Hum. Mutat. [JOURNAL]
Sun
200 papers
Disentangling Links Between Lung Cancer and Infectious Pneumonia via Real-World Data and Integrative Genomics.
Diao YF, Chen Z, Tang YF … +6 more , Xie T, Ge QY, Xie K, Cong ZZ, Shen Y, Chen S
Hum Mutat · 2026 · PMID 41624060 · Full text
Lung cancer (LC) patients frequently develop infectious pneumonia, often leading to suspension of anticancer therapy, yet the impact of LC on pneumonia progression remains unclear. This study employed a multidimensional...
Lung cancer (LC) patients frequently develop infectious pneumonia, often leading to suspension of anticancer therapy, yet the impact of LC on pneumonia progression remains unclear. This study employed a multidimensional approach to investigate whether LC constitutes a critical factor contributing to pulmonary infection onset and adverse short-term outcomes. Data from two intensive care unit databases were analyzed to assess the association between LC and pneumonia incidence and prognosis from a real-world perspective, with Mendelian randomization (MR) applied to validate causality. Additionally, post-GWAS analyses were conducted to explore comorbidity interaction patterns and potential shared therapeutic targets. Cross-sectional and cohort analyses identified LC as an independent risk factor for infectious pneumonia development and 28-day mortality, findings corroborated by sensitivity analyses across multiple models and datasets. Meta-analysis of MR results demonstrated causal relationships between genetically predicted LC and both pneumonia risk (OR = 1.103, 95% CI: 1.031-1.181, = 0.004) and short-term mortality (OR = 1.219, 95% CI: 1.100-1.350, < 0.001), with consistency across histological subtypes. After adjustment for comorbidities including chronic obstructive pulmonary disease (COPD), LC retained independent effects, while a strong LC-COPD genetic correlation was observed. Subgroup and mediation analyses revealed a two-way interplay between LC and COPD in driving pneumonia progression. Drug-target analyses suggested that modulation of the complement and coagulation cascades may benefit pneumonia patients with comorbid LC or COPD, highlighting , , and as key candidates and pointing to monocyte-centered pathways as promising therapeutic directions. These findings indicate that infection-related pulmonary inflammation in LC patients may be partly tumor-driven, challenging routine cessation of anticancer therapy and underscoring the need for comorbidity-oriented treatment strategies.
Exploring the Dynamic Changes of Intercellular Connections in Cervical Cancer: Insights From Transcriptomic Data Combined With Single-Cell Sequencing.
Ji R, Geng R, Zhang Z … +5 more , Gao F, Zhang P, Sun Y, Liu J, Zhang L
Hum Mutat · 2026 · PMID 41584728 · Full text
BACKGROUND: As a common gynecological malignancy, cervical cancer has a rising incidence rate and mortality, which has brought huge pressure to global public health. Although immunotherapy has been applied in clinical pr...
BACKGROUND: As a common gynecological malignancy, cervical cancer has a rising incidence rate and mortality, which has brought huge pressure to global public health. Although immunotherapy has been applied in clinical practice, its therapeutic effect is still far from satisfactory. METHODS: InferCNV was used to calculate the CNV score and the ssGSE, which is an algorithm to calculate the abundance of samples. CellChat analysis and pseudotime analysis were used to observe the evolution and interaction relationships between different clusters. Establish a prognostic model for CC patients using univariate, LASSO, and Cox analysis, and evaluate copy number variation and TME in low-risk groups. Finally, ssGSEA was applied to calculate the relationship between the hallmark gene sets and immune cycle steps and to calculate drug sensitivity in different risk groups using "oncopredict." A series of experiments including CCK-8 assay, clone formation, EdU assay, and Transwell assay were performed to detect the role of COL4A1 in CC. RESULTS: The epithelial cells were divided into nine clusters. Among them, Cluster 8 has a lower CNV score, a lower degree of variation, and a better prognosis. After that, Cluster 8 sends a signal to fibroblasts through the PTN signaling pathway. A cervical cancer-related model (CCM) was constructed based on the marker genes of Cluster 8, and it can effectively distinguish the prognosis. There is a great difference in standardized TMB, immune cell infiltration, and ESTIMATE scores between the groups. Nine drugs were identified which may achieve better therapeutic effects when applied to low-risk patients. Finally, knockdown of COL4A1 inhibits the proliferation and metastatic ability of CC cells. CONCLUSION: Our study revealed different interactions between subgroups in the tumor microenvironment of CC epithelial cells. We established an effective prognostic model. Ultimately, through a series of in vitro function experiments, COL4A1 was recognized as a new potential target for the therapeutic intervention of CC.
Tumor Microenvironment Characterization Identifies as an Immunosuppressive Driver in Breast Cancer.
Zhang B, Wang F, Huang H … +4 more , Zhong X, Chen Q, Liu X, Nair S
Hum Mutat · 2026 · PMID 41584727 · Full text
The various cellular composition of the tumor microenvironment (TME) comprises the fundamental units of tumor tissue. The types of stromal cells in the TME are genetically stable, with reduced risk of tumor recurrence an...
