Hum. Mutat. [JOURNAL]
Sun
200 papers
FLLL31 Induces Apoptosis via the FOXO4/BCL6 Axis to Inhibit Bladder Cancer Progression.
Han Y, Peng J, Yan W … +3 more , Wu Z, Tang Z, Ren M
Hum Mutat · 2025 · PMID 41438489 · Full text
Bladder cancer represents one of the most common malignancies globally, posing a severe threat to human health. Through compound library screening, we identified tetramethylcurcumin (FLLL31), a diketone analog of curcumi...
Bladder cancer represents one of the most common malignancies globally, posing a severe threat to human health. Through compound library screening, we identified tetramethylcurcumin (FLLL31), a diketone analog of curcumin, as exhibiting significant inhibitory effects on the malignant biological behaviors of bladder cancer cells. Although possessing diverse biological activities, the application of FLLL31 in bladder cancer has not been reported previously. To investigate the function and mechanism of FLLL31, we assessed its impact on the proliferation, migration, and invasion of T24 and 5637 cells using CCK-8, EdU, colony formation, and Transwell. The in vivo efficacy of FLLL31 was evaluated by intraperitoneal injection in BALB/c-nu mice bearing subcutaneous xenografts. Utilizing RNA-seq, qRT-PCR, Western blotting, electron microscopy, flow cytometry, and JC-1 staining, we further explored the mechanism underlying FLLL31's inhibition of malignant behaviors in bladder cancer cells. The results demonstrate that FLLL31 inhibits malignant bladder cancer behaviors by inducing apoptosis via the FOXO4/BCL6 axis. This pathway was further confirmed by the observation that lentiviral knockdown of either FOXO4 or BCL6 attenuated FLLL31-induced apoptosis. Mechanistically, FLLL31 upregulates FOXO4, leading to increased BCL6 expression. This subsequently suppresses the antiapoptotic protein Bcl-xL, thereby triggering apoptosis. These findings highlight the therapeutic potential of FLLL31 for bladder cancer and identify the FOXO4/BCL6 pathway as a promising novel target.
Homozygous Deletion of the Epigenetic Regulator in Individuals With Neurodevelopmental Disorder.
Dagan SY, Xuan H, Rips J … +6 more , Paz-Ebstein E, Baer T, Gross S, Frumkin A, Shi X, Harel T
Hum Mutat · 2025 · PMID 41438488 · Full text
encodes plant homeodomain finger protein 20 (PHF20), a component of the KAT8-containing nonspecific lethal (NSL) complex that deposits acetylation on histone H4 to activate gene expression. We report two unrelated indivi...
encodes plant homeodomain finger protein 20 (PHF20), a component of the KAT8-containing nonspecific lethal (NSL) complex that deposits acetylation on histone H4 to activate gene expression. We report two unrelated individuals with developmental delay, microcephaly, and distinctive facial features, in whom exome sequencing and chromosomal microarray analysis revealed a homozygous deletion of that segregated with the disease phenotype in their families. Breakpoint junction sequencing revealed an -mediated deletion event. Western blot in cells from an affected individual showed undetectable PHF20, while levels of other NSL complex subunits were unaltered. Transcriptomic and epigenomic analysis revealed significant downregulation of gene pathways related to cell projection and neuronal development, associated with reduced histone H4K16 acetylation at these genes. In conclusion, our data suggest that homozygous deletion of leads to a neurodevelopmental syndrome, potentially through targeted epigenetic dysregulation and altered gene expression essential for neuronal development. Identifying additional families with biallelic variants will further delineate the phenotypic spectrum, and molecular studies in neuronal cell lines will be essential for understanding the disease mechanism.
Correction to "Genotype-phenotype correlations in individuals with pathogenic variants".
Hum Mutat · 2025 · PMID 41427030 · Full text
[This corrects the article DOI: 10.1002/humu.23400.].
[This corrects the article DOI: 10.1002/humu.23400.].
Causal Relationships Between Pregnancy, Menstrual History, and Endometrial Cancer With Mediating Effects of Metabolism-Related Traits.
Zhou M, Dai S, Zhu T … +2 more , Hong S, Ren M
Hum Mutat · 2025 · PMID 41427029 · Full text
BACKGROUND: Periods and pregnancy may affect the development of endometrial cancer by affecting the secretion of sex hormones, but the causal relationship is not clear, and its mediating factors need to be explored. METH...
