Human Mutation最新文献

{"title":"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.","authors":"Shulong Ge, Qiying Zhang, Ning Liu, Xueyan Zheng, Han Xu, Li Zhang","doi":"10.1155/humu/2963117","DOIUrl":"https://doi.org/10.1155/humu/2963117","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"2963117"},"PeriodicalIF":3.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Homozygous Frameshift Mutation in <i>GREB1</i> Leads to Female Infertility.","authors":"Jinwei Yang, Linyan Yang, Bo Yan, Hongbao Li, Lin Zhang, Ting Hu, Xingyi Chao, Chuan Zhang, Yali Ni, Zhiqiang Wang","doi":"10.1155/humu/8849136","DOIUrl":"https://doi.org/10.1155/humu/8849136","url":null,"abstract":"<p><p>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 <i>GREB1</i> (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 <i>GREB1</i> protein expression via western blotting. Computational modeling predicted pathogenic structural alterations. This variant is absent in gnomAD/ExAC databases. Our findings establish <i>GREB1</i> mutations as a novel cause of female infertility, highlighting its role in endometrial receptivity regulation.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"8849136"},"PeriodicalIF":3.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant Curation of the Largest Compendium of <i>FOXL2</i> Coding and Noncoding Sequence and Structural Variants in BPES.","authors":"Charlotte Matton, Julie Van De Velde, Marieke De Bruyne, Stijn Van De Sompele, Sally Hooghe, Hannes Syryn, Miriam Bauwens, Eva D Haene, Annelies Dheedene, Martine Cools, Shoko Komatsuzaki, Ewelina Preizner-Rzucidło, Alison Ross, Christine Armstrong, Wendy Watkins, Andrew Shelling, Andrea L Vincent, Catherine Cassiman, Sascha Vermeer, David J Bunyan, Hannah Verdin, Elfride De Baere","doi":"10.1155/humu/8478740","DOIUrl":"https://doi.org/10.1155/humu/8478740","url":null,"abstract":"<p><p>Heterozygous <i>FOXL2</i> (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 <i>FOXL2</i> region, including 76 novel variants, in 864 index patients. Of these, 87% of patients were identified with a coding <i>FOXL2</i> sequence variant. The polyalanine tract is a known mutational hotspot of <i>FOXL2</i>, 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 <i>FOXL2</i>. The remaining 2% carry translocations along with chromosomal rearrangements of 3q23. This uniform and structured reclassification, incorporating the largest dataset of variants implicated in <i>FOXL2</i>-associated disease so far, will improve both the diagnosis as well as genetic counselling for individuals with BPES.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"8478740"},"PeriodicalIF":3.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deubiquitination of ETV4 by USP7 Promotes NSCLC Tumorigenesis via MAPK7 Activation.","authors":"Xue Meng, Jiaxi Zhang, Ning Zhang, Yuqi Hou, Yimeng Li, Jia Kang, Ruxin Li, Yinghui Shi, Juan Wang, Lixin Cheng, Lingxiao Xing","doi":"10.1155/humu/9432303","DOIUrl":"https://doi.org/10.1155/humu/9432303","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"9432303"},"PeriodicalIF":3.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-Exome Sequencing to Screen Personal Neoantigens With High Immunogenicity in Patients With Microsatellite Stability (MSS)-Advanced Colorectal Cancer.","authors":"Dajiang Li, Wenjing Shen, Siyu Yang, Hongmei Liu, Xiao Tan, Xinrong He, Jingchao Hao, Xinqiang Yin","doi":"10.1155/humu/3876230","DOIUrl":"https://doi.org/10.1155/humu/3876230","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"3876230"},"PeriodicalIF":3.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Single-Cell Multiomics Pipeline Maps YBX1 as a Functional Biomarker for Immune Evasion and Therapeutic Resistance in Prostate Adenocarcinoma.","authors":"Changcheng Luo, Dongxu Lin, Jingmin Yang, Kai Cui, Zhong Chen","doi":"10.1155/humu/2147624","DOIUrl":"https://doi.org/10.1155/humu/2147624","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"2147624"},"PeriodicalIF":3.