted that the Val50Ala variant disrupts the kinase domain structure, potentially impairing TAK1 function. In vitro overexpression experiments in human embryonic kidney 293T (HEK293T) cells demonstrated that the Val50Ala variant significantly reduced TAK1 phosphorylation levels. Furthermore, this variant differentially affected downstream signaling molecules (p38, p65, and JNK) compared with variants causing FMD2. Notably, stimulation with transforming growth factor- (TGF-) partially restored the altered phosphorylation patterns, suggesting a potential compensatory mechanism. Our study provides novel insights into the molecular pathogenesis of variants associated with CSCF and FMD2. We demonstrate that the p.Val50Ala variant impairs TAK1 kinase activity and differentially affects downstream signaling pathways. These findings highlight the distinct molecular fingerprints of variants causing CSCF versus FMD2 and underscore the importance of considering variants in the differential diagnosis of syndromic congenital cardiac defects, recurrent infections, and global developmental delays. Our results also suggest that TGF- signaling may offer a potential therapeutic target for modulating the effects of variants.
Transcriptomic Analysis Reveals the Role of in Hepatocellular Carcinoma and Its Association With the Wnt/-catenin Signaling Pathway.
Song C, Hou Z, Wu H … +1 more , Li X
Hum Mutat · 2026 · PMID 42040893 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) shows high incidence and mortality worldwide. , an E3 ubiquitin ligase within the TRIM family, exerts regulatory functions in various tumors. This study analyzed the expression...
BACKGROUND: Hepatocellular carcinoma (HCC) shows high incidence and mortality worldwide. , an E3 ubiquitin ligase within the TRIM family, exerts regulatory functions in various tumors. This study analyzed the expression patterns and potential functions of in HCC based on transcriptomic data. METHODS: First, the differential expression of TRIM26 between tumor and normal tissues was analyzed using the TCGA dataset and cross-validated using TIMER 2.0 and HCCDB. Enrichment analysis evaluated its association with hallmark pathways including Wnt/-catenin. A gene functional interaction network was built via GeneMANIA to explore TRIM26 and the Wnt/-catenin pathway. Immune cell infiltration was quantified by ssGSEA for immune microenvironment correlation. scRNA-seq data established an HCC single-cell atlas to define TRIM26 distribution across cell subsets. AUCell was used to assess TRIM26-pathway associations within specific cell types. RESULTS: TRIM26 was significantly upregulated in HCC tissues, and its high expression correlated with enrichment of oncogenic pathways including Wnt/-catenin, G2/M checkpoint, and TGF-. GeneMANIA showed that TRIM26 interacted directly or indirectly with Wnt/-catenin core molecules, implying its regulatory role. TRIM26 expression was closely linked to infiltration of activated B cells, CD8 T cells, and NKT cells. Single-cell analysis revealed TRIM26 was mainly expressed in hepatocytes, T/NK cells, myeloid cells, and B cells. Importantly, in hepatocytes, TRIM26 strongly correlated with Wnt/-catenin activity, which was much higher in tumor hepatocytes than normal ones. CONCLUSION: In HCC, TRIM26 was abnormally overexpressed. TRIM26 may regulate tumor progression via the Wnt/-catenin pathway and is linked to immune infiltration. Thus, TRIM26 is a potential therapeutic target for HCC.
Combined Nivolumab and Ipilimumab Therapy Promotes Immune-Mediated Cardiomyocyte Apoptosis Through TLR4-Myd88-NF-b-Driven Activation of the NLRP3 Inflammasome.
Gao M, Liu X, Wu L … +3 more , Jiang Y, Yu J, Zhang Y
Hum Mutat · 2026 · PMID 42040892 · Full text
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with serious immune-related cardiac toxicities. In this study, AC16 human cardiomyocytes were exposed to nivolumab alone or in c...
