Hum. Mutat. [JOURNAL]
Sun
200 papers
Novel and Variants in Sitosterolemia: Insights Into Haemolysis, Calcium Dysregulation and Therapeutic Challenges.
Warang P, Dongerdiye R, Dehadrai P … +5 more , Kamble P, Samanpalliwar N, Madkaikar M, Shanmukhaiah C, Kedar PS
Hum Mutat · 2026 · PMID 42111500 · Full text
Sitosterolemia is a rare autosomal recessive lipid metabolic disorder caused by mutations in or , leading to pathological accumulation of dietary plant sterols. The condition is clinically heterogeneous, presenting with...
Sitosterolemia is a rare autosomal recessive lipid metabolic disorder caused by mutations in or , leading to pathological accumulation of dietary plant sterols. The condition is clinically heterogeneous, presenting with xanthomas, premature atherosclerosis and haematological abnormalities such as stomatocytosis, haemolytic anaemia and thrombocytopenia, making diagnosis particularly challenging. We investigated four patients with unexplained inherited haemolytic anaemia and a history of recurrent transfusions to identify molecular and functional mechanisms and explore therapeutic options. Haematological work-up, including CBC, peripheral smear, reticulocyte count, EMA binding assay, red cell enzyme activity and HPLC for haemoglobinopathies, was performed, along with biochemical assays for liver, renal and lipid function. Plasma sterol levels were quantified using GC-MS, whereas functional assays included intracellular calcium flux under osmotic stress, red cell density profiling and ROS measurement. Whole-exome sequencing identified homozygous nonsense variants: a novel (p.Trp584∗) in two siblings, (p.Arg243∗) in one patient and (p.Ser129∗) in another. Two patients showed markedly elevated plasma phytosterols, predominantly stigmasterol and -sitosterol. Ezetimibe therapy (10 mg/day for 6 months) effectively reduced sterol levels but failed to normalise haemoglobin or significantly reduce overhydrated red cell populations. Functional studies demonstrated elevated intracellular Ca, enhanced influx under stress, increased ROS and a persistent population of stomatocytes. In silico prediction tools confirmed the pathogenicity of the identified variants. Persistent haemolysis despite sterol-lowering therapy suggests irreversible red cell membrane damage due to sterol incorporation, altered fluidity, oxidative stress and calcium dysregulation. Our findings indicate that combining ezetimibe with Ca-modulating therapy may represent a novel strategy to reduce haemolysis in sitosterolemia.
Identification of Two Novel Variants in and Genes in the Chinese Population With Hereditary Congenital Cataracts Using Whole Exome Sequencing.
Zhuang J, Huang N, Chen YE … +4 more , Lou H, Wang J, Fu W, Chen C
Hum Mutat · 2026 · PMID 42111499 · Full text
BACKGROUND: Genetic variants are the leading cause of congenital cataract (CC). To date, numerous genes have been implicated in the development of CC. The objective of the present study was to report two previously unrec...
BACKGROUND: Genetic variants are the leading cause of congenital cataract (CC). To date, numerous genes have been implicated in the development of CC. The objective of the present study was to report two previously unrecognized gene variants associated with CC in two unrelated Chinese families, identified through whole exome sequencing (WES). METHODS: Two unrelated Chinese families affected by CC were recruited. Cytogenetic and molecular genetic analyses were performed using karyotyping, chromosomal microarray analysis (CMA), and WES. In addition, RNA sequencing was conducted to assess differentially expressed genes in affected individuals compared with healthy controls. RESULTS: Karyotype and CMA elicited none of chromosome abnormalities in both of the families. However, WES revealed a novel missense variant NM_006891.4:c.154 T > C(p.S52P) in the gene in the proband of Family 1, which was inherited from her mother with CC. In Family 2, a novel frameshift variant NM_000276.4:c.1046dup(p.M349Ifs∗36) in the gene was identified in the fetus via WES, which was inherited from the mother who had CC. RNA sequencing further demonstrated significantly reduced mRNA expression in the fetus compared with age-matched controls. CONCLUSION: The present study reports, for the first time, two novel variants in and that were identified in the Chinese families with CC. These findings may expand the mutational spectrum of CC and highlight the utility of WES for the genetic diagnosis of patients with CC.
A Cuproptosis-Glycolysis Signature Predicts Prognosis and Highlights AURKA as a Therapeutic Target in ccRCC.
Ma CY, Zhang MX, Tan HT … +4 more , Sun CH, Sun SZ, Liu P, Wang JF
Hum Mutat · 2026 · PMID 42111498 · Full text
Cuproptosis, a recently identified form of cell death, is closely linked to glycolysis; however, the mechanistic interplay between these processes in clear cell renal cell carcinoma (ccRCC) remains to be fully elucidated...
