Hum. Mutat. [JOURNAL]
Sun
200 papers
Integrative Genomic and Functional Analysis Reveals NF1 Loss as a Modifier of DNA Damage and Replication Stress Responses in Ovarian Cancer.
He S, Liu C, Li Z … +2 more , Liao T, Wang Q
Hum Mutat · 2026 · PMID 42158468 · Full text
Neurofibromin 1 (NF1) is a tumor suppressor gene frequently altered across diverse cancer types, yet its biological significance in ovarian cancer remains incompletely characterized. Here, we integrated cohort-scale soma...
Neurofibromin 1 (NF1) is a tumor suppressor gene frequently altered across diverse cancer types, yet its biological significance in ovarian cancer remains incompletely characterized. Here, we integrated cohort-scale somatic mutation profiling with functional validation to characterize the mutational and cellular consequences of NF1 loss in ovarian cancer. Somatic mutation data from the TCGA ovarian cancer cohort were analyzed to define NF1-associated mutation types, tumor mutational burden, mutational signatures, and co-occurring alterations in DNA damage repair (DDR) pathways, together with pathway- and gene set-level functional enrichment analyses. NF1 alterations were predominantly truncating and consistent with loss-of-function events. NF1-mutant tumors did not exhibit increased global tumor mutational burden or uniform APOBEC hypermutation but showed distinct single-nucleotide substitution patterns and frequent comutations in core DDR-related genes. Functional enrichment analyses further highlighted coordinated involvement of pathways related to DNA replication, RNA processing, and proteostasis. Clinically, NF1 mutation was not independently associated with overall survival. Stable NF1 knockdown ovarian cancer models showed that NF1 depletion did not affect basal proliferation but increased sensitivity to hydroxyurea-induced replication stress, accompanied by increased H2AX accumulation. Together, these findings indicate that NF1 loss defines a DNA damage-associated mutational and cellular state in ovarian cancer. Rather than acting as a direct prognostic determinant, NF1 mutation appears to increase vulnerability to replication stress and DNA damage, providing functional insight into its role in ovarian tumor biology.
Decoding the Sphingolipid Landscape of Clear Cell Renal Cell Carcinoma: A Single-Cell-Guided Prognostic Model Built With 101 Machine Learning.
Huang J, Wang S, Zhou Y … +7 more , Zhang H, Zhang Y, Huang S, Su H, Zhu H, Lin Y, Deng G
Hum Mutat · 2026 · PMID 42158467 · Full text
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and shows marked heterogeneity in progression, metastasis, and therapeutic response. Sphingolipid metabolism ha...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and shows marked heterogeneity in progression, metastasis, and therapeutic response. Sphingolipid metabolism has emerged as an important regulator of tumor progression and the tumor microenvironment, but its cell-state-specific role in ccRCC remains unclear. METHODS: Public datasets from multiple cohorts were integrated, including single-cell RNA sequencing data from GEO and bulk transcriptomic and clinical data from Xena, ArrayExpress, and ICGC. Nonnegative matrix factorization was used to resolve cellular heterogeneity and identify sphingolipid metabolism-related characteristic genes across distinct cell subsets. A prognostic model was constructed by screening 101 machine learning combinations and validated in independent cohorts. Additional analyses included immune characterization, pathway enrichment, drug sensitivity prediction, protein-protein interaction network analysis, and mutation profiling. RESULTS: Single-cell analysis identified 23 cell clusters representing nine major cell types in ccRCC and further resolved multiple sphingolipid metabolism-related metagene-defined subclusters within immune and stromal compartments. Based on these features, 101 machine learning combinations were evaluated, and a final 12-gene prognostic signature was established using the Lasso+SuperPC model. The model showed stable prognostic performance across independent cohorts and outperformed conventional clinical variables. It was also associated with distinct immune features, predicted therapeutic vulnerabilities, and mutation-related genomic characteristics. CONCLUSION: This study provides a single-cell-guided framework for understanding sphingolipid metabolism-related heterogeneity in the ccRCC microenvironment and establishes a 12-gene prognostic signature with potential value for risk stratification and therapeutic prioritization.
Novel Variants in the SLC16A2 Gene Associated With Allan-Herndon-Dudley Syndrome in China.
Li W, Sun Z, Wu X … +4 more , Lu F, Zhou Q, Zhang X, Zhu M
Hum Mutat · 2026 · PMID 42147817 · Full text
OBJECTIVE: This study is aimed at investigating the genetic defects and clinical features of Chinese children with variants and at exploring the effects of mutant MCT8 on protein expression and subcellular localization...
OBJECTIVE: This study is aimed at investigating the genetic defects and clinical features of Chinese children with variants and at exploring the effects of mutant MCT8 on protein expression and subcellular localization through in vitro experiments. METHODS: Children with intellectual disability and abnormal serum thyroid hormone levels were screened using whole-exome sequencing (WES). We collected patients' clinical data and assessed their cognitive, linguistic, and motor abilities. Candidate variants were verified by Sanger sequencing, and their pathogenicity and evolutionary conservation were analyzed using in silico prediction tools. Protein expression and subcellular localization of mutant MCT8 were evaluated by Western blotting and immunofluorescence microscopy. RESULTS: Exome sequencing identified seven previously uncharacterized variants in 10 unrelated male patients (nine families). These included three missense mutations (p.Ala150Thr,p.Gly208Arg, and p.Gly208Asp), three frameshift mutations (p.Leu168fs, p.Ser243Cysfs, and p.Val485fs), one deletion-insertion mutation (p.Ile328_Ala329delinsThr), and one balanced translocation, t(X,12) (q13.2; q13.13). All patients exhibited global developmental delay, axial hypotonia, dystonia, and abnormal thyroid hormone profiles. In vitro experiments demonstrated significantly reduced expression of mutant proteins compared with the wild-type. Immunofluorescence showed that, in addition to residual plasma membrane localization, mutant proteins were also partially retained in the cytoplasm, whereas the wild-type protein localized exclusively to the plasma membrane. CONCLUSION: Our findings expand the genotypic and phenotypic spectrum of MCT8 deficiency. The results suggest that variants lead to a loss of function through decreased protein expression and defective plasma membrane trafficking.