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with serious immune-related cardiac toxicities. In this study, AC16 human cardiomyocytes were exposed to nivolumab alone or in combination with ipilimumab. The expression of apoptosis- and inflammation-associated proteins and key components of the TLR4-MyD88-NF-B signaling pathway was examined by Western blotting. Apoptotic responses were evaluated using flow cytometry and immunofluorescence assays. BALB/c mice were administered nivolumab or nivolumab plus ipilimumab intraperitoneally for 4 weeks followed by histopathological assessment of cardiac tissue and measurement of myocardial injury biomarkers. Network pharmacology, protein-protein interaction analysis, GO/KEGG enrichment, and molecular docking were applied to identify active constituents of and their potential targets in immune-related cardiac injury. Combined treatment with nivolumab and ipilimumab markedly increased cardiomyocyte apoptosis and elevated the expression of NLRP3 and ASC. Increased phosphorylation of IKK and NF-B p65 indicated activation of the TLR4-MyD88-NF-B signaling cascade. Knockdown of either TLR4 or NLRP3 significantly mitigated apoptosis and reduced inflammatory protein expression. In vivo, combined ICI therapy led to higher levels of myocardial injury markers and proinflammatory mediators. Network pharmacology analysis identified six major compounds from , with sinomenine showing strong predicted binding to TLR4 (binding energies ranging from -9.6 to -5.7 kcal/mol). These findings demonstrate that under the present experimental conditions, combined nivolumab and ipilimumab treatment was associated with greater activation of the TLR4-MyD88-NF-B-NLRP3 axis and greater cardiomyocyte injury than nivolumab alone. However, because the combination group received a higher total antibody dose, the current study does not distinguish whether this difference reflects increased total drug exposure, additivity, or the specific contribution of CTLA-4 blockade. Bioactive constituents of , particularly sinomenine, may represent potential cardioprotective modulators against ICI-induced cardiac injury.
Single-Cell Sequencing and Mendelian Randomization Reveal T Cell Nuclear Factor Genes in Hepatocellular Carcinoma Progression.
Chen Y, Yang X, Zhong L … +2 more , Chen K, Luo L
Hum Mutat · 2026 · PMID 42022794 · Full text
This study integrates single-cell RNA sequencing with Mendelian randomization to elucidate the role of nuclear factor of activated T cells (NFAT)-related genes in the progression of hepatocellular carcinoma (HCC). The GS...
This study integrates single-cell RNA sequencing with Mendelian randomization to elucidate the role of nuclear factor of activated T cells (NFAT)-related genes in the progression of hepatocellular carcinoma (HCC). The GSE162616 dataset was analyzed to identify differentially expressed cells and NFAT-related genes through quality control, clustering, and -score algorithms. Mendelian randomization analysis of expression quantitative trait loci (eQTL) data was performed to identify hub genes causally linked to HCC. Validation in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma cohort included survival analysis, clinical correlation, and nomogram construction. Sixteen cell clusters were resolved and annotated into five types: natural killer (NK) cells, T cells, B cells, hepatocytes, and monocytes. Differentially expressed NFAT-related genes were predominantly enriched in immune and cytokine pathways. Three genes-CACYBP, CTLA4, and RGCC-were identified as causally associated with HCC and designated as hub genes. T cells and NK cells emerged as key cellular populations, and pseudotime analysis delineated T cell differentiation trajectories. Cell-cell communication analysis revealed robust interactions between NK and B cells and between NK and T cells, primarily via the MIF-(CD74+CXCR4) axis. All three hub genes were upregulated in HCC tissues. A nomogram integrating these genes exhibited excellent diagnostic performance (AUC = 0.9). These results establish CACYBP and RGCC as risk factors and CTLA4 as a protective factor for HCC. The nomogram offers a potential tool for early diagnosis and immunotherapy guidance. Our findings highlight the value of integrating single-cell transcriptomics with Mendelian randomization for prioritizing causal genes and provide novel insights into NFAT-mediated immune regulation in HCC.
Prognostic Stratification and Subtyping of Glioblastoma Using Transient Receptor Potential Channels.
Sun R, Zhu L, Lu Z … +3 more , Wang Z, Feng S, Zhao J
Hum Mutat · 2026 · PMID 42016323 · Full text
BACKGROUND: Transient receptor potential (TRP) channels regulate Ca homeostasis and tumor malignant phenotypes, whereas their prognostic relevance and therapeutic implications in glioblastoma (GBM) remain poorly characte...