The various cellular composition of the tumor microenvironment (TME) comprises the fundamental units of tumor tissue. The types of stromal cells in the TME are genetically stable, with reduced risk of tumor recurrence and drug resistance. More and more evidence shows their clinicopathological significance and therapeutic effect in predicting prognosis. Therefore, we performed an integrated analysis of the breast cancer TME, correlating it with genomic landscapes and clinical profiles. In this work, we first conducted unsupervised hierarchical clustering on 830 tumors in the breast cancer cohort. Then, we defined three TME phenotypes and applied principal component analysis to construct a TMEscore for quantifying TME. Analysis revealed that patients stratified into the high TMEscore cohort exhibited superior survival compared to the low-scoring group. Additionally, a high TMEscore is associated with an improved response to immunotherapy. Through TME gene signature analysis, was identified as a pivotal driver of the immunosuppressive microenvironment in breast cancer. knockdown may promote dendritic cell infiltration and function, thereby inducing CD8 T cell recruitment. In summary, the immune microenvironment-derived TMEscore represents an independent prognostic biomarker in breast cancer, while emerges as a crucial molecular determinant of its immunosuppressive niche.
Acetylated Pyrimidine Metabolism Genes as Prognostic Markers and Their Influence on Immune Profiles in Lung Adenocarcinoma.
Jia K, Zhang S, He Y … +2 more , Liang L, Nair S
Hum Mutat · 2026 · PMID 41584726 · Full text
Lung adenocarcinoma is a very aggressive cancer with poor clinical results. New molecular indicators are desperately needed to improve treatment decision-making. This study looks at the relationship between the immunolog...
Lung adenocarcinoma is a very aggressive cancer with poor clinical results. New molecular indicators are desperately needed to improve treatment decision-making. This study looks at the relationship between the immunological microenvironment and genes linked to pyrimidine metabolism, particularly those that undergo acetylation, and the prognostic significance of these genes. Using publicly accessible genomic and clinical data, we used Gene Set Variation Analysis (GSVA) to identify acetylated pyrimidine pathway components that are highly correlated with survival outcomes. Three potential genes-TK1, RRM2B, and NME4-were identified for their prognostic relevance by using sophisticated predictive modeling approaches including CoxBoost and a random forest survival analysis. Using CIBERSORT deconvolution and single-sample gene set enrichment, immunological landscape disparities were identified, and it was discovered that varied gene expression-acetylation patterns were linked to varying immune cell infiltration. Gene activity and acetylation status-based low-risk patients showed positive survival patterns and higher levels of antitumor immune populations, indicating possible receptivity to immune-based treatments. Functional validation experiments targeting TK1, including RNA interference followed by proliferation (CCK-8, EdU), migration (Transwell), and wound healing assays, substantiated its role in promoting tumor aggressiveness. Collectively, our findings suggest that integrating metabolic gene signatures with immunological context offers a promising framework for precision oncology in lung adenocarcinoma.
Revealing the Action Mechanism of Exogenous Hydrogen Sulfide Intervention in Colorectal Cancer Pathogenesis Based on Multiomics Analysis and Experimental Validation.
Cui F, Yu C, Zhao W … +4 more , Shi J, Liu Y, Liu F, Nair S
Hum Mutat · 2026 · PMID 41584725 · Full text
Colorectal cancer (CRC) ranks among the leading causes of cancer-related mortality worldwide. Hydrogen sulfide (HS) has been found to possess a characteristic of anticancer, which may offer a potential novel treatment fo...
Colorectal cancer (CRC) ranks among the leading causes of cancer-related mortality worldwide. Hydrogen sulfide (HS) has been found to possess a characteristic of anticancer, which may offer a potential novel treatment for CRC. Here, we discover the potential targets and mechanism of HS intervention in CRC employing multiomics analysis and experimental validation. The key targets of HS intervention in CRC were identified by integrating differentially expressed genes (DEGs) from tumor and normal tissues, the CRC-associated genes, and the targets of HS. The STRING and Cytoscape tools were explored to obtain hub genes. Functional enrichment analysis, assessment of diagnostic and prognostic significance, single-cell datasets, and cell experiments were used to explore the impact of core targets on CRC and the potential mechanism through which HS exerts regulatory effects on CRC. Our results identified 9250 genes closely linked to CRC from DEGs and CRC-associated genes, 505 targets for HS, and 322 potential targets of HS intervention in CRC. Subsequently, five hub genes were filtered, including MAPK1, MAPK3, JUN, ESR1, and AKT1. The 322 common targets were enriched in the cellular stress responses and IL-17 signaling pathway. Additionally, MAPK3 had good diagnostic and prognostic value for CRC. JUN was highly expressed in immune cells. Cell experiments showed that sodium hydrosulfide (NaHS), a donor of HS, prominently inhibited cell proliferation, promoted cell apoptosis for CRC, and downregulated the expression of MAPK1, MAPK3, AKT1, and JUN. Taken together, this study elucidates the possible genes and therapeutic mechanisms underlying exogenous HS intervention in CRC, thereby laying a foundation for the further development of HS-based therapeutic strategies in CRC management.
IPO9 Promotes Ovarian Cancer Progression by Suppressing HMOX1-Dependent Ferroptosis.
Meng Y, Li P, Nair S
Hum Mutat · 2026 · PMID 41584724 · Full text
Ovarian cancer (OC) poses a significant threat to women's health, with current treatment strategies remaining suboptimal, necessitating the exploration of novel therapeutic targets and immune microenvironment dynamics. T...