BACKGROUND: Periods and pregnancy may affect the development of endometrial cancer by affecting the secretion of sex hormones, but the causal relationship is not clear, and its mediating factors need to be explored. METHODS: In this study, multivariable Mendelian randomization was used to analyze summary statistics of genome-wide association studies of European ancestry, to evaluate the effect of 10 period- or pregnancy-related factors on endometrial cancer. In addition, we performed the heterogeneity test and pleiotropy test to analyze the sensitivity. Because of the effect of sex hormones on body metabolism and the relationship between metabolism-related traits and cancer, we explored the mediating effect of metabolism-related traits by two-step Mendelian randomization. RESULTS: This study showed that age at menarche ( = 1.21e - 05; OR = 0.6852; 95% CI: 0.5784-0.8116), age at menopause ( = 0.00098; OR = 1.242; 95% CI: 1.0919-1.4127), and sex hormone-binding globulin (SHBG) levels ( = 7.4e - 07; OR = 0.5914; 95% CI: 0.4804-0.7281) have an independent causal relationship with the incidence of endometrial cancer. Moreover, several obesity-related traits play a mediating role in the causal relationship between age at menarche and endometrial cancer. The mediators and their mediating effects are BMI (55.54%), obesity (30.37%), waist circumference preference (27.67%), body fat percentage (17.61%), and waist-to-hip ratio (14.82%). These results are robust to sensitivity analysis. CONCLUSION: This study demonstrated the independent effect of pregnancy- and period-related factors on endometrial cancer and suggested that avoiding obesity may be an effective method to prevent endometrial cancer for patients with premature menarche.
Integrated Multiomics Unravels Hedgehog (HH) Signaling Characteristics in Pancreatic Cancer (PC) and DCBLD2 Regulates HH Signaling to Drive PC Progression.
Zhang B, Huang B, Zhao X … +5 more , Zhang B, Liu J, Bao C, Wang Z, Nair S
Hum Mutat · 2025 · PMID 41427028 · Full text
Hedgehog (HH) signaling plays a crucial role in cancer development. However, HH signaling-related molecular characteristics have not been comprehensively evaluated in pancreatic cancer (PC). This study dissected the char...
Hedgehog (HH) signaling plays a crucial role in cancer development. However, HH signaling-related molecular characteristics have not been comprehensively evaluated in pancreatic cancer (PC). This study dissected the characteristics of HH signaling in PC using integrated bulk and single-cell profiling. GSEA indicated that HH signaling is significantly enriched in PC tissue. Consensus clustering was utilized to classify PC samples into two HH signaling-related subtypes: HRGcluster A and HRGcluster B. In contrast with HRGcluster A, HRGcluster B has an earlier clinical stage, better outcome, less active level of HH signaling, higher infiltration level of CD8+ T cells and B cells, and a greater likelihood of benefiting from immunotherapy and gemcitabine chemotherapy. Moreover, an HH signaling-related prognostic model (including ANLN, SERPINB3, LY6D, and DCBLD2) with excellent prediction performance was established and validated. Further analysis indicated that ANLN, SERPINB3, LY6D, and DCBLD2 were significantly upregulated in PC and associated with poor prognosis. Single-cell analysis revealed that HH signaling is relatively more active in PC cells, and PC cells with DCBLD2 high expression had significantly higher HH signaling scores. In vitro assays further indicated that DCBLD2 knockdown downregulates HH signaling and inhibits the proliferation, migration, and invasion of PC cells. In conclusion, this study reveals that HH signaling characteristics in PC and DCBLD2 regulate HH signaling to drive PC progression, providing new perspectives and theories for the diagnosis and treatment of PC.
Metabolic and Immune Adaptations in Preterm Neonates at Early Postnatal Period: Integrated Analysis of Key Metabolites and Pathways.
Li X, Gan Y, Tan L … +5 more , Lin Y, Zhou P, Wang J, Yang B, Tang Q
Hum Mutat · 2025 · PMID 41427027 · Full text
OBJECTIVE: This study was aimed at clarifying the unique metabolic alterations in preterm neonates, distinct from full-term neonates, between the first 24 and 48 h postnatally. METHODS: A cohort of 60 preterm and 60 full...
OBJECTIVE: This study was aimed at clarifying the unique metabolic alterations in preterm neonates, distinct from full-term neonates, between the first 24 and 48 h postnatally. METHODS: A cohort of 60 preterm and 60 full-term neonates was analyzed. The metabolomic profiles of plasma samples were determined using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Multivariate statistical analyses were employed to discern metabolic differences. Multiple machine learning models were constructed to further select key metabolites. Spearman's correlation analysis was performed to assess the correlation between neonatal immune cell subsets and key metabolites. RESULTS: The study revealed 70 specific metabolic alterations in preterm neonates during the early postnatal period. Then, 32 of these metabolites were jointly selected by the Top 5 machine learning models, which exhibited high predictive performance with an AUC > 0.9. Subsequent analyses including multivariable linear regression and ROC curve revealed 12 key metabolites significantly associated with gestational age. Correlation analyses exposed significant associations between immune cells and these metabolites. Integrated pathway analysis identified 10 key metabolic pathways involved in preterm neonates. NMR-based validation confirmed two of the 12 prioritized metabolites and six additional metabolites from the broader panel, supporting the robustness of our findings. CONCLUSION: Our findings provide insights into the metabolic and immune adaptation processes in preterm neonates during the early life stage. The correlations between immune cell subsets and the key metabolites highlight a potential effect of metabolism on immune adaptation in preterm neonates. These key metabolites and pathways could serve as potential biomarkers for early diagnosis and therapeutic strategies to enhance immune function and health outcomes in preterm infants.