Cuproptosis, a recently identified form of cell death, is closely linked to glycolysis; however, the mechanistic interplay between these processes in clear cell renal cell carcinoma (ccRCC) remains to be fully elucidated. Utilizing data from the TCGA and CPTAC databases, we developed and validated a cuproptosis-glycolysis-related gene (CuG) scoring model to investigate its associations with clinical outcomes, tumor immune infiltration, immunotherapy response, and drug sensitivity. Our analysis established a robust 10-gene risk model with significant prognostic value that effectively stratifies ccRCC patients into distinct high- and low-risk groups exhibiting marked differences in clinical profiles and therapeutic responses. Through integrated bioinformatic analyses alongside in vitro and in vivo experimental validation, we identified AURKA as a key functional regulator within this signature. Beyond promoting tumor cell proliferation, migration, and invasion, AURKA may have a significant role in modulating antitumor immunity. Collectively, by establishing a clinically applicable prognostic scoring system and nominating AURKA as a potential therapeutic target, our study offers translational implications for treatment decision-making in ccRCC.
Multiomics Characterization of GCSH + Macrophages Reveals Therapeutic Vulnerabilities and Immune-Metabolic Crosstalk in Triple-Negative Breast Cancer.
Ge J, Chen T, Ma Y … +1 more , Wei S
Hum Mutat · 2026 · PMID 42111497 · Full text
BACKGROUND: Tumor-associated macrophages (TAMs) are key regulators of immune homeostasis within the tumor microenvironment (TME) and play critical roles in malignant progression. However, the molecular mechanisms linking...
BACKGROUND: Tumor-associated macrophages (TAMs) are key regulators of immune homeostasis within the tumor microenvironment (TME) and play critical roles in malignant progression. However, the molecular mechanisms linking macrophage metabolic remodeling to immune regulation remain incompletely understood. Glycine cleavage system H protein (GCSH), a core regulator of copper-dependent cell death, has been implicated in metabolic regulation in triple-negative breast cancer (TNBC), suggesting a potential role in macrophage-mediated TME remodeling. METHODS: We integrated single-cell RNA sequencing and spatial transcriptomic data from TNBC tissues to systematically characterize macrophage subpopulations with high GCSH expression. Pseudotime trajectory analysis, cuproptosis-related scoring, cell-cell communication inference, metabolic pathway enrichment, and spatial localization analyses were performed to delineate their functional heterogeneity and microenvironmental context. In addition, mutation profiling, immunogenomic analysis, drug sensitivity prediction, and in vitro and in vivo functional experiments were conducted to comprehensively evaluate the biological and therapeutic relevance of GCSH. RESULTS: GCSH expression was predominantly enriched in macrophages, particularly in early activated subsets, and was associated with enhanced amino acid and lipid metabolic activity. GCSH + macrophages exhibited extensive interactions with T cells via pathways such as MIF-CD74-CXCR4 and LGALS9-CD45, contributing to an immunosuppressive, tumor-promoting microenvironment. Spatial analysis revealed their preferential localization at the tumor core-stroma interface. Notably, GCSH missense mutations were associated with increased M1 macrophage infiltration and enrichment of immune and inflammatory pathways. Clinically, high GCSH expression correlated with poor survival, genomic instability, and chemotherapy resistance. Functional experiments demonstrated that GCSH silencing suppressed tumor cell proliferation, migration, and clonogenicity, induced apoptosis, enhanced proinflammatory cytokine secretion, and significantly inhibited tumor growth in vivo. CONCLUSION: GCSH acts as a central molecular link between macrophage metabolic reprogramming, immune suppression, and TNBC progression, highlighting its potential as both a prognostic biomarker and therapeutic target.
FBXW7-Related Neurodevelopmental Disorder: Clinical Spectrum, Molecular Mechanisms, and Tumor Predisposition.
Savasta S, Comisi FF, Fiumicelli E … +6 more , Dell'Isola GB, Di Pasquale G, Mangano GD, Zagaroli L, Salpietro V, Verrotti A
Hum Mutat · 2026 · PMID 42111496 · Full text
F-box and WD repeat domain-containing 7 () encodes the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, where it regulates proteasome-mediated degradation of key cell cycle and deve...
F-box and WD repeat domain-containing 7 () encodes the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, where it regulates proteasome-mediated degradation of key cell cycle and developmental proteins. The aim of this review is to provide a comprehensive overview of the currently available evidence on the clinical and molecular features of -related neurodevelopmental disorder (NDD). While somatic mutations in are well-established drivers of human tumors, germline variants have only recently been linked to a distinctive neurological disorder. Reported germline variants include missense, frameshift, splice-site, and larger structural variants, with the majority clustering in the WD40 domain and disrupting substrate recognition. Functional studies confirm impaired degradation of critical regulators such as cyclin E, MYC, and NOTCH1. Clinically, affected individuals present with early developmental delay, hypotonia, and impaired language acquisition, frequently accompanied by structural brain anomalies, craniofacial dysmorphisms, and variable growth abnormalities. Additional manifestations include congenital anomalies and broad gastrointestinal involvement. Wilms tumor (WT) has been reported in a few individuals carrying germline or constitutional mosaic variants, with evidence of a second somatic hit documented in tumor tissue, supporting a rare but biologically plausible role of this gene in determining WT predisposition.