Ovarian cancer (OC) poses a significant threat to women's health, with current treatment strategies remaining suboptimal, necessitating the exploration of novel therapeutic targets and immune microenvironment dynamics. This study integrates multiomics data from TCGA, GEO, and IEU-Open-GWAS, employing scRNA-seq, scPagwas, BayesPrism, and WGCNA to identify key cell subpopulations and genes, followed by functional validation through EdU, colony formation, Transwell assays, and ferroptosis markers (MDA, ROS, and ferrous ions). Results reveal MALAT1 epithelial cells as a core cell subpopulation in OC, with higher abundance correlating with shorter overall survival, suppressed immune microenvironments, and potential immunotherapy resistance, while their infiltration levels are closely associated with OC immune dynamics and somatic mutations. Further analysis identifies as a core gene upregulated in OC, promoting tumor progression by inhibiting HMOX1-dependent ferroptosis. These findings highlight MALAT1 epithelial cells as drivers of immune suppression in OC and propose IPO9 as a promising therapeutic target, offering new avenues for immunotherapy development.
Exosomal lncRNA FENDRR Orchestrates Immune Remodelling and Ferroptosis in the Comorbidity of Lung Cancer and Type 1 Myocardial Infarction.
He Y, Qian Y, Zheng Z … +4 more , Zhou Y, Li C, Wu Q, Ren M
Hum Mutat · 2026 · PMID 41584723 · Full text
Lung cancer and Type 1 myocardial infarction (T1MI) increasingly co-occur, yet the molecular basis underlying their interaction remains unclear. In this study, we combined multiomics profiling, in vivo and in vitro model...
Lung cancer and Type 1 myocardial infarction (T1MI) increasingly co-occur, yet the molecular basis underlying their interaction remains unclear. In this study, we combined multiomics profiling, in vivo and in vitro models and human clinical samples to investigate the regulatory role of the exosomal long noncoding RNA FENDRR in cancer-cardiovascular comorbidity. We found that FENDRR was markedly elevated in thrombus-derived exosomes from T1MI patients and promoted cardiomyocyte ferroptosis and ferritinophagy through the NCOA4-GPX4-P62 axis, thereby exacerbating myocardial injury. Silencing FENDRR significantly alleviated cardiac damage in the T1MI rat model. In contrast, FENDRR was consistently downregulated across multiple cancers, particularly lung adenocarcinoma (LUAD). Higher FENDRR expression was associated with favourable patient survival, and time-dependent ROC analysis demonstrated robust prognostic performance in LUAD (5 - year AUC = 0.990). Multiomics and immunogenomic analyses further revealed that FENDRR expression correlated with distinct remodelling of the tumour immune microenvironment, including alterations in immune cell infiltration, immune activation scores, chemokine and HLA gene expression and antigen-presentation capacity. These findings were supported by single-cell analyses and by enhanced CD8 T-cell and Treg infiltration in thrombi from patients with LUAD and T1MI. Collectively, our results identify FENDRR as a context-dependent regulator that promotes myocardial injury but may exert tumour-suppressive and immune-modulatory functions in lung cancer. These insights provide a mechanistic framework for cancer-cardiovascular comorbidity and highlight FENDRR as a potential biomarker and therapeutic target across disease contexts.
Proprotein Convertase Subtilisin/Kexin Type 9 Induces Platelet-Derived Transforming Growth Factor- to Promote Myocardial Fibrosis After Myocardial Infarction.
Wang Q, Huang W, Xia D … +2 more , Wang F, Nair S
Hum Mutat · 2026 · PMID 41573336 · Full text
AIMS: The recovery of cardiac function after acute myocardial infarction is crucial for the prognosis of patients with myocardial infarction. Proprotein convertase subtilisin/Kexin Type 9 (PCSK9) inhibitors are widely us...
AIMS: The recovery of cardiac function after acute myocardial infarction is crucial for the prognosis of patients with myocardial infarction. Proprotein convertase subtilisin/Kexin Type 9 (PCSK9) inhibitors are widely used in patients with acute myocardial infarction due to their potent low-density lipoprotein-lowering effects. Recent studies have shown that elevated levels of circulating PCSK9 are associated with increased platelet reactivity and thrombosis; however, the effect and mechanism of PCSK9 on cardiac repair after myocardial infarction through the induction of platelet activation remain unclear. Therefore, the objective of this study was to investigate and clarify the specific effect of PCSK9 on cardiac repair processes following myocardial infarction. The detailed molecular and cellular mechanisms through which PCSK9 regulates cardiac repair after myocardial infarction by inducing platelet activation were observed. METHODS AND RESULTS: Hearts from wild-type (WT) C57BL/6J mice and PCSK9 knockout (PCSK9/) mice were subjected to left coronary artery (LAD) ligation to establish a myocardial infarction model. Six weeks postoperation, echocardiographic analysis and Masson staining revealed that inhibiting the increase in PCSK9 expression after myocardial infarction significantly reduced myocardial fibrosis. Transcriptome sequencing of mouse myocardial tissue suggested that PCSK9 suppresses immune regulation and adhesion pathways and that the platelet marker integrin subunit alpha 2b (Itga2b) is a potential key molecule. Subsequent in vivo and in vitro experiments demonstrated that PCSK9 promotes platelet activation and induces the fibrogenic phenotypic transformation of fibroblasts by transforming growth factor- (TGF-). In further studies, coculture experiments of fibroblasts and platelets revealed that PCSK9 promotes the conversion of fibroblasts to myofibroblasts by inducing platelet-derived TGF- secretion. CONCLUSION: PCSK9 promotes platelet activation, induces the secretion of platelet-derived TGF-, and thereby accelerates myocardial fibrosis after myocardial infarction.