BACKGROUND: Transient receptor potential (TRP) channels regulate Ca homeostasis and tumor malignant phenotypes, whereas their prognostic relevance and therapeutic implications in glioblastoma (GBM) remain poorly characterized. METHODS: We curated a comprehensive compendium of 522 TRP-related genes from MSigDB, KEGG, and GeneCards. Differential expression analysis across clinical variables in The Cancer Genome Atlas Glioblastoma cohort (TCGA-GBM; = 529) identified 193 TRP-associated genes significantly linked to patient outcomes. Using univariate Cox regression followed by LASSO-Cox regularization, we developed a seven-gene transient receptor potential-related prognostic risk score (TRPRS). The model was rigorously validated in three independent external cohorts. Integrated multiomics analyses encompassed genomic alterations, tumor immune microenvironment profiling, and drug sensitivity prediction. Functional validation focused on the top-ranked gene, IFNGR2, using in vitro glioma models. RESULTS: TRPRS robustly stratified GBM patients into high- and low-risk groups with significantly distinct overall survival across all four datasets (AUC = 0.72-0.81). Genomically, high-TRPRS tumors were enriched for PTEN loss and 9q21.3 amplification, whereas low-TRPRS tumors frequently harbored TP53 mutations and 1q21.3 deletions. High TRPRS was associated with diminished cytotoxic T-cell infiltration and predicted resistance to multiple therapeutics-including cisplatin, carmustine, gefitinib, buparlisib, and afatinib. Notably, TIDE analysis revealed significantly reduced likelihood of response to immune checkpoint blockade in high-TRPRS GBM, a pattern consistently observed in immunotherapy-treated cohorts of melanoma, renal cell carcinoma, and bladder cancer. Functional assays demonstrated that IFNGR2 knockdown suppressed glioma cell proliferation and attenuated NF-B signaling, underscoring its role as a key driver within the TRP network. DISCUSSION: TRPRS provides a robust, biologically grounded tool for simultaneous prognostication and therapy guidance in GBM, highlighting TRP signaling as a therapeutic vulnerability.
HSPB6: A Potential Prognostic Biomarker, Inhibiting the Epithelial-Mesenchymal Transition (EMT) Process Through the PI3K/Akt Signaling Pathway Based on the Machine Learning and Experimental Validation.
Wang JS, Qiu YF, Zhang L … +4 more , Ji B, Liang S, Wang YX, Zhu HX
Hum Mutat · 2026 · PMID 42016322 · Full text
Bladder cancer (BC) is a prevalent malignant tumor worldwide, posing a significant public health burden and challenge to human society. Current therapeutic modalities for BC include surgical treatment, radiotherapy, chem...
Bladder cancer (BC) is a prevalent malignant tumor worldwide, posing a significant public health burden and challenge to human society. Current therapeutic modalities for BC include surgical treatment, radiotherapy, chemotherapy, targeted therapy, and immunosuppressive therapy. However, almost all patients experience disease progression and ultimately succumb to BC. Our study demonstrated that elevated expression of Heat Shock Protein Beta-6 (HSPB6) correlated with higher clinical grades and stages, establishing it as an independent prognostic risk factor for BC. Enrichment analysis indicated that HSPB6 is associated with the extracellular matrix in BC. Experimental validation revealed that HSPB6 overexpression inhibits the proliferation of BC cell line T24. This effect may be achieved by inhibiting the PI3K/Akt signaling pathway, which in turn leads to inhibition of epithelial-mesenchymal transition (EMT). Furthermore, we developed a prognostic risk model that incorporated DDR2, DPYSL3, MFAP5, PDGFRB, and SPOCD1, allowing accurate prediction of patient outcomes based on immunological status. In conclusion, this study highlights that HSPB6 overexpression can restrain the proliferation of BC cells and inhibit EMT, underscoring its potential as a diagnostic marker and therapeutic target in BC.
Multiomics Analysis Identifies Chromosomal Instability-Associated Immune-Related Signatures in Hepatocellular Carcinoma by Integrating Weighted Gene Coexpression Network Analysis (WGCNA) and Machine Learning.
Li Z, Zhong B, Zhang Q … +3 more , Sun L, Li X, Hu X
Hum Mutat · 2026 · PMID 42016321 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is a top cause of cancer-related death globally, with late diagnosis due to nonspecific early symptoms. Current single-factor prognostic models cannot reflect tumor heterogeneit...
BACKGROUND: Hepatocellular carcinoma (HCC) is a top cause of cancer-related death globally, with late diagnosis due to nonspecific early symptoms. Current single-factor prognostic models cannot reflect tumor heterogeneity, so a comprehensive tool for risk stratification and personalized treatment is needed. METHODS: This study employed WGCNA on publicly available datasets (TCGA and GSE54236) to identify core genes associated with chromosomal instability (CIN) in HCC. We initially screened 73 candidate genes, which were then refined to a final set of 20 core genes through an optimization process involving 101 machine learning algorithms. Specifically, the StepCox[both] combined with CoxBoost model was selected as the optimal model, with a concordance index (c-index) of 0.709. We subsequently developed a multidimensional risk-scoring model by integrating the expression levels of these core genes with patient clinicopathological parameters and immune cell infiltration data. The model's performance was evaluated through survival analysis and chemotherapeutic drug sensitivity prediction. Additionally, functional assays were conducted to validate the roles of key genes in promoting the proliferation and invasion of HCC cells. RESULTS: The model effectively stratified patients into high- and low-risk groups. High-risk patients exhibited poorer survival, increased immune cell (particularly T cell) infiltration, higher sensitivity to chemotherapeutics like 5-fluorouracil and paclitaxel, and a higher TP53 mutation rate. Low-risk patients were characterized by frequent CTNNB1-ARID2 comutations and a more active antitumor immune microenvironment. Additionally, SSRP1 and SETDB1 were verified to promote the proliferation and invasion of HCC cells. CONCLUSION: This integrated model, combining genomic and immunological features, is a reliable prognostic tool for HCC patient stratification and personalized chemotherapy, promising for clinical translation and precision medicine in HCC.