Likely Pathogenic/Pathogenic Variants in the Spliceosome Complex Genes SNRNP200, SF3B1, SF3B2, and SF3B4 Implicated in Nonsyndromic Orofacial Cleft.
Ranji P, Pairet E, Helaers R … +5 more , Brouillard P, Bayet B, Gerdom A, Revencu N, Vikkula M
Hum Mutat · 2025 · PMID 41427026 · Full text
The genetic basis of nonsyndromic orofacial cleft (NsOFC) remains elusive, although associations have been identified with various genetic loci. NsOFC has a less pronounced genetic background than syndromic orofacial cle...
The genetic basis of nonsyndromic orofacial cleft (NsOFC) remains elusive, although associations have been identified with various genetic loci. NsOFC has a less pronounced genetic background than syndromic orofacial cleft (SyOFC), albeit Mendelian inheritance has been identified. Our hypothesis was that genes related to spliceosome function may contribute to NsOFC pathophysiology, as they do for some syndromic cases. Exome sequencing was conducted on 224 unrelated NsOFC probands. We performed filtering and analyses of predicted pathogenicity of rare variants using Highlander. We focused on 26 genes encoding spliceosome proteins. Subsequently, bioinformatic tools, such as AlphaFold, and PyMol, were applied to generate three-dimensional structures to interpret the effects of the identified variants on protein structure and interaction domains. We found six likely damaging variants: three heterozygous missense variants in small nuclear ribonucleoprotein U5 200 kDa subunit () in three multiplex NsOFC families, and two missense and one splice site variant in splicing factor 3b subunit 1 (), 4 (), and 2 () in two posterior CP families and a complete CP patient, respectively. These results suggest that variants in the spliceosome complex genes, observed in 2.7% of NsOFC cases in our cohort, may contribute to disease susceptibility as potential risk factors.
Stem Cell-Related Gene CALR as a Novel Prognostic Factor for Bladder Cancer: Implications for Immunotherapy.
Ling Z, He S, Li T … +3 more , Zhang J, Liu B, Ren M
Hum Mutat · 2025 · PMID 41427025 · Full text
Cancer stem cells (CSCs) are a unique category of cells located within tumors, characterized by their exceptional self-renewal abilities and capacity to differentiate into different types of tumor cells. These cells are...
Cancer stem cells (CSCs) are a unique category of cells located within tumors, characterized by their exceptional self-renewal abilities and capacity to differentiate into different types of tumor cells. These cells are crucial in processes such as tumor metastasis, recurrence, and resistance to treatment. Nevertheless, their particular roles in bladder urothelial carcinoma (BLCA) require deeper exploration. This investigation firstly assessed the relationships between genes associated with CSCs and both the prognostic outcomes and responses to immunotherapy in patients with BLCA using cluster analysis methods. Among the genes linked to stem cells, CALR was identified as the most notable prognostic marker by the XGBoost algorithm. Additionally, the study explored the correlation between CALR and immune cell infiltration, as well as its interaction with mitomycin using molecular docking methods. In vitro experiments further validated that CALR affects BLCA stem cells. Utilizing multiple machine learning approaches, this study identified 14 essential stem cell-associated genes, underscoring their significance for BLCA diagnosis and potential therapeutic targeting. Critically, CALR demonstrates a strong correlation with prognostic outcomes and immunotherapy responses in BLCA, consistent with experimental findings indicating its elevated expression in BLCA and association with poor prognosis. Laboratory investigations have demonstrated that reducing CALR expression can lessen the stemness features of BLCA. Our results highlight the critical role of genes related to stem cells in BLCA and identify CALR as a promising target associated with stem cell functionality.
Identification of Aging-Related Hub Genes (ATP11B, RBBP7, DOCK10, and NUP160) as Potential Biomarkers and Therapeutic Targets in Sepsis.
Sun X, Geng S, Wang Z … +1 more , Chen Q
Hum Mutat · 2025 · PMID 41394771 · Full text
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. This study investigated...
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. This study investigated the relationship between aging, immunity, and sepsis by analyzing six human aging-related gene sets (656 genes). We identified 16 aging-related differentially expressed genes (DEGs) in sepsis. Among these, ATP11B, RBBP7, DOCK10, and NUP160 demonstrated the strongest connectivity with other genes and exhibited significant predictive power. Functional enrichment analysis (GO and KEGG) revealed distinct signaling pathway profiles between high-risk and low-risk sepsis groups (stratified based on risk scores). These dysregulated pathways, associated with multiple immune cells, were primarily linked to transcriptional dysregulation in cellular processes and cancer-related pathways. Experimental validation assays corroborated the roles of ATP11B and RBBP7. Collectively, our bioinformatic and experimental findings indicate that ATP11B, RBBP7, DOCK10, and NUP160 are implicated in the pathogenesis and progression of sepsis. But their potential for sepsis biomarkers still requires further verification.
Integrative Transcriptomic and Machine Learning Analysis Identifies Key Senescence-Associated Secretory Phenotype Genes Associated With Immune Dysregulation in Periodontitis.