Constitutional Epimutation Screening Requires Highly Sensitive Assays to Identify Lynch Syndrome Patients With Very Low Mosaic Methylation Level.
Facon C, Vermaut C, Delattre L … +22 more , Flament C, Dardenne A, Brahimi A, Lejeune S, Cattan S, Bonnet F, Basset N, Bensen A, Dupré A, Berthet P, Dhooge M, Colas C, Mouret-Fourme E, Delhomelle H, Nambot S, Baurand A, Planes M, Menjard J, Benusiglio PR, Pigny P, Buisine MP, Leclerc J
Hum Mutat · 2026 · PMID 42147816 · Full text
Constitutional epimutations of the gene are an alternative cause of Lynch syndrome, in which inactivation of an allele of a mismatch repair (MMR) gene results from promoter methylation, rather than a pathogenic genetic...
Constitutional epimutations of the gene are an alternative cause of Lynch syndrome, in which inactivation of an allele of a mismatch repair (MMR) gene results from promoter methylation, rather than a pathogenic genetic variant. These epimutations are often mosaic, and methylation levels ranging from ~50% monoallelic methylation to low-level methylation (1%-5%) are observed in the blood of epimutation carriers. Using a specific and highly sensitive droplet digital methyl-specific PCR (ddMSP) assay, six patients with very low methylation levels (< 1%) were identified in a series of 142 patients with a -methylated tumor diagnosed before age 61, who had been referred to the clinical lab between 2020 and 2024. These patients were initially missed by standard pyrosequencing assay, emphasizing the need for highly sensitive assays for constitutional epimutation screening. To confirm that methylated DNA molecules detected by ddMSP did not correspond to circulating tumor DNA rather than germline DNA, multiple validation analyses were performed, including validation of the constitutional origin of methylation on other sources of germline DNA and tumoral analysis. Taking into account the other patients identified as epimutation carriers by pyrosequencing during the same 5-year period, 13.1% of patients with a -methylated tumor before age 61 were diagnosed as Lynch syndrome patients, which changed their clinical follow-up. These findings highlight the relevance of recommendations for systematic epimutation screening using highly sensitive assays in patients with -methylated tumors diagnosed before age 61. Such screening will increase the number of patients diagnosed with Lynch syndrome caused by a constitutional epimutation, improving patient care and outcomes, as well as genetic counseling.
Experimental Validation and Bioinformatics Analysis Elucidate the Role of MTDH-Mediated PTEN Ubiquitination and Degradation in Podocyte Injury in Diabetic Kidney Disease.
Zheng Z, Tao D, Wu W … +10 more , Zhang H, Shen L, He X, Zheng X, Long Y, Yang J, Chen X, Peng F, Long H, Luo C
Hum Mutat · 2026 · PMID 42147815 · Full text
Diabetic nephropathy (DN) stands as a primary contributor to end-stage renal disease. Podocyte injury is a key factor underlying proteinuria in DN. Metadherin (MTDH) participates in podocyte apoptosis and promotes renal...
Diabetic nephropathy (DN) stands as a primary contributor to end-stage renal disease. Podocyte injury is a key factor underlying proteinuria in DN. Metadherin (MTDH) participates in podocyte apoptosis and promotes renal tubular injury in DN. However, its role in podocyte damage and podocyte cytoskeleton remodeling requires further investigation. PTEN plays a crucial role in maintaining podocyte integrity; however, the mechanisms governing PTEN stability in DN remain poorly understood. This study is aimed at investigating the specific functional role of MTDH in PTEN regulation using db/db diabetic mice, human kidney biopsy samples from DN patients, and cultured mouse podocytes exposed to high glucose (HG). MTDH expression was markedly increased in DN kidneys and HG-stimulated podocytes. Elevated MTDH resulted in decreased PTEN protein expression levels without altering PTEN mRNA expression, suggesting a posttranscriptional regulatory mechanism. Further assays demonstrated that MTDH promoted PTEN degradation through the ubiquitin-proteasome pathway. Through bioinformatics analysis of the GSE96804 dataset from the Gene Expression Omnibus (GEO) database, obtaining 13,289 differentially expressed genes and comparing them with the known ubiquitin ligase-encoding genes obtained from the Genecards database, we identified candidate hub genes involved in PTEN ubiquitination-mediated degradation. RNA sequencing identified ubiquitin-conjugating enzyme E2N (UBE2N) as a critical downstream mediator positively regulated by MTDH. Subsequent coimmunoprecipitation experiments confirmed direct interactions between PTEN and UBE2N, enhancing PTEN ubiquitination. Knockdown of UBE2N attenuated MTDH-induced PTEN degradation and podocyte cytoskeletal remodeling. Collectively, our findings reveal a novel regulatory axis wherein MTDH accelerates PTEN ubiquitination and proteasomal degradation via UBE2N, contributing to podocyte injury in DN. Targeting MTDH-driven PTEN ubiquitination degradation presents a promising therapeutic strategy to protect podocytes and mitigate diabetic kidney injury.