Variant Curation of the Largest Compendium of Coding and Noncoding Sequence and Structural Variants in BPES.
Matton C, Van De Velde J, De Bruyne M … +19 more , Van De Sompele S, Hooghe S, Syryn H, Bauwens M, D Haene E, Dheedene A, Cools M, Komatsuzaki S, Preizner-Rzucidło E, Ross A, Armstrong C, Watkins W, Shelling A, Vincent AL, Cassiman C, Vermeer S, Bunyan DJ, Verdin H, De Baere E
Hum Mutat · 2026 · PMID 42100494 · Full text
Heterozygous (non)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely p...
Heterozygous (non)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely penetrant eyelid malformation and incompletely penetrant primary ovarian insufficiency (POI). We collected variants from our in-house database, generated via clinical genetic testing and downstream research testing in the Center for Medical Genetics Ghent, Belgium (2001-2024) and via literature and other resources in the same period. All retrieved variants were categorized using ACMG/AMP classifications to increase the knowledge of pathogenicity. We collected 413 unique genetic defects of the region, including 76 novel variants, in 864 index patients. Of these, 87% of patients were identified with a coding sequence variant. The polyalanine tract is a known mutational hotspot of , illustrated here by the high percentage of pathogenic polyalanine expansions (24%). Furthermore, the molecular spectrum in typical BPES index patients is characterized by 8% coding deletions and 3% deletions located up- and downstream of . The remaining 2% carry translocations along with chromosomal rearrangements of 3q23. This uniform and structured reclassification, incorporating the largest dataset of variants implicated in -associated disease so far, will improve both the diagnosis as well as genetic counselling for individuals with BPES.
A Homozygous Frameshift Mutation in Leads to Female Infertility.
Yang J, Yang L, Yan B … +7 more , Li H, Zhang L, Hu T, Chao X, Zhang C, Ni Y, Wang Z
Hum Mutat · 2026 · PMID 42100493 · Full text
Primary infertility affects 15% of couples worldwide, yet many genetic causes remain unknown. Through whole-exome sequencing of a woman with primary infertility and repeated embryo implantation failure, we identified a n...
Primary infertility affects 15% of couples worldwide, yet many genetic causes remain unknown. Through whole-exome sequencing of a woman with primary infertility and repeated embryo implantation failure, we identified a novel homozygous frameshift mutation in (c.5364delC, p.Ala1789Argfs∗42). Sanger sequencing confirmed heterozygous carrier status in both parents. Functional studies demonstrated the absence of nonsense-mediated mRNA decay but abnormal protein expression via western blotting. Computational modeling predicted pathogenic structural alterations. This variant is absent in gnomAD/ExAC databases. Our findings establish mutations as a novel cause of female infertility, highlighting its role in endometrial receptivity regulation.
Deubiquitination of ETV4 by USP7 Promotes NSCLC Tumorigenesis via MAPK7 Activation.
Meng X, Zhang J, Zhang N … +8 more , Hou Y, Li Y, Kang J, Li R, Shi Y, Wang J, Cheng L, Xing L
Hum Mutat · 2026 · PMID 42100492 · Full text
Transcriptional dysregulation in cancer is accompanied by an anabolic transcriptional response driving proliferation and metabolic adaptation. We previously found that oncogenic ETS variant transcription factor 4 (ETV4)...
Transcriptional dysregulation in cancer is accompanied by an anabolic transcriptional response driving proliferation and metabolic adaptation. We previously found that oncogenic ETS variant transcription factor 4 (ETV4) overexpression is associated with DNA replication, glycolytic metabolism, tumor progression, and poor prognosis in non-small cell lung cancer (NSCLC). ETV4 is markedly overexpressed in multiple NSCLC datasets, including TCGA-LUAD and TCGA-LUSC. Importantly, ETV4 expression positively correlates with ubiquitin-specific protease 7 (USP7) and mitogen-activated protein kinase 7 (MAPK7) levels. While the E3 ligase constitutive photomorphogenesis protein 1 (COP1) is known to regulate ETV4 ubiquitination and degradation, ETV4 deubiquitination remains unclear. Our study reveals that USP7 deubiquitinates ETV4 and protects it from K11- and K48-linked ubiquitination and proteasomal degradation in NSCLC cells. ETV4 transcriptionally controls the expression of the MAPK pathway key gene MAPK7, which encodes extracellular signal-regulated kinase 5 (ERK5), and participates in the regulation of cell proliferation. Genetic knockdown or pharmacological inhibition of USP7 affects the transcriptional activity of ETV4 on its target gene MAPK7/ERK5. USP7 inhibitor P22077 significantly attenuates ETV4-MAPK7-induced cell proliferation in vitro and tumor growth in vivo. Furthermore, elevated ETV4, USP7, and ERK5 protein expressions are associated with poor prognosis of NSCLC patients. These findings identify that USP7 regulates the deubiquitination, stability, and transcriptional activity of ETV4, contributing to the malignant phenotype of ETV4. Inhibition of USP7 might be a promising target in NSCLC with the dysregulation of ETV4 or hyperactivated MAPK signaling.