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Germline <i>XAF1</i> Mutation in Patients With Gastrointestinal Cancers.","authors":"Guan-Xin Xu, Hang Zhang, Chang-Xing Wang, Ying-Zhi Zhang, Ping-Ping Lv, Chun Feng, Yao Ning, Miao Shen, Sai Zhang, Min Jin, Dan-Qing Yu","doi":"10.1155/humu/4279712","DOIUrl":"https://doi.org/10.1155/humu/4279712","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>In a family with GI cancer, we identified a mutation of <i>XAF1</i> (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.</p><p><strong>Conclusion: </strong>Our study provides evidence that a <i>XAF1</i> 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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"4279712"},"PeriodicalIF":3.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>GLUT1</i> rs1385129G>A Raised the Risk and Poor Prognosis of Lung Cancer: A Case-Control Study.","authors":"Zhi Li, Dedong Wang, Jinbin Chen, Di Wu, Shuyu Tang, Jinyi Huang, Yibin Deng, Xinhua Wang, Fuman Qiu, Lei Yang, Jiachun Lu","doi":"10.1155/humu/9935937","DOIUrl":"https://doi.org/10.1155/humu/9935937","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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 (<i>GLUT1</i> rs1385129G>A, <i>GLUT11</i> rs6003939A>C, <i>GLUT12</i> rs1484180G>A and <i>ENO2</i> rs11064467C>T) and the risk of LC. Follow-up data and the TCGA database were used to evaluate the relationship between <i>GLUT1</i> rs1385129G>A and <i>GLUT1</i> expression with the clinical progression of LC.</p><p><strong>Results: </strong>Only <i>GLUT1</i> rs1385129G>A was found to be associated with increased risk of LC in this two-stage case-control study (<i>p</i> < 0.05). Further analysis of the expression levels of <i>GLUT1</i> in <i>GLUT1</i> rs1385129G>A genotypes showed that they were positively correlated with the number of A alleles (<i>p</i> < 0.01), and the GA genotype had a moderate effect on <i>GLUT1</i> expression, whereas the AA genotype had a strong effect (GA vs. GG: Cohen's <i>d</i> = 0.768, 95<i>%</i> CI = 0.20-1.02; AA vs. GG: Cohen's <i>d</i> = 1.890, 95<i>%</i> 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<i>%</i> CI = 1.20-1.57). Furthermore, the survival curve of LC plotted using the GEPIA website showed that the group with high expression of <i>GLUT1</i> had an increased risk of poor prognosis compared with the low (Log-rank <i>p</i> < 0.01; HR = 1.40). The same result was obtained from the Kaplan-Meier Plotter database (Log-rank <i>p</i> < 0.01; HR = 1.34).</p><p><strong>Conclusion: </strong>Altogether, <i>GLUT1</i> rs1385129G>A may increase the risk of LC and contribute to a poor prognosis by upregulating <i>GLUT1</i> expression.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"9935937"},"PeriodicalIF":3.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Role of <i>HNRNPA3</i> in Breast Cancer Progression, Immune Microenvironment, and Therapeutic Sensitivity: A Multiomics and Functional Prediction Study.","authors":"Lijie Gong, Yang Xu, Weihui Guo, Xufan Cai, Fanrong Zhang, Jie Ma, Houquan Tao, Weiliang Feng","doi":"10.1155/humu/5519745","DOIUrl":"https://doi.org/10.1155/humu/5519745","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"5519745"},"PeriodicalIF":3.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periostin Safeguards EGFR-Driven Genomic Instability and Sustains the Immune-Suppressive Niche in Glioblastoma.","authors":"Hongjun Liu, Shasha Tan, Jian Qi, Zhenjiang Du, Jinliang You, Sajjad Muhammad, Xiaoping Tang, Jianji Li","doi":"10.1155/humu/9501906","DOIUrl":"https://doi.org/10.1155/humu/9501906","url":null,"abstract":"<p><p>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) (<i>p</i> < 2.2 × 10^-16). 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.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 ","pages":"9501906"},"PeriodicalIF":3.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}