Systematic Pathway Screening via Integrated Machine Learning Identifies FOXO-Mediated Transcription Signature for Robust Immunotherapy Response Prediction in Non-Small Cell Lung Cancer.
Wu S, Deng C, Fan C … +20 more , Liang Q, Zhu L, Mou W, Huang H, Wu K, Li Y, Deng G, Xu L, Xie J, Hong C, Deng Y, Li X, Wu C, Yang T, Luo P, Wong HZH, Jiang A, Lin A, Chen X, Ren M
Hum Mutat · 2026 · PMID 41561639 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC), accounting for 80% of lung cancer cases, remains a leading cause of cancer-related mortality globally. While immune checkpoint inhibitors (ICIs) have improved outcomes, the...
BACKGROUND: Non-small cell lung cancer (NSCLC), accounting for 80% of lung cancer cases, remains a leading cause of cancer-related mortality globally. While immune checkpoint inhibitors (ICIs) have improved outcomes, their efficacy is limited to a subset of patients, necessitating robust biomarkers for personalized immunotherapy response prediction. METHODS: We integrated transcriptomic data from 584 NSCLC patients across four cohorts treated with ICIs. Using 12,025 pathways from MSigDB, we applied 101 machine learning algorithm combinations (e.g., random survival forest [RSF], least absolute shrinkage and selection operator [Lasso], and Cox proportional hazards model with component-wise likelihood-based boosting [CoxBoost]) to identify prognostic signatures. OAK was used as the training set and Ravi, Jung, and Poplar as the validation set. The optimal pathway and algorithm combination was determined based on the average concordance index (-index) ranking in the validation sets, and a predictive model was generated. Performance was assessed by -index, receiver operating characteristic (ROC) analysis, and survival analysis. Biological relevance was evaluated through gene set enrichment analysis (GSEA), immune infiltration profiling, and immunohistochemistry (IHC). RESULTS: The FOXO-mediated transcription pathway combined with Lasso-RSF algorithms emerged as the top predictor. The derived FOXO-related signature (FRS) stratified patients into high-risk and low-risk groups, with high-risk patients showing significantly worse progression-free survival (PFS) and overall survival (OS) across all cohorts ( < 0.05). FRS outperformed clinical variables and 43 published models in predictive accuracy. IHC confirmed elevated expression of FRS-associated genes (PCK1, IGFBP1) in nonresponders. Immune profiling revealed enriched antitumor immunity in low-FRS patients. CONCLUSION: FRS, a machine learning-derived pathway signature, robustly predicts immunotherapy response and survival in NSCLC. Its integration of FOXO-mediated immune regulation offers a clinically translatable tool for precision oncology.
Albiflorin-Mediated MAP2K1 Targeting and HIF-1 Signaling Inhibition Contribute to the Therapeutic Efficacy in Hyperuricemia-Associated Cognitive Impairment.
Xiao H, Huang X, Yao R … +5 more , Liu J, Duan L, Wang S, Gao J, Ren M
Hum Mutat · 2026 · PMID 41561638 · Full text
This study investigated the therapeutic effects and mechanisms of fruit pod extract (EMP) and its main component albiflorin (AF) on hyperuricemia-associated cognitive impairment (HUA-CI). A HUA-CI mouse model was establ...
This study investigated the therapeutic effects and mechanisms of fruit pod extract (EMP) and its main component albiflorin (AF) on hyperuricemia-associated cognitive impairment (HUA-CI). A HUA-CI mouse model was established, with cognitive function evaluated via Morris water maze. Hippocampal pathology, inflammation, oxidative stress, and apoptosis were assessed using HE staining, ELISA, TUNEL, and Western blotting. Network pharmacology predicted EMP's targets, and molecular docking analyzed AF-MAP2K1 binding. In vitro experiments used UA-stimulated BV2 and HT22 cells to explore AF's effect on HIF-1 signaling. EMP significantly improved cognitive function and reduced pathological damage in the hippocampus of HUA-CI mice. It exerted protective effects by inhibiting inflammatory responses, alleviating oxidative stress, and preventing cell apoptosis. Network pharmacology analysis revealed that EMP acts through multiple targets and pathways, particularly via the strong binding affinity between AF and MAP2K1. Both in vivo and in vitro studies demonstrated that AF inhibited the HIF-1 signaling pathway, thereby reducing microglial activation and associated inflammation, mitigating uric acid-induced neuronal apoptosis, enhancing antioxidant defenses, and protecting neuronal function. Our research indicates that EMP exerts multi-target therapeutic effects on HUA-CI; AF plays a key role by targeting MAP2K1 and inhibiting HIF-1 signaling.
Molecular Landscape and Predictive Significance of Programmed Cell Death-Related Genes in Sepsis.
Min S, Zhang T, Chen S … +1 more , Ren M
Hum Mutat · 2026 · PMID 41542228 · Full text
Sepsis, a systemic inflammatory response to infection, remains a significant health challenge with high morbidity and mortality rates. The molecular mechanisms underlying sepsis, particularly the role of programmed cell...