Construction of a Diagnostic Model and Drug Prediction for Postischemic Stroke Cognitive Impairment Based on Machine Learning Screening of Lactate Metabolism- and Pyroptosis-Related Genes.
Ge S, Zhang Q, Liu N … +3 more , Zheng X, Xu H, Zhang L
Hum Mutat · 2026 · PMID 42100491 · Full text
Reliable molecular biomarkers for poststroke cognitive impairment (PSCI) remain limited. Using publicly available bulk transcriptomic and single-cell RNA-seq datasets from GEO, we investigated lactate metabolism- and pyr...
Reliable molecular biomarkers for poststroke cognitive impairment (PSCI) remain limited. Using publicly available bulk transcriptomic and single-cell RNA-seq datasets from GEO, we investigated lactate metabolism- and pyroptosis-related signatures and developed a diagnostic model. Differential expression analysis, KEGG pathway enrichment, and weighted gene coexpression network analysis (WGCNA) were performed, followed by multialgorithm feature selection (LASSO, SVM-RFE, and random forest). A logistic regression classifier was trained in the discovery cohort and externally validated in an independent cohort. Glycolysis/lactate metabolism, HIF-1 signaling, and NOD-like receptor-related pathways were enriched in PSCI-associated samples, and key coexpression modules were strongly correlated with ischemic injury traits. Cross-model consensus identified LDHA, GSDMD, and CASP1 as hub genes, yielding an AUC of 0.912 (95% bootstrap CI: 0.841-0.983) in the training cohort and 0.885 (95% bootstrap CI: 0.798-0.972) in the validation cohort. Immune deconvolution and scRNA-seq validation suggested increased proinflammatory microglia-associated signals, with relatively higher LDHA expression in microglia than in neurons; cell-cell communication analysis highlighted inflammatory interactions including IL1B-IL1R1. Connectivity map (CMap) analysis nominated candidate compounds, and molecular docking predicted favorable binding between oxamate and LDHA (binding energy = -9.5 kcal/mol). Collectively, these findings propose a compact LDHA/GSDMD/CASP1 biomarker panel for PSCI diagnosis and provide hypothesis-generating therapeutic leads that warrant further experimental validation.
Identification of a Germline Mutation in Patients With Gastrointestinal Cancers.
Xu GX, Zhang H, Wang CX … +8 more , Zhang YZ, Lv PP, Feng C, Ning Y, Shen M, Zhang S, Jin M, Yu DQ
Hum Mutat · 2026 · PMID 42094237 · Full text
BACKGROUND: Gastrointestinal (GI) cancers can be attributed to the interplay between genetic and environmental factors. To date, apart from certain cancer syndromes, the genetic factors underlying familial GI cancers hav...
BACKGROUND: Gastrointestinal (GI) cancers can be attributed to the interplay between genetic and environmental factors. To date, apart from certain cancer syndromes, the genetic factors underlying familial GI cancers have not been clearly elucidated. METHODS: Blood samples were collected from six members of a family with GI cancer for whole exome sequencing to identify suspicious germline mutations. Subsequently, 148 patients with GI cancers (including esophageal and gastric cancers) and 283 cancer-free patients were recruited. The frequency of the suspected mutations in both groups was determined using Sanger sequencing. Furthermore, immunofluorescence (IF) assays for XAF1 protein expression were performed in paraffin-embedded surgically resected tumor tissues from patients with GI cancer, with or without the mutation. RESULTS: In a family with GI cancer, we identified a mutation of (c.454+1372G>A), which is a nonsense mutation in Exon 4b that results in a truncated XAF1 Isoform 5. Sanger sequencing of sporadic cancer patients and cancer-free populations further verified that the frequency of this mutation was enriched in patients with GI cancer. Additionally, IF assays revealed that XAF1 protein expression was lower in the mutated group than in the nonmutated group. CONCLUSION: Our study provides evidence that a mutation (c.454+1372G>A) leads to repressed expression of XAF1 and is associated with a predisposition to GI tumorigenesis, especially in esophageal and gastric cancers.
rs1385129G>A Raised the Risk and Poor Prognosis of Lung Cancer: A Case-Control Study.