Cross-Cohort Transcriptomic Integration Identifies IFIT2 as a Translational Diagnostic Biomarker and Functional Driver of Inflammation-Linked Tubular Injury in Chronic Kidney Disease.
Zhang X, Chen X, Yang Y … +1 more , Zhang Y
Hum Mutat · 2026 · PMID 42147814 · Full text
Chronic kidney disease (CKD) is a major global health burden characterized by progressive loss of renal function, persistent inflammation, and tubular epithelial injury, yet reproducible diagnostic biomarkers that also h...
Chronic kidney disease (CKD) is a major global health burden characterized by progressive loss of renal function, persistent inflammation, and tubular epithelial injury, yet reproducible diagnostic biomarkers that also have functional relevance remain insufficiently defined. Here, we integrated multiple independent CKD transcriptomic cohorts from GEO (GSE32591 and GSE66494 as training datasets, with GSE180394 as an external validation dataset) using rigorous batch-effect correction and differential expression analysis to identify consistently dysregulated genes across platforms. Shared CKD-upregulated genes were predominantly enriched in immune and inflammatory biological processes, and module-level analyses prioritized a core set of hub genes showing stable activation across cohorts. Based on these hubs, we constructed a composite diagnostic gene signature using a standardized Z-score-based scoring approach, which demonstrated a robust discriminative performance in both training and external validation cohorts. Among candidate genes ranked by diagnostic performance, IFIT2 emerged as a reproducibly upregulated marker with strong diagnostic utility. Mechanistically, IFIT2 was inducible in human renal tubular epithelial cells (HK-2 and primary RPTEC) under CKD-relevant inflammatory (IFN-) and profibrotic (TGF-1) stimulation. Importantly, shRNA-mediated IFIT2 knockdown mitigated IFN--induced reductions in cell viability, decreased apoptosis, and attenuated the induction of tubular injury markers (KIM1 and LCN2) and inflammatory mediators (IL6 and CXCL10). Together, these results support IFIT2 as a promising candidate biomarker linking inflammation to tubular injury in CKD, providing a translational rationale for further biomarker-guided stratification and therapeutic targeting in future studies.
The miR-146a/ Axis Potentially Mediates the Protective Effect of Dexmedetomidine Against Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.
Chen X, Wang D, Du J … +6 more , Li J, Wang Z, Chen B, Yao X, Li S, Li N
Hum Mutat · 2026 · PMID 42147813 · Full text
BACKGROUND: This study comprehensively examined the mechanism of the roles of dexmedetomidine (Dex) and miR-146a in chronic obstructive pulmonary disease (COPD). METHODS: COPD models were established employing cigarette...
BACKGROUND: This study comprehensively examined the mechanism of the roles of dexmedetomidine (Dex) and miR-146a in chronic obstructive pulmonary disease (COPD). METHODS: COPD models were established employing cigarette smoke extract (CSE)-exposed airway epithelium cell 16HBE and cigarette smoke-treated Sprague-Dawley rats, followed by interference with Dex and transfection. CCK-8 and flow cytometry assays were employed for the detection of cell viability and apoptosis. Further, the levels of factors related to the NF-B pathway, inflammation, and apoptosis were measured by ELISA, qRT-PCR, and Western blot. RESULTS: Dex and miR-146a mimic notably inhibited the inflammation and apoptosis of CSE-induced 16HBE cells via modulating the levels of TNF-, IL-6, IL-8 (inflammatory cytokines), and caspase-3, Bcl-2, and Bax (apoptosis-associated proteins), whereas miR-146a inhibitor exerted opposite effects. Moreover, Dex modulated the levels of both miR-146a and its downstream target immunoglobulin superfamily Member 11 (). The protective effects of miR-146a on COPD were reversed following intervention. Further, the phosphorylation of NF-B and IKK suggested that the effects of Dex/miR-146a/ axis on COPD were related to the NF-B pathway. CONCLUSION: Our in vitro and in vivo studies showed that Dex alleviated CSE-induced COPD via modulating the miR-146a//NF-B axis.
Expanding the Genotypic Landscape of Congenital Stationary Night Blindness in an Ethnically Diverse Canadian Population.
Ling J, Pindwarawala M, Gregory-Evans CY … +2 more , Kirby M, Gregory-Evans K
Hum Mutat · 2026 · PMID 42147812 · Full text
Congenital stationary night blindness (CSNB) is a rare and typically nonprogressive group of genetically heterogeneous disorders resulting in impaired night vision and high myopia with varying levels of visual impairment...
Congenital stationary night blindness (CSNB) is a rare and typically nonprogressive group of genetically heterogeneous disorders resulting in impaired night vision and high myopia with varying levels of visual impairment. Despite being a rare disease with a prevalence of 1:294,000, variants in 22 genes have been associated with specific CSNB phenotypes. Approximately, 13% of cases remain without a genetic diagnosis, highlighting the importance of ongoing genetic studies. Clinical and diagnostic information was collected retrospectively from patients who were diagnosed with CSNB. Patients underwent full ophthalmic examination, including best-corrected visual acuity (BCVA), direct and indirect ophthalmoscopy, retinal imaging, and full field electroretinography. All patients underwent panel-based genetic testing for complete and incomplete CSNB genes to identify DNA variants from buccal swab samples. In the 49-patient cohort (from 38 families) with complete and incomplete CSNB, a conclusive molecular diagnosis was found in 30 patients (61.2%) with a known disease-causing variant in a CSNB gene. We identified 21 novel variants in five genes (, , , 197, and ), and in one patient, the genetic defect remains to be identified. After modeling and clinical correlation, 18 of these novel variants were considered pathogenic or likely pathogenic. When compared with ethnicity, CSNB was overwhelmingly present in White people, and we did not find any Indigenous people with CSNB. Prevalence of CSNB in the Mennonite community was estimated to be 1:967, approximately 300 times the expected prevalence. Establishing a molecular diagnosis of CSNB is critical because it enables many actionable outcomes including further family testing, genetic counseling, and access to future clinical trials.