Sepsis, a systemic inflammatory response to infection, remains a significant health challenge with high morbidity and mortality rates. The molecular mechanisms underlying sepsis, particularly the role of programmed cell death (PCD), are not fully understood. This study is aimed at elucidating the transcriptomic changes associated with sepsis, emphasizing PCD, and identifying potential diagnostic biomarkers. Transcriptome data from sepsis and control samples were extracted from the GEO website. Differential expression analysis identified genes perturbed in sepsis. WGCNA revealed 14 highly connected modules, with the turquoise module showing the strongest association with sepsis. A set of 262 hub genes was identified, which were mainly associated with apoptotic signaling pathways. Seven prognostic-related overlapping feature genes (PRGs) were identified. More importantly, the diagnostic model, constructed using eight machine learning algorithms, exhibited high efficacy in distinguishing sepsis patients from controls. The validation of feature genes at the scRNA-seq level adds a layer of robustness to our conclusions. The strong association of genes like S100A9 and KLHL3 with neutrophils, pivotal players in sepsis, suggests potential avenues for therapeutic targeting. Our comprehensive analysis has unveiled the significant role of PCD in sepsis. The insights gained from this study provide a foundation for future therapeutic interventions.
Integrative Multiscale Analysis Reveals EFNA1-Driven Immune Remodeling Promotes Colorectal Cancer Lymph Node Metastasis.
Ning W, Qiao N, Zhou L … +4 more , Li Z, Zhang L, Song X, Chen S
Hum Mutat · 2026 · PMID 41542227 · Full text
BACKGROUND: Nodal involvement constitutes a pivotal prognostic indicator in colorectal carcinoma, yet the transcriptional machinery governing lymphatic dissemination and tumor-microenvironment crosstalk remains poorly el...
BACKGROUND: Nodal involvement constitutes a pivotal prognostic indicator in colorectal carcinoma, yet the transcriptional machinery governing lymphatic dissemination and tumor-microenvironment crosstalk remains poorly elucidated. Conventional bulk sequencing methodologies lack sufficient resolution to deconvolve functionally distinct malignant subclones that drive the metastatic cascade. METHODS: We employed an integrative analytical framework combining tissue-level gene expression profiling from TCGA and GEO repositories with eight single-cell transcriptomic datasets comprising 266,995 individual cells. A phenotype-guided computational algorithm was implemented to delineate metastasis-driving malignant populations through correlating clinical parameters with cellular transcriptional profiles. Gene regulatory networks and transcription factor activity inference systematically decoded the molecular programs underlying metastatic phenotypes. Ligand-receptor pairing analysis mapped intercellular communication architectures between neoplastic cells and microenvironmental constituents. Experimental validation encompassed genetic perturbation studies, functional characterization assays, and pharmacological response evaluation in preclinical systems. RESULTS: We discovered a phenotypically distinct malignant population exhibiting robust associations with lymph node involvement and adverse clinical outcomes across nine independent validation cohorts. Regulatory network dissection identified IRF9 as the master transcriptional orchestrator of this metastatic program through coordination of a discrete gene module. Relative to their nonmetastatic counterparts, these aggressive cells establish markedly expanded intercellular communication networks, characterized by prominent VEGF-driven angiogenic signaling to endothelial compartments and integrin-laminin-mediated adhesion with stromal elements. EFNA1 emerged as a key signaling mediator demonstrating preferential enrichment in this metastatic subset. Elevated EFNA1 levels correlated with progressive disease stages and microsatellite-stable subtypes while showing inverse relationships with PD-L1 expression and T cell infiltration density-suggesting a unique immunoevasion mechanism. Genetic ablation of Efna1 substantially impaired cellular proliferation, motility, and invasion capabilities, while simultaneously augmenting Linifanib sensitivity, indicating synergistic therapeutic potential. CONCLUSIONS: Our investigation reveals a transcriptionally defined malignant population under IRF9 control that orchestrates immunosuppressive microenvironmental reprogramming via EFNA1-mediated signaling networks. The EFNA1-Linifanib combination may represent a potential therapeutic approach to mitigate anti-angiogenic resistance and restrain metastatic progression in colorectal carcinoma.
Detection of Rare Thalassemia Variants Using Accurate Circular Consensus Long-Read Sequencing.
Zhou X, Chen Y, Chen S … +7 more , Lian J, Liu Y, Yang T, Wu S, Liu J, Huang X, Yang X
Hum Mutat · 2026 · PMID 41532136 · Full text
OBJECTIVE: The aim of this study is to evaluate the efficacy of accurate circular consensus long-read sequencing in the detection of rare thalassemia. METHODS: Conventional molecular analysis on globin genes has limitati...
OBJECTIVE: The aim of this study is to evaluate the efficacy of accurate circular consensus long-read sequencing in the detection of rare thalassemia. METHODS: Conventional molecular analysis on globin genes has limitations because of the broad spectrum of genetic variants, complex genetics, and genotype-phenotype correlation. Accurate circular consensus long-read sequencing is a novel tool that detects complex variants in the thalassemia gene based on third-generation sequencing. In this study, we screen out suspected rare thalassemia carriers by hemoglobin analysis and conventional molecular analysis, and evaluate the efficacy of accurate circular consensus long-read sequencing in the detection of rare thalassemia. RESULTS: Based on the traditional screening of thalassemia gene, an additional 16 (17.67%) cases of clinically significant variants of rare thalassemia were identified by accurate circular consensus long-read sequencing in this study, including 12-point variants and 4 deletion variants: HBB: (SEA)-HPFH, HBB: c.268_281delAGTGAGCTGCACTG, HBB: (Chinese) G + (A)0, and :c.91-93delGAG. CONCLUSION: Accurate circular consensus long-read sequencing has a promising prospect in detecting rare thalassemia gene variants and may improve the detection rate of carriers.