Li Z, Wang D, Chen J … +8 more , Wu D, Tang S, Huang J, Deng Y, Wang X, Qiu F, Yang L, Lu J
Hum Mutat · 2026 · PMID 42094236 · Full text
BACKGROUND: Energy metabolism reprogramming of cancer cells with the abnormal glycolytic capacity represents a novel direction of tumor therapy. Nevertheless, there is a lack of evidence linking genetic variations in gly...
BACKGROUND: Energy metabolism reprogramming of cancer cells with the abnormal glycolytic capacity represents a novel direction of tumor therapy. Nevertheless, there is a lack of evidence linking genetic variations in glycolysis-related genes to the risk and clinical progression of lung cancer (LC). This study is aimed at clarifying the genetic effect of glycolytic pathway-related genes on the occurrence and development of LC. METHODS: In this two-stage case-control study, we enrolled 300 LC patients and 600 healthy controls, as well as 1248 case-control pairs from several hospitals in Guangzhou, to evaluate the association between the genetic variations of glycolysis-related genes ( rs1385129G>A, rs6003939A>C, rs1484180G>A and rs11064467C>T) and the risk of LC. Follow-up data and the TCGA database were used to evaluate the relationship between rs1385129G>A and expression with the clinical progression of LC. RESULTS: Only rs1385129G>A was found to be associated with increased risk of LC in this two-stage case-control study ( < 0.05). Further analysis of the expression levels of in rs1385129G>A genotypes showed that they were positively correlated with the number of A alleles ( < 0.01), and the GA genotype had a moderate effect on expression, whereas the AA genotype had a strong effect (GA vs. GG: Cohen's = 0.768, 95 CI = 0.20-1.02; AA vs. GG: Cohen's = 1.890, 95 CI = 0.93-3.57). The results were further verified by eQTL analysis based on the GTEx database. The GA and AA genotypes were associated with worse prognosis in LC compared with the GG genotype, as determined by Cox regression (GA + AA vs. GG: HR = 1.37, 95 CI = 1.20-1.57). Furthermore, the survival curve of LC plotted using the GEPIA website showed that the group with high expression of had an increased risk of poor prognosis compared with the low (Log-rank < 0.01; HR = 1.40). The same result was obtained from the Kaplan-Meier Plotter database (Log-rank < 0.01; HR = 1.34). CONCLUSION: Altogether, rs1385129G>A may increase the risk of LC and contribute to a poor prognosis by upregulating expression.
A Single-Cell Multiomics Pipeline Maps YBX1 as a Functional Biomarker for Immune Evasion and Therapeutic Resistance in Prostate Adenocarcinoma.
Luo C, Lin D, Yang J … +2 more , Cui K, Chen Z
Hum Mutat · 2026 · PMID 42087896 · Full text
Translating high-resolution multiomics data into clinically actionable biomarkers is critical for overcoming therapeutic resistance and tumor heterogeneity in prostate adenocarcinoma (PRAD). To decode the complex immunos...
Translating high-resolution multiomics data into clinically actionable biomarkers is critical for overcoming therapeutic resistance and tumor heterogeneity in prostate adenocarcinoma (PRAD). To decode the complex immunosuppressive tumor microenvironment (TME) and identify robust prognostic targets, we developed a systematic biomarker discovery pipeline integrating single-cell RNA sequencing (scRNA-seq) mapping and high-dimensional network analysis. By deconvoluting scRNA-seq profiles from over 35,000 PRAD cells, nonnegative matrix factorization (NMF) of the malignant epithelial compartment revealed nine distinct transcriptional metaprograms (MPs). High-dimensional weighted gene coexpression network analysis (hdWGCNA) pinpointed PRAD-MP7 as the core proliferative engine and nominated the malignant-specific gene YBX1 as the master prognostic hub. To establish clinical utility evidence, we validated YBX1 across six independent global PRAD cohorts, where its overexpression robustly predicted poor overall survival (OS) and relapse-free survival (RFS). In vitro functional validation via siRNA-mediated knockdown in DU-145 and PC-3 cells significantly attenuated proliferative and invasive capacities, impairing cell viability and downregulating key progression markers (Ki-67, MMP2, and MMP9). Crucially, immunogenomic profiling mapped YBX1 expression to an "immune-excluded" TME, characterized by depleted CD8+ T cell and dendritic cell infiltration alongside elevated immune checkpoint networks. Serving as a bridge to clinical translation, YBX1 effectively predicted clinical responses in three immunotherapy cohorts and demonstrated broad resistance to 12 chemotherapeutic and targeted agents. Our multiomics integration pipeline highlights YBX1 as a dual-functional oncogene that couples malignant proliferation with immune evasion, establishing it as a highly translational biomarker and an actionable target for precision PRAD management.
Exploring the Role of in Breast Cancer Progression, Immune Microenvironment, and Therapeutic Sensitivity: A Multiomics and Functional Prediction Study.
Gong L, Xu Y, Guo W … +5 more , Cai X, Zhang F, Ma J, Tao H, Feng W
Hum Mutat · 2026 · PMID 42087895 · Full text
BACKGROUND: Breast invasive carcinoma (BRCA) remains a leading cause of female cancer mortality, necessitating novel biomarkers and therapeutic targets. Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) emerges as a p...