Zeng J, Huang J, He J … +4 more , Tan J, Duan M, Song Y, Yang L
Hum Mutat · 2025 · PMID 41377896 · Full text
Periodontitis (PD) is a chronic inflammatory disorder marked by immune dysregulation and progressive tissue destruction. Cellular senescence and the senescence-associated secretory phenotype (SASP) have been increasingly...
Periodontitis (PD) is a chronic inflammatory disorder marked by immune dysregulation and progressive tissue destruction. Cellular senescence and the senescence-associated secretory phenotype (SASP) have been increasingly recognized as pivotal drivers of chronic inflammation. However, their specific contributions to PD remain insufficiently clarified. In this study, integrative bioinformatic analyses were conducted across transcriptomic datasets, employing least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and eXtreme gradient boosting algorithms to identify SASP-related genes of significance. ICAM1, CXCL12, and MMP3 were found to be markedly upregulated in PD and demonstrated strong diagnostic potential through receiver operating characteristic and artificial neural network models. Functional enrichment analysis indicated their involvement in immune cell adhesion, migration, and infection-associated pathways. Immune infiltration profiling revealed disrupted immune landscapes, with ICAM1 exhibiting a negative correlation with resting mast cells. Experimental validation using real-time quantitative polymerase chain reaction and immunohistochemistry on clinical samples confirmed elevated expression of these genes at both the mRNA and protein levels. Moreover, dexamethasone was identified via molecular docking as a potential therapeutic compound targeting ICAM1 and CXCL12. Collectively, these findings advance the understanding of SASP associated with immune regulation in PD and suggest potential biomarkers and therapeutic targets for early diagnosis and intervention.
Whole Genome Sequencing Improves the Identification of Pathogenic and Novel Variation in Nonsyndromic Hearing Loss.
Rentas S, Rajagopalan R, Ayazseven T … +4 more , Sarmady M, Raible SE, Krantz ID, Abou Tayoun AN
Hum Mutat · 2025 · PMID 41367487 · Full text
BACKGROUND: Genetic testing is essential to the diagnosis of nonsyndromic bilateral sensorineural hearing loss (BSNHL), where pathogenic variants in are the most common cause. Current testing strategies often fail to pr...
BACKGROUND: Genetic testing is essential to the diagnosis of nonsyndromic bilateral sensorineural hearing loss (BSNHL), where pathogenic variants in are the most common cause. Current testing strategies often fail to provide a comprehensive diagnosis and typically require the use of multiple testing methodologies. This study evaluated the diagnostic utility of genome sequencing (GS) in a cohort with heterozygosity for pathogenic variants and BSNHL. METHODS: A retrospective cohort of 23 individuals with BSNHL and a heterozygous pathogenic variant in underwent targeted resequencing and variant reinterpretation. Those without biallelic variants upon single gene reanalysis proceeded to exome sequencing (ES) using a large virtual panel of hearing loss-associated genes. Subjects with no definitive diagnosis from ES subsequently underwent GS. Variants were interpreted using hearing loss-specific ACMG guidelines and published literature. RESULTS: Three individuals were diagnosed with biallelic pathogenic variants upon single gene reanalysis. ES identified a definitive or likely diagnosis in five different hearing loss-related genes in 5/20 (25%) individuals, while two additional cases remained inconclusive due to novel or ambiguous variants in two other hearing loss-associated genes. GS of the remaining 15 cases yielded diagnoses in three individuals, including the identification of deletions in and , and a recently characterized 125 kb deletion overlapping , which refines a critical upstream regulatory region associated with -related hearing loss. Overall, 11/23 (48%) individuals received a diagnosis with our stepwise testing approach, with GS providing sequencing coverage of all findings. CONCLUSION: GS improves diagnostic yield in patients with BSNHL, capturing both SNVs and CNVs missed by ES and targeted testing, and supports its adoption as a comprehensive first-tier diagnostic test for nonsyndromic hearing loss.
Insights Into the Pathological Glycosylation Associated With COG6-CDG.
Pakanová Z, Krchňák M, Nemčovič M … +19 more , Kodríková R, Ondrušková N, Štufková H, Giertlová M, Okáľová K, Stretavská P, Martineková S, Mezenská RZ, Urminská M, Škopková M, Andrésová A, Lysinová M, Belujská L, Šalingová A, Beke G, Račková L, Honzík T, Hansíková H, Baráth P
Hum Mutat · 2025 · PMID 41362306 · Full text
BACKGROUND AND AIMS: Congenital disorders of glycosylation (CDG) are rare diseases caused by defects in protein glycosylation. We present an infant with multisystemic clinical involvement, diagnosed with COG6-CDG. METHOD...