Integrating Bulk and Single-Cell RNA-Seq Reveals Glycolysis-Associated Macrophages and Its Related Tumor Subgroup Signatures to Predict Prognosis and Therapy in Clear Cell Renal Cell Carcinoma.
Li Y, Chen Y, Wang L … +5 more , Yuan S, Wu L, Sun H, Wang D, Lv H
Hum Mutat · 2026 · PMID 42147811 · Full text
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common histological type of RCC and is marked by aggressive nature and poor survival. However, therapeutic options remain limited and yield suboptimal outco...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common histological type of RCC and is marked by aggressive nature and poor survival. However, therapeutic options remain limited and yield suboptimal outcomes. Macrophages exhibit marked heterogeneity within ccRCC, exerting a substantial impact on the malignant progression of tumors and resistance to therapeutics. METHODS: This study utilized single-cell sequencing and transcriptomics to identify a subset of macrophages associated with glycolysis and the most interactive tumor subpopulation, in order to explore the link between macrophages and ccRCC risk. Moreover, employing machine learning techniques, we crafted a precise gene signature to predict patient prognosis, with clinical implications. RESULTS: We identified a macrophage subpopulation primarily characterized by glycolytic metabolism and a closely associated tumor cell subpopulation, both significantly correlated with poor prognoses in ccRCC patients. Then, we use hdWGCNA to identify key genes and functional modules of cell subgroups, and use 101 types of machine learning methods to establish a prognosis model of six genes: CENPA, ITM2B, TUBA1B, TNFSF13B, SNX3, and TNNT1 in the RNAseq cohorts of ccRCC patients. Patients in the high-risk group exhibited poorer prognoses, with functional enrichment indicating the presence of modules associated with malignant progression. Additionally, immune infiltration analysis revealed higher levels of immune cell infiltration in this group, suggesting their potential responsiveness to immunotherapeutic interventions. CONCLUSION: Our study introduces a novel, robust ccRCC prognostic model, providing new insights and potential therapeutic strategies for precision treatment of ccRCC patients.
Integrative Mendelian Randomization and Multiomics Analysis Identifies CAF-Derived Complement Factor B as a Prognostic Biomarker and Therapeutic Vulnerability in Breast Cancer.
Xiang H, Ren N, Wang T … +3 more , Zheng X, Kang Z, Dong Y
Hum Mutat · 2026 · PMID 42147810 · Full text
BACKGROUND: Complement factor B (CFB), a key component of the alternative complement pathway, has been implicated in tumor-related inflammation; however, its causal role and therapeutic relevance in breast cancer remain...
BACKGROUND: Complement factor B (CFB), a key component of the alternative complement pathway, has been implicated in tumor-related inflammation; however, its causal role and therapeutic relevance in breast cancer remain unclear. By integrating genetic epidemiology, multiomics transcriptomics analyses, and AI-assisted drug prediction, we aimed to clarify the biological and clinical significance of CFB in breast cancer. RESULTS: Mendelian randomization analysis suggested a potential causal association between circulating CFB levels and breast cancer risk (OR = 1.048, 95% CI: 1.018-1.078, = 0.001). Single-cell transcriptomic analysis identified cancer-associated fibroblasts (CAFs) as the primary cellular source of CFB within the tumor microenvironment. High CFB expression was significantly associated with advanced clinical stage, lymph node metastasis, and poor overall survival and was confirmed as an independent prognostic factor (HR = 2.35, 95% CI: 1.55-3.56, < 0.001). Tumors with elevated CFB displayed immunosuppressive characteristics, including increased regulatory T cells and M2 macrophages, higher TIDE scores, and strong correlations with immune checkpoint molecules. AI-based drug sensitivity prediction and validation analyses revealed that CFB-high tumors exhibited enhanced sensitivity to PARP inhibitors. Additional mutation-related bioinformatic analyses showed that CFB-mutated tumors were associated with higher TMB, increased MSI-H proportion, an immunosuppressive microenvironment, and enhanced predicted sensitivity to PARP inhibitors. Mechanistically, CFB expression strongly correlated with PARP1 ( = 0.77), and CAF-derived CFB enhanced olaparib-induced DNA damage in TNBC models. CONCLUSION: Through integrative traditional and AI-driven approaches, this study supports CFB as a genetically associated risk protein with potential causal relevance and as a prognostic and therapeutic biomarker at both the expression and mutation levels in breast cancer. These findings provide a mechanistic and translational basis for precision therapy targeting CFB-overexpressing tumors.
Integrative Systems Biology and Experimental Validation Unveil GALNT14 as a Novel Diagnostic Biomarker and Therapeutic Target for Sepsis.
Zhu X, Zhai Y, Yao J … +2 more , Chen Y, Ge W
Hum Mutat · 2026 · PMID 42147809 · Full text
BACKGROUND: Sepsis lacks reliable biomarkers for early diagnosis and treatment. This study integrates systems biology approaches, weighted gene coexpression network analysis (WGCNA), and experimental validation to identi...