BACKGROUND: Breast invasive carcinoma (BRCA) remains a leading cause of female cancer mortality, necessitating novel biomarkers and therapeutic targets. Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) emerges as a potential regulator in tumor progression and immune modulation, yet its comprehensive role in BRCA remains uncharacterized. METHODS: We conducted an integrated multiomics analysis of HNRNPA3 in BRCA using data from TCGA, GEO datasets, single-cell RNA sequencing, and spatial transcriptomics. Bioinformatics approaches included differential expression analysis, survival analysis, functional enrichment, immune microenvironment characterization, and drug sensitivity prediction. RESULTS: HNRNPA3 was significantly upregulated in BRCA tissues and correlated with advanced tumor grade, metastasis, and poor prognosis across multiple cohorts. Functional enrichment revealed HNRNPA3's involvement in cell cycle regulation and immune-related pathways. Immune profiling demonstrated that high HNRNPA3 expression was associated with altered immune cell distribution, particularly CD4+ T cells, and reduced immunotherapy response. Spatial transcriptomics confirmed predominant HNRNPA3 expression in malignant regions. Drug sensitivity analysis identified potential therapeutic agents (CD-437 and talazoparib) targeting HNRNPA3-associated pathways. CONCLUSION: HNRNPA3 functions as a critical oncogenic regulator in BRCA by promoting tumor progression through cell cycle dysregulation and immune microenvironment remodeling. Its strong association with therapy resistance positions HNRNPA3 as both a prognostic biomarker and promising therapeutic target for breast cancer intervention strategies.
Whole-Exome Sequencing to Screen Personal Neoantigens With High Immunogenicity in Patients With Microsatellite Stability (MSS)-Advanced Colorectal Cancer.
Li D, Shen W, Yang S … +5 more , Liu H, Tan X, He X, Hao J, Yin X
Hum Mutat · 2026 · PMID 42087894 · Full text
To develop a personalized neoantigen therapy strategy for microsatellite stability (MSS)-advanced colorectal cancer (CRC), neoantigens from collected human CRC samples were screened, and the feasibility and effectiveness...
To develop a personalized neoantigen therapy strategy for microsatellite stability (MSS)-advanced colorectal cancer (CRC), neoantigens from collected human CRC samples were screened, and the feasibility and effectiveness of these neoantigens in treating CRC were explored. Whole-exome sequencing and transcriptome sequencing were performed to identify somatic mutations, RNA expression, and human leukocyte antigen alleles. Based on these data, neoantigen candidates were predicted, and their immunogenicity was evaluated. Selected neoantigens from patients elicited enhanced T-cell responses in CRC peripheral blood lymphocytes. Mutated peptides SOX9-V144M, ZNF169-A275S, CDH4-V456M, NIM1K-T66M, and MAP3K9-R1008Q were more effective than nonmutated ones in Patient 1. Vaccination with mutant peptides ZNF169-A275S and CDH4-V456M inhibited tumor growth in an autologous humanized CRC mouse model. Highly immunogenic neoantigens are strong candidates for personalized cancer therapy, showing promise for translating into effective treatments for CRC patients with advanced disease.
Periostin Safeguards EGFR-Driven Genomic Instability and Sustains the Immune-Suppressive Niche in Glioblastoma.
Liu H, Tan S, Qi J … +5 more , Du Z, You J, Muhammad S, Tang X, Li J
Hum Mutat · 2026 · PMID 42087893 · Full text
Glioblastoma (GBM) heterogeneity limits the efficacy of EGFR-targeted therapies. Here, we present a spatially stratified single-cell atlas of IDH-wildtype GBM to dissect the impact of EGFR amplification on tumor architec...
Glioblastoma (GBM) heterogeneity limits the efficacy of EGFR-targeted therapies. Here, we present a spatially stratified single-cell atlas of IDH-wildtype GBM to dissect the impact of EGFR amplification on tumor architecture. We demonstrate that EGFR amplification disrupts the spatial coupling between evolutionary state and anatomical location, resulting in premature acquisition of invasive phenotypes-a phenomenon we term "accelerated evolutionary velocity." Unlike nonamplified tumors which maintain a strict "Core-to-Margin" developmental gradient, malignant cells in EGFR-amplified tumors acquire invasive mesenchymal traits preemptively regardless of their spatial niche. This accelerated evolution parallels the Core behaving as a "genotoxic stress reservoir" characterized by elevated chromosomal instability (CIN) ( < 2.2 × 10). This genotoxic stress coincides with the emergence of a localized tumor-myeloid axis and an immune-suppressive niche. Using the PriorityScore2 framework, we prioritized Periostin (POSTN) as a top-tier clinically relevant candidate. In the high-CIN environment of EGFR-amplified GBM, in silico network perturbation suggested that POSTN may function as a candidate modulator of mitotic fidelity, potentially buffering against lethal genomic instability while sustaining rapid clonal evolution. Validated across multicenter cohorts, POSTN showed robust upregulation, strong diagnostic performance (AUC = 0.961), and significant prognostic relevance, emerging as a potential therapeutic vulnerability linking accelerated evolution with immune privilege in the GBM ecosystem.