BACKGROUND AND AIMS: Congenital disorders of glycosylation (CDG) are rare diseases caused by defects in protein glycosylation. We present an infant with multisystemic clinical involvement, diagnosed with COG6-CDG. METHODS: Serum and transferrin-linked N-glycans, as well as serum and apolipoprotein CIII-linked O-glycans, were analyzed by MALDI mass spectrometry. Mutation analysis was performed by next-generation sequencing. Functional studies assessed COG6 subunit expression, cooperating subunits, and retrograde transport. GlycoWorks RapiFluor-MS-based N-glycan labeling with HPLC-FLD and ESI-Orbitrap mass spectrometry enabled further comprehensive glycoprofile analysis. RESULTS: Aberrant glycosylation typical of combined N- and O-glycosylation defects was detected. Mutation analysis identified a novel homozygous variant in the gene: c.906_907delinsA, p.(His302GlnfsTer4), introducing a premature stop codon and producing a truncated protein of only 304 amino acids. The diagnosis of COG6-CDG was confirmed by the complete absence of the COG6 subunit, impairment of two other cooperating subunits, and delayed retrograde transport. Independent glycoprofile analyses by HPLC-FLD and ESI-Orbitrap revealed a set of potential glycobiomarkers of COG6-CDG, including underprocessed N-glycans Hex3-5HexNAc2, Hex3-5HexNAc3, Hex3-4HexNAc4, and Hex4HexNAc3-4NeuAc1. CONCLUSION: This study describes a novel COG6 variant leading to complete loss of protein function and major glycosylation abnormalities. Multiomics analysis provided deeper insights into the molecular mechanisms of this rare disease and the function of the gene and demonstrated how the mutation results in significant alterations in the patient's (glyco)phenotype.
Reclassification of VUS Using ACMG/AMP Criteria Adapted for Sarcomeric Genes Related to Hypertrophic Cardiomyopathy: Resolution Rate and Considerations.
Caroselli S, Corona G, Fabiani M … +13 more , Manzoni M, Micolonghi C, Savio C, Germani A, Bragliola S, Maselli V, Rubattu S, Musumeci B, Tini G, Visco V, Petrucci S, Novelli V, Piane M
Hum Mutat · 2025 · PMID 41357762 · Full text
BACKGROUND: Genetic testing is valuable to confirm molecular diagnosis in nearly 60% of cases suspected of hypertrophic cardiomyopathy (HCM). However, the interpretation of variants, especially those of uncertain signifi...
BACKGROUND: Genetic testing is valuable to confirm molecular diagnosis in nearly 60% of cases suspected of hypertrophic cardiomyopathy (HCM). However, the interpretation of variants, especially those of uncertain significance (VUSs), remains challenging for laboratories and clinicians. In April 2024, the ClinGen Cardiomyopathy Variant Curation Expert Panel (VCEP) adapted the ACMG/AMP criteria for eight of the sarcomeric genes (, , , , , , , and ), providing a refined framework for variant interpretation in these genes. This retrospective study re-evaluated 69 VUSs identified in 84 HCM patients between 2017 and 2024, aiming to resolve uncertainty and reduce the VUS rate. METHODS: Here, two groups of curators reinterpreted variants with the most recent data using the Cardiomyopathy VCEP specifications until a consensus was reached. To streamline the process, we created a semiautomated decision support tool based on these gene-specific rules. RESULTS: The application of the Cardiomyopathy VCEP specifications resulted in the reclassification of 17.4% ( = 12/69, 95% CI: 10.2%-28.0%) of VUS, whereas the new data alone were not sufficient. Out of the reclassified variants, 91.7% ( = 11/12) were downgraded to benignity (involving 17 patients), and 8.3% were upgraded to pathogenicity (involving one patient), with a mean reclassification time of 68.3 months, corresponding to 5.7 years. The most applied criteria were related to population (PM2 = 55%; BA1/BS1 = 16%), bioinformatic prediction (PP3 = 45%; BP4 = 25%), and critical domains (PM1 = 21%). However, most codes suffer from a lack of evidence (segregation data, functional assays, and case-control studies). When comparing this curation with classifications in public databases, 13.3% ( = 8/60) and 16.2% ( = 11/68) of variants listed as having inconclusive significance in ClinVar and CardioClassifier were, respectively, reclassified in this study. CONCLUSION: Using gene-specific ACMG/AMP criteria reduces the rate of VUS, increasing diagnostic yield, and informing clinical management in the context of HCM. Nonetheless, ongoing efforts to generate evidence and promote standardization remain essential to improve variant interpretation.
Integrated Genomic and Functional Characterization of Palmitoylation in Clear Cell Renal Cell Carcinoma.