BACKGROUND: Sepsis lacks reliable biomarkers for early diagnosis and treatment. This study integrates systems biology approaches, weighted gene coexpression network analysis (WGCNA), and experimental validation to identify novel diagnostic and therapeutic targets. METHODS: Four sepsis-related GEO datasets were analyzed to identify differentially expressed genes (DEGs) and coexpression modules. Machine learning algorithms screened candidate biomarkers from the intersection of DEGs and module hub genes, validated via ROC analysis and immune infiltration assessment. The biological function of the top candidate was verified in vitro using LPS-stimulated THP-1 cells. RESULTS: was identified as a robust diagnostic biomarker (AUC = 0.79), showing significant correlation with neutrophil and monocyte infiltration. In vitro validation confirmed upregulation in the sepsis model. Functionally, knockdown significantly inhibited proinflammatory cytokines (IL-1, IL-6, and TNF-), whereas its overexpression exacerbated the inflammatory response and modulated cell apoptosis. CONCLUSION: Through a synergistic framework of AI-driven bioinformatics and wet-lab verification, this study identifies as a promising diagnostic biomarker and therapeutic target, mechanistically linking it to the regulation of inflammatory responses in sepsis.
A Propionate Metabolism-Based Gene Signature Reveals Immunogenomic and Transcriptomic Determinants of Prognosis in Glioblastoma Through Multiomics Integration.
Li M, Liu J, Liu Z … +2 more , Liu X, Lun P
Hum Mutat · 2026 · PMID 42147808 · Full text
Glioblastoma (GBM) remains a lethal brain tumor with limited prognostic tools. Metabolic reprogramming, particularly in understudied pathways like propionate metabolism, may offer new biomarkers. Here, we identified a no...
Glioblastoma (GBM) remains a lethal brain tumor with limited prognostic tools. Metabolic reprogramming, particularly in understudied pathways like propionate metabolism, may offer new biomarkers. Here, we identified a novel prognostic signature based on seven propionate metabolism-related genes (SLC9A1, ELANE, ACADS, SOAT2, MYD88, ADSL, and BMP2) from the TCGA-GBM cohort. A risk scoring model was constructed via LASSO Cox regression effectively stratified patients into high- and low-risk groups with significant survival differences, which was also validated in independent GEO datasets. Multiomics analysis revealed that the high-risk group was associated with an immunosuppressive microenvironment, characterized by increased immune checkpoint expression and distinct immune cell infiltration. Mutational profiling showed a strong association with key driver alterations, including enrichment of RB1 mutations in high-risk and IDH1 mutations in low-risk patients. Single-cell RNA-seq (scRNA-seq) analysis confirmed the specific enrichment of signature genes within malignant cells, and coexpression network analysis (hdWGCNA) further linked the high-risk phenotype to transcriptional modules. In conclusion, we established and validated a robust metabolic gene signature that not only predicts prognosis but also delineates a high-risk GBM subtype defined by integrated metabolic, immunogenomic, and transcriptional features, providing new insights into the determinants of GBM aggressiveness.
Secretory Lysosome-Related Gene Signature Defines the Immune Microenvironment and Identifies RGS2 as a Prometastatic Factor in Hepatocellular Carcinoma.
Ye Z, Tang B, Zhang Y … +6 more , Chen H, Li J, Ye Z, Liu X, Li J, Li D
Hum Mutat · 2026 · PMID 42147807 · Full text
INTRODUCTION: Hepatocellular carcinoma (HCC) is a highly aggressive tumour with significant heterogeneity and a poor response to immunotherapy. Secretory lysosomes (SLs) control immunological responses and cellular homeo...
INTRODUCTION: Hepatocellular carcinoma (HCC) is a highly aggressive tumour with significant heterogeneity and a poor response to immunotherapy. Secretory lysosomes (SLs) control immunological responses and cellular homeostasis; however, the significance of secretory lysosome-related genes (SLRGs) in HCC prognosis and treatment is unclear. This work sought to create a predictive signature based on immune lysosome-related genes (immLysorgs) and to evaluate RGS2's functional role in HCC progression. METHODS: We identified 13 immLysorgs in MSigDB and evaluated genomic and clinical data from the TCGA-LIHC and GSE76427 cohorts. Molecular subtypes were identified using nonnegative matrix factorization and consensus clustering. A predictive model (immLysoS) was built using LASSO and multivariate Cox regression with four genes: GZMH, KLRB1, RGS2, and SLC6A1. Model performance was validated across multiple cohorts. The involvement of RGS2 in HCC was examined using functional studies such as CCK-8, colony formation, migration assays, and a xenograft model. RESULTS: Two subtypes (C1/C2) and two genotypes (A/B) were found, with the C2 and A groups exhibiting increased survival and immune infiltration. The immLysoS signature efficiently divided patients into risk categories, with low-risk individuals having much higher overall and progression-free survival. High immLysoS scores were associated with advanced disease, higher grade, and more TP53 and CTNNB1 mutations. Low-risk patients responded better to PD-L1 inhibitors with sorafenib. RGS2 knockdown drastically reduced HCC cell proliferation, migration, and tumor development both in vitro and in vivo. DISCUSSION: The immLysoS signature is an effective tool for risk assessment and therapy advice in HCC, as it links SL-related genes to immunological characteristics and therapeutic response. RGS2 emerges as a possible oncogenic driver and therapeutic target, necessitating additional research into its processes in the HCC microenvironment.
Integrative Analysis of Vitamin D-Associated Genetic Variants Reveals Cis-Regulatory Architecture and Multigenic Mechanisms Underlying Chronic Disease-Relevant Pathways.