Multiomics Analysis of Nucleotide Metabolism Highlights the Important Role of Adenylate Kinase 4 in Pancreatic Cancer.
Li J, Yao Y, Zhang W … +1 more , Zhang D
Hum Mutat · 2026 · PMID 42087892 · Full text
Nucleotide metabolism significantly influences tumor cell proliferation, yet its specific profile in pancreatic cancer remains inadequately understood. This study was aimed at characterizing the nucleotide metabolic prof...
Nucleotide metabolism significantly influences tumor cell proliferation, yet its specific profile in pancreatic cancer remains inadequately understood. This study was aimed at characterizing the nucleotide metabolic profile in pancreatic cancer and assessing the contribution of the key gene adenylate kinase (AK) 4. Multiomics data, including transcriptomic, single-cell sequencing, spatial transcriptomic, and metabolomics datasets, were obtained from publicly accessible platforms. The impact of AK4, a key gene of nucleotide metabolism, on the proliferation and migration of pancreatic cancer cells was investigated using various molecular biological techniques. Nucleotide pathway-related metabolites exhibited marked differences in abundance between pancreatic cancer tissues and normal pancreatic tissues. Single-cell sequencing analysis identified MKI67 and myeloid cells as subsets with overactive nucleotide metabolism. Immune cells from tumor tissues had a higher score of nucleotide metabolism than those from the normal pancreas. Spatial transcriptomics revealed spatial features of nucleotide metabolism in pancreatic cancer. Pancreatic cancer patients displayed distinct clinical heterogeneity in nucleotide metabolism, with elevated nucleotide signaling correlating with poorer patient prognosis. Furthermore, tumor subtypes showed variations in immune microenvironment features and immune checkpoint expression, which may explain their differential prognoses. A nucleotide metabolic-derived prognostic panel had the potential to predict the clinical outcomes of patients with pancreatic cancer. The AK4 gene played a central role in nucleotide metabolism, and its overexpression in clinical pancreatic cancer samples was frequently linked to adverse patient outcomes. Cell-based experiments revealed that AK4 knockdown suppressed pancreatic cancer cell proliferation and migration. Abnormal nucleotide metabolism pathways are implicated in pancreatic cancer onset and progression.
Pathophysiological Significance of Variants of the HAND1 Gene Promoter in Congenital Atrial Septal Defects: A Study in 632 Chinese Subjects.
Qi JL, Chen HX, Hou HT … +2 more , Yang Q, He GW
Hum Mutat · 2026 · PMID 42079346 · Full text
BACKGROUND: Atrial septal defect (ASD) is a common congenital heart disease (CHD) and genetic variation in the HAND1 gene is associated with cardiac development. The variants in the promoter region of the HAND1 gene are...
BACKGROUND: Atrial septal defect (ASD) is a common congenital heart disease (CHD) and genetic variation in the HAND1 gene is associated with cardiac development. The variants in the promoter region of the HAND1 gene are unknown. METHODS: We performed Sanger sequencing of DNA from 632 subjects (320 ASD patients and 312 healthy controls). The identified variants were also subjected to further cellular functional validation, electrophoretic mobility shift analysis (EMSA), and JASPAR database analysis. RESULTS: A total of 12 variants were identified in the promoter region of HAND1 gene, seven of which were found only in 10 ASD patients (g.3658 T > C [rs1287904093], g.3689 A > G, g.3714 G > A [rs140545341], g.3771 C > T [rs2113306555], g.3961 T > G, g.4411 A > T [rs1034236730], and g.4512 G > T) and three of the variants (g.3689 A > G, g.3961 T > G, and g.4512 G > T) were newly discovered. Further cellular functional validation showed that these seven variants reduced the transcriptional activity of HAND1 gene promoter (p < 0.05). The results of EMSA and the analysis of the JASPAR database suggest that these variants may have altered a series of transcription factor binding sites (TFBs), leading to altered HAND1 protein expression as well as the development of ASD. CONCLUSIONS: Thus, the present study provides new insights into the role of the promoter region of HAND1 gene, which could lead to a better understanding of the genetic basis of ASD formation and potential treatments.
Ubiquitination-Associated Ductal-Fibroblast Crosstalk Shapes Tumor Progression and Prognosis in Pancreatic Ductal Adenocarcinoma.