Multiomics Biomarkers for Differential Diagnosis of Pleural Effusion: Integration of Proteomic Markers and Single-Cell Transcriptomics.
Zhang Z, Zhan S, Tang Y … +5 more , Ling Z, Wu J, Rui D, Wei X, Ming M
Hum Mutat · 2026 · PMID 42006152 · Full text
BACKGROUND: Differential diagnosis of pleural effusion remains challenging despite medical thoracoscopy (MT). We investigated whether integrating proteomic biomarkers with single-cell transcriptomics and genomic mutation...
BACKGROUND: Differential diagnosis of pleural effusion remains challenging despite medical thoracoscopy (MT). We investigated whether integrating proteomic biomarkers with single-cell transcriptomics and genomic mutation profiling could improve diagnostic accuracy and reveal mechanistic insights. METHODS: We prospectively enrolled 564 patients with pleural effusion undergoing medical thoracoscopy. Pleural fluid biomarkers (adenosine deaminase, carcinoembryonic antigen, cytokeratin-19 fragment, neuron-specific enolase) were measured. Single-cell RNA sequencing profiled immune landscapes across disease etiologies. Driver mutation profiling was performed on malignant pleural effusion samples using targeted next-generation sequencing encompassing 15 cancer-related genes. Diagnostic performance was evaluated against histopathological diagnosis. RESULTS: Final diagnoses included inflammatory PE ( = 95, 16.8%), tuberculous PE ( = 299, 53.0%), and malignant PE ( = 170, 30.1%). For tuberculous PE, ADA achieved AUC 0.916 (sensitivity 83.3% and specificity 89.4%). For malignant PE, combined CEA/CYFRA21-1 achieved AUC 0.957 (sensitivity 98.2% and specificity 98.7%). Single-cell analysis revealed distinct immune signatures: Tuberculous PE showed M1 macrophage polarization (M1/M2 ratio 9.48) strongly correlating with ADA levels (rho = 0.68, < 0.001), whereas malignant PE exhibited immunosuppressive features with elevated M2 macrophages and reduced NK cells. Mutation profiling of malignant PE revealed EGFR (46.5%), TP53 (34.7%), and PIK3CA (8.2%) as the most frequently mutated genes. EGFR-mutant tumors exhibited significantly higher CEA levels ( = 0.033) and more immunosuppressive microenvironments with increased M2 macrophages ( < 0.001) and decreased CD8+ T cells ( < 0.001). The sequential multibiomarker algorithm achieved 96.5% sensitivity and 98.7% specificity for malignant PE detection, with 85.3% overall three-way classification accuracy. CONCLUSIONS: Multiomics integration combining proteomic biomarkers with single-cell immune profiling and genomic mutation characterization achieves high diagnostic accuracy for pleural effusion while revealing disease-specific immune mechanisms and mutation-driven therapeutic opportunities.
Delving Into the Depths of : In Silico Identification of Deleterious Nonsynonymous SNPs Associated With Cardiovascular Diseases.
Waleed Iqbal M, Shahab M, Sun X … +6 more , Akter S, Zheng G, Shazly GA, Bourhia M, Dauelbait M, Yuan Q
Hum Mutat · 2026 · PMID 42006151 · Full text
BACKGROUND AND AIM: Nonsynonymous single nucleotide polymorphisms (nsSNPs) in angiotensin Type II receptor () have been identified as a potential cause of cardiovascular illness in humans. Identifying structurally and fu...