Zhang D, Zhang K, Deng M … +5 more , Ma J, Zhu J, Shen S, Xie J, Chen C
Hum Mutat · 2025 · PMID 41357761 · Full text
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly aggressive cancer with a poor prognosis. Palmitoylation, a posttranslational modification, plays a key role in regulating cancer progression and immune resp...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly aggressive cancer with a poor prognosis. Palmitoylation, a posttranslational modification, plays a key role in regulating cancer progression and immune responses. However, its influence on ccRCC prognosis and immune therapy efficacy remains underexplored. METHODS: Multiple publicly available ccRCC datasets were integrated and harmonized through batch effect correction. A prognostic model based on palmitoylation-related genes was constructed using a combination of 101 machine learning algorithms. Single-cell RNA sequencing was employed to analyze cellular heterogeneity within the tumor microenvironment. Genomic profiling, including tumor mutational burden (TMB), copy number variation (CNV), and tumor stemness, was conducted to identify genomic differences between the high- and low-risk groups. Immune infiltration levels were assessed using various algorithms to compare immune profiles across patient subgroups, while immune therapy responses were predicted using multiple prediction models. Experimental validation of ZDHHC18, a key gene in the prognostic model, was performed in ccRCC cell lines (786-O and Caki-1) to evaluate its impact on cell proliferation, migration, and invasion. RESULTS: The palmitoylation-related prognostic model effectively stratified ccRCC patients into the high- and low-risk groups, with distinct differences in survival outcomes. Genomic analysis demonstrated higher TMB and CNV alterations in the high-risk group. Immune response predictions indicated that low-risk patients were more likely to benefit from immunotherapy. Additionally, ZDHHC18 was significantly upregulated in ccRCC tumor tissues, and its knockdown notably inhibited cell proliferation, migration, and invasion. CONCLUSION: Palmitoylation-related genes, particularly ZDHHC18, serve as promising prognostic biomarkers and predictive indicators for immune therapy in ccRCC. These findings offer new insights into ccRCC biology and highlight potential therapeutic targets for improving patient outcomes.
Consensus Integration of Multiomics Data With Machine Learning Algorithms Reveals Heterogeneous Molecular Subtypes and Enables Personalized Treatment Strategies for Hepatocellular Carcinoma.
Jin Z, Fang K, Zhang X … +3 more , Song M, Jiang H, Liu Y
Hum Mutat · 2025 · PMID 41333555 · Full text
BACKGROUND: Cancers are characterized by high heterogeneity. This study seeks to identify the factors driving hepatocellular carcinoma (HCC) heterogeneity to aid in prognostic stratification and inform personalized treat...
BACKGROUND: Cancers are characterized by high heterogeneity. This study seeks to identify the factors driving hepatocellular carcinoma (HCC) heterogeneity to aid in prognostic stratification and inform personalized treatment approaches. METHODS: We used a computational pipeline to integrate multiomics data from HCC patients, applying 10 clustering algorithms. These results were combined with a machine learning framework to identify high-resolution molecular subtypes (MSs) and to create a robust molecular subtype-related risk score (MSRRS). Subsequent integrated bioinformatics algorithms further analyzed the heterogeneity of HCC at the level of molecular pathways, therapeutic response, and tumor microenvironment, thereby assessing potential clinical value. RESULTS: Through multiomics clustering, we identified two heterogeneous MSs associated with prognosis, with MS2 exhibiting a more favorable prognostic outcome. Subsequently, we applied bootstrap resampling-based univariate Cox regression and Boruta algorithm to screen for more clinically relevant genes from the marker genes of each MS. Next, we benchmarked seven survival-related machine learning algorithms for overall survival (OS) using nested cross-validation. The hyperparameter-tuned Ridge survival model outperforms other tuned models and was therefore used to develop a robust MSRRS. MSRRS demonstrated superior performance in predicting patient OS in multiple independent HCC cohorts. Downstream analysis suggested that MSRRS has the potential to guide individualized targeted therapy, chemotherapy, and immunotherapy for HCC and to assess the tumor microenvironment. Pathway enrichment analysis identified the cell cycle as a crucial driver of heterogeneity differences between the two subtypes. Finally, we confirmed that KIF2C may be the most central MSRRS gene and demonstrated by in vitro experiments that KIF2C could promote G2/M transition in HCC cells by targeting CDK1/CCNB1/PLK1 signaling. CONCLUSION: The novel MSs and robust MSRRS we identified effectively exposed the heterogeneity of HCC and have the potential to predict prognosis and guide individualized precision therapy.
The Role of Key Glycolytic Enzymes in the Diagnosis, Treatment, and Immune Microenvironment of Colorectal Cancer.
Gu H, Liu C, Cai E … +2 more , Cao Y, Liu J
Hum Mutat · 2025 · PMID 41311582 · Full text
Colorectal cancer is acknowledged as the fifth most common cause of cancer-related mortality, presenting significant challenges for patient outcomes due to its relatively gradual progression and the subtle nature of its...
Colorectal cancer is acknowledged as the fifth most common cause of cancer-related mortality, presenting significant challenges for patient outcomes due to its relatively gradual progression and the subtle nature of its initial symptoms. Carbohydrates, essential nutrients in cellular function, participate in various metabolic processes, including glycolysis, oxidative phosphorylation, and the pentose phosphate pathway. Recent studies have established that irregularities in carbohydrate metabolism play a critical role in tumor cell growth, development, and treatment resistance. Glycolysis serves as a crucial regulatory component of metabolism in cancer cells, influencing cell growth, proliferation, and functionality by modifying carbohydrate utilization. By diminishing oxidative phosphorylation activity and enhancing energy production through glycolysis, tumor cells augment their proliferative capacity and partially evade immune responses. As a result, glycolysis significantly contributes to tumor progression. We have comprehensively outlined the functions of glycolysis and its key enzymes concerning the diagnosis, treatment strategies, and immune microenvironment of colorectal cancer, with the goal of delivering innovative insights and perspectives for the clinical management and diagnosis of this condition.