Fu Y, Zhou X, Jiang L … +7 more , Zhang S, Gu Y, Zhuang Z, Huang G, Xu Z, Xu P, Zhong X
Hum Mutat · 2026 · PMID 42079345 · Full text
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a complex tumor microenvironment. Ubiquitination regulates key oncogenic processes and microenvironmental remodeling; howev...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a complex tumor microenvironment. Ubiquitination regulates key oncogenic processes and microenvironmental remodeling; however, its cell type-specific activity and spatial organization within the PDAC microenvironment remain poorly understood. MATERIALS AND METHODS: Single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq datasets of PDAC were integrated for multiomics analysis. Ubiquitination activity was quantified using gene-set scoring algorithms, followed by cell-communication and spatial interaction analyses. Prognostic models were constructed using bulk cohorts, and key findings were validated through gene-silencing functional assays. RESULTS: Ubiquitination activity was significantly increased in PDAC tissues compared with adjacent normal tissues, with ductal epithelial cells and fibroblasts showing the most prominent elevation. High ubiquitination states were associated with enhanced ductal-fibroblast interactions and distinct spatial patterns linked to invasion-associated tumor regions. Integration of ubiquitination-associated gene signatures identified a robust prognostic model, highlighting an extracellular matrix-related factor consistently overexpressed in tumors and associated with poor survival. Functional assays demonstrated that suppression of this factor inhibited proliferation, migration, invasion, and survival of pancreatic cancer cells. CONCLUSION: Ubiquitination organizes ductal-fibroblast crosstalk within the PDAC microenvironment and links spatial tumor ecology with disease aggressiveness and patient prognosis. Targeting ubiquitination-associated microenvironmental programs may offer new strategies for prognostic stratification and therapeutic intervention.
X-Linked Hypophosphatemia Caused by a New Partial Insertion of LINE-1 in the Gene.
Li D, Peng W, Kang L … +3 more , Geng J, Lu Y, Lu J
Hum Mutat · 2026 · PMID 42079344 · Full text
X-linked hypophosphatemia (XLH), primarily caused by mutations of the gene, is the most common cause of genetic rickets. Pediatric cases of XLH typically present with elevated levels of serum fibroblast growth factor 23...
X-linked hypophosphatemia (XLH), primarily caused by mutations of the gene, is the most common cause of genetic rickets. Pediatric cases of XLH typically present with elevated levels of serum fibroblast growth factor 23 (FGF23), hypophosphatemia, rickets, and impaired growth. Here, we report a 2-year-old boy diagnosed with XLH, presenting with short stature, genu varum, and hypophosphatemia. Sanger sequencing revealed a novel mutation of the gene, comprising a 62-bp poly-T and a 421-bp long interspersed element-1 (LINE-1) insertion into exon 22, which appears to induce the hypophosphatemia. This study presents the first documented case of XLH associated with a partial LINE-1 insertion in . We suggest that LINE-1 transposon element insertions be considered in XLH patients lacking other known mutations.
ILF3 Regulates Cell Proliferation and Metastasis by Competitively Antagonizing the Interaction Between HMGCL and USP38 in Hepatocellular Carcinoma.
Luo Q, Xiao L, Deng G … +4 more , Deng T, Zhao W, Wang R, Hu X
Hum Mutat · 2026 · PMID 42063616 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. Previous studies have reported that interleukin enhancer-binding factor 3 (ILF3) is involved in the regulation of multiple cancers. This...
BACKGROUND: Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. Previous studies have reported that interleukin enhancer-binding factor 3 (ILF3) is involved in the regulation of multiple cancers. This study investigated the molecular mechanisms whereby ILF3 promotes HCC progression. METHODS: ILF3 expression levels were determined through immunohistochemistry (IHC) and Western blot (WB) analyses. The biological functions of ILF3 in HCC were evaluated using both in vitro assays and in vivo animal models. Co-immunoprecipitation (Co-IP) was carried out to identify HMGCL as a binding partner of ILF3. To clarify the potential molecular pathways underlying ILF3-mediated regulation of HCC malignant behaviors, protein stability assays and in vitro ubiquitination experiments were performed. RESULTS: ILF3 was significantly upregulated in HCC. The patients with high expression of ILF3 showed poor prognosis in our cohort. ILF3 knockdown inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo in this study. Mechanistically, ILF3 was found to be bound to HMGCL and to accelerate its protein degradation. Additionally, we found that ILF3 promotes HCC cell proliferation and metastasis through HMGCL. Overexpression of HMGCL in ILF3-upregulated HCC cells could significantly reverse the proliferation and invasion role of ILF3 on HCC cells. Moreover, USP38 was identified as a deubiquitinating enzyme that participates in promoting the stability of HMGCL. ILF3 disrupted the interaction between USP38 and HMGCL, thereby enhancing HMGCL ubiquitination and accelerating its degradation. CONCLUSION: ILF3 promotes the proliferation and metastasis of HCC by enhancing the ubiquitination of HMGCL by interfering with the interaction between the deubiquitinase USP38 and HMGCL.
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