RNA-Seq of Cultured Peripheral Blood Lymphocytes Improves Identification of Cryptic Splicing Defects in Rare Disease Diagnostics.
Ren J, Dai C, Meng F … +14 more , Zhang P, Xie C, Xiao W, He W, Yuan S, Li X, Zhang Q, Tang W, Hu L, Chen Z, Lu G, Du J, Zeng S, Lin G
Hum Mutat · 2026 · PMID 41523913 · Full text
Accurate identification of the genetic determinants of rare diseases is essential for effective recurrence-risk management and informed reproductive decision-making. Although whole-exome sequencing (WES) and whole-genome...
Accurate identification of the genetic determinants of rare diseases is essential for effective recurrence-risk management and informed reproductive decision-making. Although whole-exome sequencing (WES) and whole-genome sequencing (WGS) have significantly improved diagnostic capabilities, a subset of affected families still receives no definitive molecular diagnosis. RNA sequencing (RNA-seq) has emerged as a promising complementary diagnostic tool, yet its clinical implementation in the context of preconception genetic counseling remains underexplored. We used phytohemagglutinin-activated peripheral blood cells (PHACs) as a robust RNA source and enhanced conventional RNA-seq through the integration of three analytical innovations: (1) transcript isoform distribution (TID) analysis, (2) realignment against the MANE (Matched Annotation from NCBI and EMBL-EBI) reference transcriptome, and (3) pharmacological induction-based cryptic splicing detection. This optimized pipeline was applied to 55 rare-disease families with negative WES/WGS results who were undergoing preconception genetic counseling. Based on prior evaluations, families were grouped as VUS ( = 7), suspected-gene/variant-negative ( = 10), and unsolved/no-candidate ( = 38). PHACs showed reduced interindividual variability and higher RNA integrity than fresh PBMCs (median RIN: 9.77 vs. 8.97; < 0.0001). The optimized workflow improved diagnostic yield by 2.2-fold (20% vs. 9%). Stratified analysis revealed positive rates of 71% (VUS), 40% (suspected-gene/variant-negative), and 5.2% (unsolved/no-candidate). Among the 11 positive cases, 10 received definitive diagnoses, leading to diverse reproductive decisions. This enhanced RNA-seq workflow provides a clinically applicable and scalable strategy for improving molecular diagnostics in reproductive and preconception settings, offering a valuable model for future clinical transcriptomics.
Integrated Multiomics Analysis Reveals a Migrasome-Related Signature for Prognosis and Immunotherapy Response in Lung Adenocarcinoma.
Zhou J, Song T, Wang N … +5 more , Liang C, Jiang M, Zhang X, Gao H, Feng Q
Hum Mutat · 2026 · PMID 41523912 · Full text
BACKGROUND: Migrasomes, a newly identified subtype of extracellular vesicles generated during cell migration, play crucial roles in tumor microenvironment modulation. However, their systematic characterization in lung ad...
BACKGROUND: Migrasomes, a newly identified subtype of extracellular vesicles generated during cell migration, play crucial roles in tumor microenvironment modulation. However, their systematic characterization in lung adenocarcinoma (LUAD) remains unexplored. This study is aimed at deciphering migrasome-related molecular features and their clinical significance through multiomics integration. METHODS: We integrated bulk transcriptomes (541 LUAD samples from TCGA/GEO) with single-cell RNA-seq (GSE156632). Migrasome-related genes (MIGgenes) were identified through WGCNA and differential expression analysis. A machine learning framework incorporating 10 algorithms generated 101 combinatorial models, with the optimal prognostic signature (MIGsig) selected via 10-fold cross-validation. Biological mechanisms were investigated through ssGSEA, TME analysis, and in vitro validation. RESULTS: Our analysis revealed significant migrasome activity enrichment in endothelial cells and fibroblasts, with 115 cross-omics MIGgenes identified including 31 prognostic markers. The Lasso-Cox-derived 3-gene signature (GSTM5/DNASE1L3/PDGFB) demonstrated robust predictive performance (training set index = 0.703; validation set GSE50081 AUC = 0.678). The low-MIGsig group exhibited characteristic "hot tumor" features, including elevated immune infiltration and higher tumor mutational burden, and significantly improved immunotherapy response rates in the IMvigor210 cohort. Finally, MIGsig-related genes were further validated by in vitro experiments and public database. CONCLUSIONS: This study establishes the first migrasome-based prognostic model for LUAD, demonstrating both independent survival prediction capability and clinical utility for identifying immunotherapy beneficiaries. The MIGsig signature provides novel biological insights into migrasome-mediated tumor-immune interactions and represents a promising tool for precision oncology applications in LUAD management.
Itaconate-Related Gene Signatures as Prognostic Markers in Colon Cancer: Insights From Transcriptomic and Spatial Analysis.