The Role of Inflammatory Factors in the Pathogenesis of Gestational Diabetes Mellitus and May Be Potential Biomarkers for Its Diagnosis and Prognosis.
Guo Y, Zheng X, Jiao J … +2 more , Wu H, An Y
Hum Mutat · 2025 · PMID 41293068 · Full text
BACKGROUND: The biomarkers associated with gestational diabetes mellitus (GDM) remain incompletely understood. This article is aimed at investigating whether inflammatory factors may contribute as risk factors for GDM. M...
BACKGROUND: The biomarkers associated with gestational diabetes mellitus (GDM) remain incompletely understood. This article is aimed at investigating whether inflammatory factors may contribute as risk factors for GDM. METHODS: The study included 160 adult patients with GDM, who were enrolled as the experimental group. Additionally, 280 healthy individuals from the same time period were selected as the control group. Cytokine expression levels were measured using a flow cytometer with fluorescence, while gene polymorphisms were analyzed through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The cytokines examined included interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-), and interferon-gamma (IFN-). RESULTS: Significantly higher expression levels of IL-1, IL-6, IL-10, and TNF- were detected in GDM patients ( < 0.05). Additionally, the study identified specific polymorphisms-IL-1 -511 C/T, IL-10 -1082 G/A, IL-6 -174 G/C, and TNF- -308 G/A-that were significantly associated with an increased risk of GDM ( < 0.05). IL-6, TNF-, and IL-1 levels significantly differed among genotypes of IL-6 -174 G/C, TNFA -308 G/A, and IL-1B -511 C/T, respectively ( < 0.01), with risk-associated alleles linked to higher cytokine expression. No significant differences were observed for IL-10 -1082 G/A or IFN- +874 A/T. These results suggest that select polymorphisms may regulate cytokine levels relevant to GDM inflammation. CONCLUSION: Elevated plasma levels of IL-1, IL-6, IL-10, and TNF- have been observed in patients with GDM. Furthermore, polymorphisms such as IL-1 -511 C/T, IL-6 -174 G/C, IL-10 -1082 G/A, IFN- +874 A/T, and TNF- -308 G/A show a strong correlation with an increased risk of GDM in the Han women from northern China (specifically, Hebei Province). Pregnant women with ACC haplotypes of IL-10 have a lower risk of GDM. Cytokine gene polymorphisms in IL-6, TNF-, and IL-1B are associated with altered inflammatory profiles in GDM, suggesting a genetic contribution to disease-related immune dysregulation. Our study suggests that these factors hold potential as biomarkers for the diagnosis and clinical prognosis of GDM in Han women from northern China (Hebei Province).
BST2 Drives Epithelial Ovarian Cancer Progression via Macrophage M2 Polarization, Neural Remodeling, and Immunosuppressive Microenvironment Formation.
Zhang L, Huang X, Wang S … +4 more , Chen S, Wang J, Chen L, Sun P
Hum Mutat · 2025 · PMID 41281378 · Full text
BACKGROUND: Epithelial ovarian cancer (EOC) ranks as the most lethal of gynecological cancers. Despite advances in therapeutic interventions that have marginally extended survival rates, the early detection and managemen...
BACKGROUND: Epithelial ovarian cancer (EOC) ranks as the most lethal of gynecological cancers. Despite advances in therapeutic interventions that have marginally extended survival rates, the early detection and management of EOC pose significant hurdles. Consequently, identifying novel therapeutic targets is imperative for enhancing the survival outcomes of patients afflicted with this malignancy. PURPOSE: This research is aimed at exploring the functions of Bone Marrow Stromal Antigen 2 (BST2) in the pathogenesis of EOC and their influence on macrophage polarization, evaluating their viability as targets for immunotherapy. METHODS: Gene expression profiles and clinical data of EOC patients were retrieved from the TCGA repository to develop prognostic models centered on BST2. The expression patterns of BST2 in HGSOC cell lines were quantified via RT-qPCR and Western blot analyses. The impact of BST2 on the proliferative, migratory, and invasive capacities of EOC cells was assessed through gene silencing and gene overexpression experiments. RESULTS: Elevated levels of BST2 expression were observed in EOC tissues, correlating with adverse prognostic indicators. Enhanced BST2 expression facilitated EOC cell growth, motility, and invasiveness, whereas BST2 suppression mitigated these oncogenic attributes. In vivo assessments revealed that BST2 augmentation modified the macrophage phenotypes within grafted ovarian tumors, with BST2 diminution reversing these effects. CONCLUSION: The findings propose that BST2 acts as a pivotal facilitator in the progression of ovarian carcinoma. The expression metrics of BST2 may serve as prognostic markers for patient outcomes in EOC. These findings suggest that BST2 is a key promoter of ovarian cancer progression, and its expression may serve as a prognostic marker. The mechanisms uncovered, including the modulation of macrophage polarization and neural marker expression, indicate that targeting BST2 represents a potential future strategy for immunotherapy in EOC.