BACKGROUND AND AIM: Nonsynonymous single nucleotide polymorphisms (nsSNPs) in angiotensin Type II receptor () have been identified as a potential cause of cardiovascular illness in humans. Identifying structurally and functionally relevant alterations in is critical to investigate possible therapeutic targets. METHODS: A comprehensive computational pipeline was employed to evaluate deleterious nsSNPs using multiple prediction algorithms, including SIFT, PolyPhen-2, CADD, REVEL, Mutation Assessor, MetaLR, I-Mutant, MutPred, and Phylo3D. Molecular docking and molecular dynamic simulation strategies were further utilized to thoroughly validate these nsSNPs. Additionally, gene-gene interaction networks were constructed to explore 's functional associations. RESULTS: Our findings indicated that four nsSNPs, including rs200599388, rs1556673810, rs3729979, and rs1556673736, potentially have the most deleterious effect on the gene. MD simulations revealed that these variants induced increased structural fluctuations and conformational instability compared with the wild-type protein. Gene-gene interaction analysis indicated that participates in several key regulatory pathways relevant to cardiovascular physiology. CONCLUSION: These findings will form the basis to design precision medicines for cardiovascular diseases in the future and welcome further preclinical and clinical investigations.
STIM1 as an Early Predictive Biomarker for Acute Respiratory Distress Syndrome (ARDS) and Its Potential Mechanisms.
Deng S, Wu Q, Zhou D … +4 more , Wang L, Nan F, Dong F, Li J
Hum Mutat · 2026 · PMID 42006150 · Full text
Acute respiratory distress syndrome (ARDS) mainly results in severe respiratory failure and significant morbidity. This study decisively investigated the effectiveness and clinical importance of stromal interaction molec...
Acute respiratory distress syndrome (ARDS) mainly results in severe respiratory failure and significant morbidity. This study decisively investigated the effectiveness and clinical importance of stromal interaction molecule 1 (STIM1) mRNA as an early predictive biomarker for the outcomes and severity of ARDS cases. A total of 72 mechanically ventilated patients were included in the study, consisting of 51 with ARDS and 21 without. The STIM1 mRNA levels in blood and bronchoalveolar lavage fluid (BALF) from these cases were assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Additionally, lung tissues were collected from six patients (three with ARDS and three without) for hematoxylin-eosin staining, immunohistochemistry, and Western blot analysis. A predictive nomogram was constructed using STIM1 mRNA level and assessed for its ability to predict the severity and mortality of ARDS. A higher STIM1 mRNA level was associated with increased ARDS severity and patient mortality. Thus, STIM1 may serve as a novel biomarker for the early prediction of clinical outcomes and disease status of ARDS cases. Additionally, analysis of the GSE database revealed the MAPK signaling pathway as a key mechanism underlying the function of STIM1 in ARDS.
Integrative Genomic Analysis Identifies MAGT1 as a Key Regulator of Proliferation and Poor Prognosis in Breast Cancer.
Zhao L, Song Z
Hum Mutat · 2026 · PMID 42006149 · Full text
OBJECTIVE: Magnesium transporter 1 (MAGT1) plays a crucial role in magnesium homeostasis and immune regulation, yet its clinical significance and functional role in breast cancer remain largely unexplored. METHODS: The e...
OBJECTIVE: Magnesium transporter 1 (MAGT1) plays a crucial role in magnesium homeostasis and immune regulation, yet its clinical significance and functional role in breast cancer remain largely unexplored. METHODS: The expression pattern and prognostic value of MAGT1 in breast cancer were analyzed using data from The Cancer Genome Atlas (TCGA) and validated by immunohistochemistry on a tissue microarray comprising 60 patient samples. Genomic alteration analysis of MAGT1 with BRCA clinical implications was performed. The biological functions of MAGT1 were investigated in vitro using MCF-7 and MDA-MB-231 cell lines. MAGT1 expression was knocked down by siRNA, and its effects on cell proliferation, colony formation, DNA synthesis, migration, and invasion abilities were inhibited through MTT assays, colony formation assays, EdU assays, wound healing assays, and Transwell assays. Immune cell infiltration associated with MAGT1 expression was analyzed using bioinformatics tools. RESULTS: MAGT1 was significantly overexpressed in breast cancer tissues compared with adjacent normal tissues. High MAGT1 expression was strongly associated with advanced tumor stage, poorer histological grade, and unfavorable patient prognosis, serving as an independent risk factor for overall survival. MAGT1 mutations were not statistically significantly associated with overall survival (OS) in breast cancer, but MAGT1 mutations were closely associated with ERBB2 and CDH1. Bioinformatic analysis revealed a correlation between MAGT1 expression and altered immune cell infiltration within the tumor microenvironment. In vitro functional assays demonstrated that silencing MAGT1 markedly inhibited the proliferative capacity, clonogenicity, migration, and invasion of breast cancer cells. CONCLUSION: Our findings indicate that MAGT1 is frequently upregulated in breast cancer and correlates with aggressive tumor behavior and poor clinical outcomes. MAGT1 promotes key oncogenic phenotypes in breast cancer cells and may influence the immune landscape, highlighting its potential as both a prognostic biomarker and a promising therapeutic target.
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