Zhang T, Meng J, Wang Q … +6 more , Zhang P, Li H, Wei H, Chen D, Bai C, Nair S
Hum Mutat · 2026 · PMID 41523911 · Full text
Colon cancer is one of the most prevalent malignant tumors. Accurate evaluation of patient prognosis and optimization of treatment strategies continue to be major research focuses in colon cancer. Based on The Cancer Gen...
Colon cancer is one of the most prevalent malignant tumors. Accurate evaluation of patient prognosis and optimization of treatment strategies continue to be major research focuses in colon cancer. Based on The Cancer Genome Atlas (TCGA) database, this study is the first to comprehensively analyze the expression, biological roles, and prognosis of itaconate and Hallmark pathway-related genes in colon cancer using bulk transcriptomics, single-cell transcriptomics, and spatial transcriptomics data. Through strict screening in 448 colon cancer patients from TCGA database (training set) and 7 colon cancer prognostic models from the Gene Expression Omnibus (GEO) database (including 1473 cases in the validation set), 10 prognosis-related genes (TIMP1, FJX1, CD36, CXCL1, ETS2, CDKN2A, INHBB, PLEC, TUBB2, and P4HA1) were selected. The optimal prognostic prediction model (Enet [alpha = 0.2]) was constructed and validated, which showed good prognostic predictive value in both the training and validation sets (average C-index > 0.7) and was superior to previous conventional clinical features and 22 prognostic models developed by researchers in the past 4 years. ScRNAseq (GSE225857) and spatial transcriptomics analyses clarified the cell-specific expression and spatial distribution characteristics of these genes in the tumor microenvironment (TME), with high functional scores mainly enriched in epithelial and stromal cells. Tissue microarray (TMA) showed that the high-risk group had higher tumor mutation burden (TMB) and higher expression of immune checkpoint genes, suggesting higher sensitivity to immunotherapy. Drug sensitivity analysis identified four potentially effective drugs, such as sepantronium bromide, which had better effects on high-risk patients. This study provides a theoretical basis and new targets for precise prognosis and stratified treatment of colon cancer.
Characterization of Copy Number Variants in Hereditary Cancer Patients Through NGS Shows a Distinctive PALB2 Contribution to the Diagnostic Yield.
Bonamici L, Artuso L, Marino M … +12 more , Toss A, Sidoti D, Barbieri E, Venturelli M, Marchi I, Pescucci C, Manfredini R, Papi L, Dominici M, Cortesi L, Tenedini E, Tagliafico E
Hum Mutat · 2026 · PMID 41488399 · Full text
The extensive use of next-generation sequencing (NGS) multi-gene panels and advanced analysis algorithms have led to the identification of numerous genetic variants associated with breast, ovarian, and pancreatic cancer....
The extensive use of next-generation sequencing (NGS) multi-gene panels and advanced analysis algorithms have led to the identification of numerous genetic variants associated with breast, ovarian, and pancreatic cancer. Copynumber variations (CNVs), defined as deletions and duplications of specific DNA regions, account for up to 10% of pathogenic variants and can affect any of the cancer-predisposing genes. Despite this, CNVs' contribution beyond BRCA1 and BRCA2 remains underexplored. This observational study analyzed data from 2949 patients, primarily affected by breast or ovarian cancer, who underwent NGS testing with a 22-gene hereditary cancer panel between 2018 and 2023, with a focus on CNV results. In line with comparison studies, a total diagnostic yield of 14.8% was observed with pathogenic variants in BRCA1, BRCA2, CHEK2, ATM, and PALB2 accounting for most of positive findings. In contrast, CNVs were found in 1.4% of patients, displaying a peculiar distribution pattern. PALB2 exhibited the highest frequency of pathogenic CNVs (66.7%), representing 62.2% of all PALB2 pathogenic variants. Notably, 24 out of 28 PALB2 CNV carriers shared the deletion of Exon 11. Further investigations revealed identical breakpoints and common geographical origins, and moreover, the same haplotype for some of the families suggests a relatively recent founder effect. Simultaneous sequence and copy number analyses resulted in likely higher positive predictive value of the test and, more interestingly, disclosed an unforeseen single contribution of CNVs in PALB2 gene, confirming geography as a key factor in shaping human genetic variations.
Developing Del2Phen: A Novel Phenotype Description Tool for Chromosome Deletions.
Rraku E, Medina TD, van Ravenswaaij-Arts CMA … +5 more , Slofstra MK, Swertz MA, Dijkhuizen T, Johansson LF, Engwerda A
Hum Mutat · 2026 · PMID 41488398 · Full text
Information on the health-related consequences of rare chromosome disorders is often limited, posing challenges for both patients and their families. The Chromosome 6 Project aims to bridge this knowledge gap for structu...