Yue J, Zhang J, Xu K … +2 more , Han P, Tan B
Hum Mutat · 2026 · PMID 42136963 · Full text
Vitamin D is a pleiotropic regulator of immune, metabolic, and endocrine homeostasis and has been implicated in a broad spectrum of chronic diseases. Although genome-wide association studies (GWAS) have identified numero...
Vitamin D is a pleiotropic regulator of immune, metabolic, and endocrine homeostasis and has been implicated in a broad spectrum of chronic diseases. Although genome-wide association studies (GWAS) have identified numerous genetic variants associated with vitamin D-related traits, most signals reside in noncoding regions, limiting biological interpretation and disease-oriented translation. Here, we present an integrative analytical framework to interpret vitamin D-associated genetic variation by linking variant-level associations to cis-regulatory architecture, gene-level aggregation, and functional organization. Vitamin D-related traits were curated from the GWAS Catalog using ontology-guided criteria. Genome-wide significant variants were functionally annotated and mapped to nearby genes using a standardized ± 50-kb cis-regulatory window. Independent variants were aggregated at the gene level to prioritize robust candidate genes for downstream analysis. We found that vitamin D-associated variants were widely distributed across the genome and were predominantly enriched in noncoding regulatory regions. Cis-regulatory mapping revealed extensive SNP-gene multiplicity, reflecting complex local regulatory architectures. Gene-level aggregation identified a prioritized set of genes supported by multiple independent variants, which converged on pathways central to chronic disease biology, including immune regulation, metabolic processes, endocrine signaling, and intracellular signal transduction. Network-based integration further revealed modular regulatory structures characterized by coordinated pathway convergence. Together, these results indicate that vitamin D-associated genetic variation contributes to chronic disease susceptibility through coordinated cis-regulatory and multigenic mechanisms rather than isolated gene effects.
Integrative Single-Cell and Spatial Transcriptomics Reveal Organelle Stress-Associated Heterogeneity and Immune Microenvironment Remodeling in Lung Adenocarcinoma.
Chang X, Li M, Wang C … +4 more , Zhou X, Zhao Y, Chen S, Zhang L
Hum Mutat · 2026 · PMID 42136962 · Full text
BACKGROUND: Lung adenocarcinoma (LUAD) exhibits marked heterogeneity. Organelle stress-adaptive programs that tumor cells develop under hypoxia, nutrient limitation, and proteostasis pressure may drive functional reprogr...
BACKGROUND: Lung adenocarcinoma (LUAD) exhibits marked heterogeneity. Organelle stress-adaptive programs that tumor cells develop under hypoxia, nutrient limitation, and proteostasis pressure may drive functional reprogramming of tumor biology, remodel the immune microenvironment, and ultimately influence the benefits of immunotherapy. Therefore, it is necessary to systematically characterize the coordinated changes across organelle stress-related pathways in LUAD, establish a subtyping and prognostic stratification framework, and identify key molecules as well as potential cell-cell communication axes. METHODS: Transcriptomic profiles and clinical follow-up data from The Cancer Genome Atlas LUAD (TCGA-LUAD) cohort and public cohorts were collected. Pathway activities were quantified using organelle stress-related gene sets, and core stress programs associated with overall survival (OS) and progression-free survival (PFS) were screened by Cox regression and Kaplan-Meier analyses. Nonnegative matrix factorization (NMF) was used for unsupervised subtyping and stability evaluation. Functional enrichment, genomic features, and immune landscapes were compared between subtypes, and potential benefit from immune checkpoint blockade (ICB) was inferred using tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS). Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were integrated to characterize malignant cell states, spatial niches, and cell-cell communication networks. In LUAD cell lines, the candidate gene was silenced by small interfering RNA (siRNA), and phenotypic assays were performed to validate its effects. RESULTS: The organelle stress activity-based system robustly classified LUAD into two biologically distinct subtypes (the mitochondrial-ribosome biogenesis, MRB, subtype and the lysosomal catabolism, LC, subtype), which showed systematic differences in prognosis and functional programs. The MRB subtype exhibited enhanced stress and metabolic adaptation accompanied by immune exclusion features, whereas the LC subtype showed a relatively immune-active tumor microenvironment. Immunotherapy-related analyses suggested divergent trends in potential ICB benefit between the two subtypes. Multiscale evidence highlighted SLC16A14 (MCT14) as a key node linking stress heterogeneity to malignant progression. At the single-cell level, SLC16A14 was mainly expressed in malignant cells, and communication analyses suggested that CALCR-related signaling may mediate tumor-endothelial interactions and contribute to an immune-excluded microenvironment. In vitro, SLC16A14 silencing suppressed tumor cell proliferation, invasion, and migration, supporting its role as a key molecule connecting stress adaptation and tumor progression. CONCLUSION: We established an organelle stress program-based subtyping and prognostic framework for LUAD, revealed the coupling between stress adaptation and TME remodeling, and proposed SLC16A14 and its associated communication network as potential intervention targets, providing multiomics evidence for interpreting LUAD heterogeneity and for stratifying immunotherapy and combination strategies.
Integrated Bulk and Single-Cell Transcriptomic Analysis Reveals Xenobiotic Metabolism Genes Drive Progression From Liver Cirrhosis to Hepatocellular Carcinoma.
Xu H, Li Y, Zhao R … +4 more , Ma S, Hu N, Yu S, Lv X
Hum Mutat · 2026 · PMID 42136961 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors globally, with liver cirrhosis (LC) recognized as a significant precursor. Xenobiotic metabolism plays a pivotal role in liver dise...