Integrated Analysis of Single-Cell RNA Sequencing and Machine Learning Reveals a T Cell-Specific PANoptosis Signature Predicting Prognosis and Immunotherapy in Prostate Cancer.
Wang H, Li W, Deng W … +3 more , Wu J, Li K, Huang X
Hum Mutat · 2025 · PMID 41281377 · Full text
BACKGROUND: Prostate cancer (PCa) ranks among the most prevalent malignancies, with prognosis heavily influenced by diagnostic stage. The role of PANoptosis in T cell-based immunotherapy has garnered growing attention re...
BACKGROUND: Prostate cancer (PCa) ranks among the most prevalent malignancies, with prognosis heavily influenced by diagnostic stage. The role of PANoptosis in T cell-based immunotherapy has garnered growing attention recently. This study is aimed at establishing a T cell-specific PANoptosis signature (TSPS) to predict prognosis and immunotherapy response in patients with PCa. METHODS: Single-cell RNA sequencing (scRNA-seq) data from the GSE185344 dataset were used to identify T cell-specific genes. A comprehensive machine learning pipeline incorporating 10 distinct algorithms was employed to construct a consensus prognostic TSPS. RESULTS: The scRNA-seq analysis identified T cells as the predominant cell type, and cell-cell communication analysis indicated heightened activation of specific immune-related signaling pathways in PCa. A consensus prognostic signature comprising nine key genes was developed, demonstrating superior predictive accuracy for clinical outcomes compared to conventional clinical variables. A TSPS-based nomogram was also constructed, displaying strong predictive capability for survival outcomes in patients with PCa. Patients in the high-risk group exhibited greater intratumor heterogeneity, increased immune infiltration, and higher immunosuppression scores, suggesting reduced immunotherapy benefits. Validation with four independent immunotherapy cohorts verified that patients in the low-risk group exhibited more favorable immunotherapy responses. Additionally, 18 compounds were determined as therapeutic options for high-risk patients with PCa. In vitro experiments demonstrated that expression was upregulated in PCa, and knockdown significantly inhibited PCa cell proliferation and invasion. CONCLUSION: We established a consensus prognostic TSPS for PCa, offering a potential foundation for future personalized approaches in risk stratification, prognostic evaluation, and treatment selection for patients with PCa.
, , and Are Identified as Shared Druggable Immune-Regulatory Axis in Atrial Fibrillation and Atherosclerosis Through Integrative In Silico and In Vitro Analysis.
Zheng H, Yang L, Zhu P … +1 more , Lin Y
Hum Mutat · 2025 · PMID 41262879 · Full text
BACKGROUND: Atrial fibrillation (AF) and atherosclerosis (ATH) are increasingly recognized as interconnected cardiovascular conditions with shared immune and inflammatory underpinnings. However, the molecular mechanisms...
BACKGROUND: Atrial fibrillation (AF) and atherosclerosis (ATH) are increasingly recognized as interconnected cardiovascular conditions with shared immune and inflammatory underpinnings. However, the molecular mechanisms linking their pathogenesis remain poorly defined. METHODS: A multiplatform transcriptomic analysis was conducted using publicly available microarray datasets for AF and ATH. Differentially expressed genes (DEGs) were identified using linear modeling and batch correction. A total of 29 overlapping DEGs were found between AF and ATH, from which five immune-related DEGs were identified using the ImmPort database. LASSO regression selected three genes, that is, , and , as optimal immune-regulatory hub genes. Functional enrichment, drug-target interaction profiling, transcriptional regulatory network modeling, immune infiltration estimation, and single-cell RNA-seq analysis were conducted using R-based pipelines, DGIdb, iRegulon, CIBERSORTx, ImmuCellAI, and CellChat. To experimentally validate their regulatory role in AF, in vitro assays were performed using angiotensin II-treated mouse cardiac fibroblasts (MCFs). Gene-specific knockdown was achieved via siRNA transfection, followed by RT-qPCR, western blotting, colony formation, wound healing, and proliferation assays using Thermo Fisher-validated kits and reagents. RESULTS: Transcriptomic pathway enrichment revealed strong involvement of MAPK signaling, phosphatase regulation, and T cell immunomodulatory pathways. Drug-gene interaction analysis identified four immune DEGs as druggable targets. Transcription factor regulatory modeling identified nine TFs converging on , , and . Immune deconvolution analysis revealed macrophage and dendritic cell enrichment in both conditions, with broader immune remodeling in AF. Single-cell RNA-seq localized , , and to T cells, macrophages, and fibroblasts, with divergent intercellular signaling inferred via CellChat. In vitro, siRNA-mediated knockdown of , , and in Ang II-stimulated cardiac fibroblasts significantly suppressed their expression and attenuated fibroblast activation, while knockdown showed supporting effects showing the pathogenic relevance of the core immune-regulatory axis in AF-ATH. CONCLUSION: This integrative study identifies , , and as shared immune-regulatory genes in AF and ATH, with transcriptomic and in vitro evidence supporting their pathogenic role and potential as dual-disease therapeutic targets.
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