Information on the health-related consequences of rare chromosome disorders is often limited, posing challenges for both patients and their families. The Chromosome 6 Project aims to bridge this knowledge gap for structural aberrations involving chromosome 6 by providing parents of affected children with information on the expected phenotypes of their child. To achieve this, detailed phenotype and genotype data are collected directly from parents worldwide and supplemented with data from literature reports, resulting thus far in a dataset of over 500 individuals. This comprehensive data pool was used to develop Del2Phen, a software tool introduced in this paper that generates aberration-specific phenotype information for chromosome disorders. Del2Phen identifies individuals with a deletion or duplication similar to that of a new patient (index) and produces a clinical description for the index based on phenotypic features observed in these genotypically similar individuals. Genotypic similarity is determined using existing knowledge on the haploinsufficiency effect of genes and established gene-phenotype relationships. The optimal genotypic similarity parameters for chromosome 6 deletions were evaluated, which led to thorough and reliable clinical descriptions based on sufficiently large groups of individuals with highly similar deletions. Although currently optimised for chromosome 6 deletions, Del2Phen can also be applied to deletions involving other chromosomes and is easily adapted for use on duplications, given sufficient data are available. Del2Phen can already be used to expedite data analysis for chromosome disorders, thus aiding healthcare professionals in delivering appropriate clinical care. Lastly, this tool will be integrated into an interactive website designed for parents of children with a chromosome 6 aberration, providing essential health information in a timely and accessible manner.
The Emerging Spectrum: From Distal Arthrogryposis to Congenital Myopathy.
Altin N, Mamchaoui K, Ohana J … +16 more , Bigot A, Corradi B, Maragliano L, Madia F, Ognibene M, Nosrati MSS, Paladini D, Iacomino M, Rashid A, Bodamer O, Quijano-Roy S, Punetha J, Capra V, Zara F, Trollet C, Scala M
Hum Mutat · 2025 · PMID 41473596 · Full text
Distal arthrogryposis (DA) is a group of nonprogressive congenital muscular disorders affecting distal limb joints, without concurrent neuromuscular disease. Ten different types of DAs are known, with many different gene...
Distal arthrogryposis (DA) is a group of nonprogressive congenital muscular disorders affecting distal limb joints, without concurrent neuromuscular disease. Ten different types of DAs are known, with many different genes involved. Dominant variants in (MIM ∗600692) cause DA type 2B2 (MIM #618435), a severe condition featuring dysmorphism, distal contractures, and deformities of hands and feet. encodes the fast skeletal troponin T, an essential component of the troponin complex that is necessary for calcium-coupled contraction initiation in the striated muscle. Recently, homozygous splicing variants in have been reported in two subjects with a distinctive congenital myopathy, only partially overlapping DA2B2. However, no functional evidence was provided. In this study, we investigated two patients presenting with myopathic conditions at different ends of the spectrum. One subject showed DA, whereas the second displayed a severe congenital myopathy featuring hypotonia, DA, and dysmorphism. Through exome sequencing, we identified the de novo missense change p.(Arg63His) in Subject #1 and biallelic variants in Subject #2, featuring a splicing and a stop gain variant. The p.(Arg63His) was predicted to affect the stability of troponin T3 in silico, and we confirmed this by western blot. Then, employing different biochemical approaches, we showed that the truncated variants identified in #2 (p.[Tyr13∗] and c.480+5G>A) lead to loss of the full-length protein. Our findings refine and expand the genotype-phenotype spectrum, suggesting that recessive -related congenital myopathy should be considered a discrete entity caused by biallelic loss-of-function variants.
Development of Novel PANoptosis-Related Gene Signatures to Predict the Prognosis of Patients With Stomach Adenocarcinoma.
Wu X, Sun L, Liu P … +3 more , Wang Q, Wang Y, Nair S
Hum Mutat · 2025 · PMID 41438490 · Full text
BACKGROUND: PANoptosis, as an inflammatory programmed cell death, is involved in tumor development. This study set out to discover novel PANoptosis-correlated prognostic signatures in stomach adenocarcinoma (STAD), a pre...
BACKGROUND: PANoptosis, as an inflammatory programmed cell death, is involved in tumor development. This study set out to discover novel PANoptosis-correlated prognostic signatures in stomach adenocarcinoma (STAD), a prevalent malignancy of the digestive system. METHODS: STAD samples were derived from a public database, and PANoptosis-related genes (PRGs) were acquired from existing reports. Prognosis-related PRGs were screened by univariate Cox regression analysis. Molecular subtypes of STAD were identified by the "ConsensusClusterPlus" package. The "Limma" package was employed to filter differentially expressed genes (DEGs) between different subtypes. PANoptosis-related prognostic signatures in STAD were identified to establish the RiskScore model. The RiskScore and some of the clinical features were integrated to establish a nomogram. Immune cell infiltration and TIDE score in different risk groups were compared. Correlation between immune checkpoint genes, drug sensitivity, and RiskScore was analyzed by the Spearman method. The biological function of PANoptosis-related signature genes in STAD was preliminarily explored by in vitro cell experiments. RESULTS: Based on 18 prognosis-related PRGs, two molecular subtypes of STAD were recognized, and the C1 subtype showed a lower overall survival (OS) rate than the C2 subtype. Further, three PANoptosis-related signature genes (, , and ) were determined to establish a RiskScore model that could accurately assess the prognostic outcomes for STAD patients. Then, by integrating RiskScore with clinical features, a nomogram was established. The high-risk group had higher immune cell infiltration and TIDE score and lower OS rate than those with a low risk. RiskScore was positively correlated with nine immune checkpoint genes. Besides, we screened 23 drugs that significantly correlated with RiskScore. In vitro cell experiments showed that the mRNA and protein levels of , , and were upregulated in the STAD cell line and that knockout significantly reduced cancer cell proliferation, migration, and invasion levels and increased the apoptotic capacity of the STAD cell line. CONCLUSION: This study established a PANoptosis-related RiskScore model for assessing STAD patient prognosis, which could contribute to the personalized treatment of STAD.
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