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors globally, with liver cirrhosis (LC) recognized as a significant precursor. Xenobiotic metabolism plays a pivotal role in liver diseases, where the liver's primary function as a detoxifying organ directly influences health and tumor development. Therefore, exploring the function of genes associated with xenobiotic metabolism in patients with HCC and LC is crucial for advancing diagnosis and treatment strategies. METHODS: This study integrated bulk transcriptome RNA sequencing and single-cell RNA sequencing data of HCC and LC from the GEO database. Differential expression analysis, GO and DO enrichment analyses, and PPI network construction were performed to identify hub genes. ROC curve analysis was used to assess the diagnostic value of these genes, and potential therapeutic drugs were predicted using drug databases. The expression of the identified hub genes was validated in clinical tissue samples (≥ 10 pairs) by qRT-PCR and Western blot. Functional assays, including wound healing, transwell migration, and invasion assays, were conducted following siRNA-mediated knockdown of selected hub genes in Huh7 hepatoma cells. RESULTS: We identified five key xenobiotic metabolism-related hub genes: AKR1C3, CYB5A, ADH1C, MAOA, and ALDH2. These genes were significantly overexpressed in HCC and LC tissues compared with normal tissues and were associated with xenobiotic metabolism, substance abuse, alcohol use disorders, and cancer. ROC curve analysis indicated that these hub genes have high diagnostic value in HCC and LC. Potential drug prediction identified six compounds, including retinal, isopropanol, and disulfiram, which may have therapeutic effects. Clinical tissue validation confirmed that all five hub genes were significantly upregulated at both mRNA and protein levels in HCC and LC tissues compared with normal controls ( < 0.05). Functional experiments demonstrated that knockdown of ALDH2 or AKR1C3 significantly impaired the migration and invasion abilities of Huh7 cells, with a reduction of over 50% in transwell assays ( < 0.05). CONCLUSION: This study systematically analyzed the expression characteristics and functional significance of xenobiotic metabolism-related genes in HCC and LC by integrating multiple high-throughput sequencing technologies. Experimental validation confirmed the upregulation of these hub genes in clinical tissues and demonstrated that ALDH2 and AKR1C3 promote hepatoma cell migration and invasion, providing experimental evidence for their potential roles in disease progression. Potential drugs targeting these hub genes were preliminarily investigated.
Role of Macrophage-Related Genes GAS7 and ZEB2 in Acute Myocardial Infarction Pathogenesis.
Liu Z, Song J, Li L … +3 more , Fan Z, Xie G, Yang L
Hum Mutat · 2026 · PMID 42136960 · Full text
BACKGROUND: Acute myocardial infarction (AMI) involves complex immune responses and cellular interaction mechanisms. Although the pathogenesis of AMI is now preliminarily understood, there is still a lack of biomarkers t...
BACKGROUND: Acute myocardial infarction (AMI) involves complex immune responses and cellular interaction mechanisms. Although the pathogenesis of AMI is now preliminarily understood, there is still a lack of biomarkers that can accurately and rapidly diagnose its disease characteristics. METHODS: This study analyzed single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data related to AMI from the Gene Expression Omnibus (GEO) database. Data preprocessing and clustering were performed using Seurat, and cell-cell communication was analyzed using CellChat. Functional enrichment was performed using clusterProfiler. Key transcription factors were identified using SCENIC, and module-specific genes associated with macrophages in AMI were identified using high-dimensional weighted gene coexpression network analysis (hdWGCNA). These were combined with WGCNA to identify genes associated with AMI. Molecular docking was then used to predict potential targeted drugs for AMI. In addition, an oxygen-glucose deprivation (OGD)-induced AC16 cardiomyocyte model combined with quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the expression patterns of the key regulators and biomarkers. RESULTS: This study identified six cell types in AMI, including adipocytes, cardiomyocytes, endothelial cells, fibroblasts, macrophages, and smooth muscle cells. CellChat showed that cell-cell communication intensity was generally enhanced in AMI. hdWGCNA identified the M5 and M8 modules as significantly associated with macrophages. SCENIC analysis found that and were important regulatory factors of macrophages. WGCNA screened the brown module as significantly associated with AMI, enriched in immune and inflammatory response pathways. The final integration of all analysis results identified and as potential biomarkers for AMI, and receiver operating characteristic (ROC) curves validated the good diagnostic performance of the two genes for AMI. Furthermore, qRT-PCR in an OGD-induced AC16 cardiomyocyte model confirmed the upregulation of , , , and , consistent with the transcriptomic findings. Molecular docking indicated that has a good binding affinity with sulforaphane. CONCLUSION: This study revealed the cellular communication characteristics in the pathogenesis of AMI and identified and as potential biomarkers for AMI based on macrophage characteristics. It also elucidated their targeted therapeutic drugs, providing new insights into the mechanism and treatment of AMI.
Decoding Pathogenic Mutational Landscapes in Alzheimer's Disease Through Integrated Transcriptomics.
Ma W, Zhou F, Cai H … +1 more , Fang L
Hum Mutat · 2026 · PMID 42131724 · Full text
Alzheimer's disease (AD) is increasingly understood as a disorder driven not only by amyloid and tau pathology but also fundamentally shaped by underlying genetic mutations. By integrating multiple AD gene expression dat...
Alzheimer's disease (AD) is increasingly understood as a disorder driven not only by amyloid and tau pathology but also fundamentally shaped by underlying genetic mutations. By integrating multiple AD gene expression datasets with machine learning approaches-including random forest, XGBoost, LASSO, and SVM-we identified 172 differentially expressed genes, with TUBB2A, RTN4, and YWHAZ emerging as top mutation-associated hub genes. Critically, TUBB2A not only exhibited strong diagnostic potential (AUC = 0.822) but also harbored somatic mutations in our patient cohort, directly linking mutational events to disease manifestation. Unsupervised clustering revealed two distinct AD subtypes: one marked by widespread early gene overexpression and another (Cluster 2) dominated by endoplasmic reticulum stress-likely reflecting divergent mutational landscapes. Pseudotemporal trajectory analysis demonstrated a continuous progression from normal samples to Cluster 2, suggesting that a pivotal mutational event may initiate this transition and accelerate disease progression. These findings underscore the central role of somatic and germline mutations-particularly in TUBB2A-in AD pathogenesis. Our study strongly supports a paradigm shift toward mutation-centric biomarker development and advocates for SNP-based strategies to enable early diagnosis and personalized therapeutic interventions tailored to individual mutational profiles.
Convergent Immune-Coagulation Programs Underlie Gastrointestinal Bleeding Risk in Portal Vein Tumor Thrombosis-Associated Hepatocellular Carcinoma and Portal Hypertension.
Rutao X, Zhuxiang X, Jichun Z … +7 more , Tinghui Z, Kewei Z, Qingqing W, Ding Y, Xiyang C, Chengxin W, Bin H
Hum Mutat · 2026 · PMID 42131723 · Full text
BACKGROUND: Portal vein tumor thrombosis (PVTT) and portal hypertension are major contributors to gastrointestinal bleeding in hepatocellular carcinoma (HCC), yet the molecular programs linking vascular pathology, immune...
BACKGROUND: Portal vein tumor thrombosis (PVTT) and portal hypertension are major contributors to gastrointestinal bleeding in hepatocellular carcinoma (HCC), yet the molecular programs linking vascular pathology, immune dysregulation, and bleeding risk remain incompletely defined. METHODS: Bulk transcriptomic datasets related to PVTT (GSE77509 and GSE69164) and noncirrhotic portal hypertension (GSE77627) were analyzed using differential expression and weighted gene coexpression network analysis to identify robust disease-associated genes. A six-gene core signature was derived by intersecting differentially expressed genes with intramodular hub genes across datasets. Bleeding risk-associated biological programs, including coagulation, complement activation, angiogenesis, hypoxia, and inflammatory signaling, were quantified using ssGSEA. Immune infiltration was estimated using CIBERSORTx. Single-cell RNA-sequencing data from PVTT (GSE149614) were analyzed to resolve cell type-specific expression patterns and intercellular communication. Associations with survival, DNA methylation, immune infiltration, drug sensitivity, and molecular interactions were evaluated using public cancer genomics resources. Functional validation was performed using siRNA-mediated knockdown and drug treatment assays in HepG2 and Huh7 cells, followed by proliferation, colony formation, and wound healing assays. RESULTS: Bleeding risk-related biological programs exhibited dataset-specific activation patterns and correlated with expression of the six-gene signature. Single-cell analysis revealed heterogeneous, cell type-specific expression across malignant, stromal, endothelial, and immune populations. OGFRL1 and WDR62 were significantly associated with overall survival and showed methylation-linked transcriptional regulation. Genetic silencing or pharmacological targeting of these genes significantly suppressed HCC cell proliferation, clonogenicity, and migration in vitro. Drug signature analysis and molecular docking supported potential interactions of nocodazole with OGFRL1 and testosterone with WDR62, which phenocopied knockdown effects. CONCLUSION: These findings identify immune-coagulation dysregulation as a molecular link between PVTT, portal hypertension, and gastrointestinal bleeding risk in HCC and functionally validate OGFRL1 and WDR62 as biologically and therapeutically relevant targets.
Multiomics and Genomic Alteration Characterization Identifies VDAC1 as a Mitochondrial-Associated Biomarker in Pancreatic Cancer.
Sun W, Wang Y, Qiao X … +12 more , Zhou S, Liu Z, Yang S, Zhang D, Wang D, Zhou H, Qi F, Zhang M, Wu B, Tan Y, Cen L, Zhang B
Hum Mutat · 2026 · PMID 42111501 · Full text
Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biological behavior and limited therapeutic responsiveness. Identifying genetically and biologically interpretable biomarkers remains critical for im...
Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biological behavior and limited therapeutic responsiveness. Identifying genetically and biologically interpretable biomarkers remains critical for improving molecular stratification of this malignancy. Here, we performed an integrative analysis combining bulk transcriptomics, genomic alteration profiling, immune-response modeling, and functional validation to characterize the clinical relevance of voltage-dependent anion channel 1 (VDAC1) in PDAC. Genomic analyses demonstrated that VDAC1 exhibits a low somatic mutation frequency in PDAC and that its dysregulated expression may be partly associated with copy number alterations. Transcriptomic analyses further showed that VDAC1 is significantly upregulated in tumor tissues and associated with unfavorable clinical outcomes. Multiomics characterization indicated that high VDAC1 expression is linked to mitochondrial metabolic programs and reduced cytotoxic immune signatures. Functional validation demonstrated that VDAC1 silencing impaired pancreatic cancer cell proliferation and disrupted mitochondrial homeostasis, including reduced mitochondrial membrane potential, ATP production, and mitochondrial reactive oxygen species levels. In addition, VDAC1 perturbation reduced immunosuppressive cytokine output, suggesting a tumor-intrinsic connection between mitochondrial metabolic regulation and immune-related programs. Collectively, this study provides a genomic alteration-informed multiomics framework supporting VDAC1 as a mitochondrial-associated biomarker in PDAC and highlights its potential relevance for molecular characterization of pancreatic cancer.
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