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PubMed2026

TFPI-high myofibroblast states and a meta-program-related five-gene prognostic signature in breast cancer.

Intratumoral heterogeneity and tumor-microenvironment interactions limit prognostic stratification in breast cancer, but the prognostic relevance and cellular context of recurrent transcriptional meta-programs remain unclear. We aimed to derive a meta-program-related prognostic signature and characterize its component transcripts at single-cell resolution. Six paired institutional tumors and adjacent non-tumor tissues served as a proof-of-concept comparison. Univariable Cox screening and least absolute shrinkage and selection operator Cox regression were used to derive a five-gene score from a prespecified meta-program-related candidate set in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) training cohort; the score was tested internally and assessed in GSE20685 using fixed coefficients and cohort-specific median cutoffs. GSE161529 single-cell transcriptomic data were used to map signature transcripts across 136,526 quality-controlled cells, while donor-aware pseudobulk analysis compared upper- and lower-quartile TFPI expression states in annotated myofibroblasts. The score comprised TCN1, FOXJ1, PIGR, SLAIN1, and TFPI and was associated with overall survival in the training, testing, and external cohorts, with concordance indices of 0.782, 0.756, and 0.721, respectively. TFPI transcripts were detected across endothelial, fibroblast, and myofibroblast compartments. TFPI-high myofibroblasts showed transcriptional enrichment of extracellular matrix and collagen fibril organization, transforming growth factor beta signaling, epithelial-mesenchymal transition, and myogenesis, together with lower oxidative phosphorylation and fatty acid metabolism programs. In bulk TCGA-BRCA tissue, TFPI expression correlated positively with stromal (r = 0.48), immune (r = 0.25), and composite microenvironment scores (r = 0.40; all p < 0.001). These findings identify a hypothesis-generating five-gene bulk-tissue prognostic signature and an expression-associated TFPI-high myofibroblast state but do not establish a discrete lineage, the cellular source of bulk TFPI, a TFPI-dependent mechanism, or clinical utility. Independent prospective cohorts, spatial and protein-level validation, and functional perturbation studies are required.

Journal Article↗

PubMed2026

A CFH- and SPINT2-based prognostic signature for cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant tumor with a poor prognosis, and reliable biomarkers for postoperative risk stratification remain limited. This study aimed to develop and validate a CFH- and SPINT2-based prognostic signature to support postoperative risk stratification and inform adjuvant therapy selection in CCA through integrative machine learning and single-cell transcriptomics. METHODS: Differentially expressed genes were screened from GSE26566. Integrative machine learning (least absolute shrinkage and selection operator-Cox, random forest, and univariate Cox regression) was performed in the training cohort (GSE89749; n=115) to construct a risk model, which was externally validated in two independent cohorts: cohort 1 (E-MTAB-6389; n=75) and cohort 2 [The Cancer Genome Atlas Cholangiocarcinoma (TCGA-CHOL) data set; n=36]. Systematic analysis was conducted and included examinations of immune infiltration [via single-sample gene set enrichment analysis (ssGSEA)], pathway enrichment (via hallmark GSEA), cellular localization (via single-cell RNA sequencing), and drug sensitivity (via the Genomics of Drug Sensitivity in Cancer 2 database). RESULTS: Two genes, CFH and SPINT2, were identified and incorporated into a prognostic risk score. High-risk patients in the training cohort had a significantly worse overall survival (log-rank P=0.02). External validation was performed in two independent cohorts. In validation cohort 1, the risk group was an independent prognostic factor [hazard ratio =2.27, 95% confidence interval (CI): 1.18-4.37; P=0.01]. In validation cohort 2, the model demonstrated acceptable discriminative ability (concordance index =0.721; 3-year area under the curve =0.692). The high-risk group exhibited an immunosuppressive microenvironment characterized by increased infiltration of macrophages and myeloid-derived suppressor cells, along with the activation of epithelial-mesenchymal transition, inflammatory response, and NF-κB signaling pathways. Single-cell analysis revealed a cell-type-specific expression pattern: CFH was predominantly expressed in fibroblasts, while SPINT2 was mainly expressed in malignant cells. Drug sensitivity analysis demonstrated that the high-risk group was more sensitive to gemcitabine, cisplatin, poly(ADP-ribose) polymerase (PARP) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors, whereas the low-risk group was more sensitive to lapatinib. CONCLUSIONS: The CFH- and SPINT2-based prognostic signature may serve as an independent biomarker for postoperative risk stratification in CCA. High-risk patients, characterized by fibroblast-derived CFH enrichment and malignant-cell SPINT2 loss, exhibit an immunosuppressive microenvironment and may be more suitable for gemcitabine-based chemotherapy or PARP/mTOR inhibitors, whereas low-risk patients may benefit from less intensive adjuvant strategies or HER2/EGFR-targeted lapatinib. Prospective validation is warranted before clinical implementation.

Cholangiocarcinoma (CCA)↗

PubMed2026

Sodium Overload-Related Molecular Subtypes and a Four-Gene Prognostic Signature Predict Survival, Immune Landscape, and Therapeutic Response in Acute Myeloid Leukemia.

Sodium overload has recently emerged as a critical metabolic stressor involved in cancer progression; however, its molecular characteristics and clinical relevance in acute myeloid leukemia (AML) remain unexplored. RNA-seq data sets, clinical annotations, and mutational profiles of AML patients were annotations from The Cancer Genome Atlas and integrated with Genotype-Tissue Expression normal samples. Sodium overload-related genes (SORGs) were obtained from GeneCards. Differentially expressed SORGs (DESORGs) screened by applying the limma statistical model, followed by univariate Cox proportional hazards regression, consensus clustering, functional enrichment, immune infiltration analysis, and pathway evaluation. A prognostic signature was developed through least absolute shrinkage and selection operator regression followed by multivariate Cox modeling. The model's performance was further verified in two external GEO data sets (GSE71014 and GSE37642). Nomogram construction, subgroup analysis, tumor mutational burden (TMB) assessment, drug sensitivity prediction, transcription factor (TF) analysis, and competing endogenous RNA (ceRNA) network analyses were also performed. A total of 57 DESORGs were identified, and 2 sodium overload-related molecular subtypes exhibited distinct survival, immune infiltration, and inflammatory pathway activation. A robust four-gene signature (DOCK1, GABRE, HTR7, ACSM1) stratified patients into high- and low-risk categories with significantly different survival across training and validation cohorts. High-risk patients displayed increased immune infiltration, higher TMB, reduced sensitivity to multiple chemotherapeutic drugs, and inferior predicted response to PD-L1 blockade. TF and ceRNA networks revealed multilayered transcriptional and post-transcriptional regulation of the signature genes. This study identifies sodium overload-related molecular heterogeneity in AML and establishes a validated four-gene prognostic signature that integrates genomic, immunologic, and therapeutic features, offering potential utility for personalized risk assessment and treatment optimization.

Humans↗

PubMed2026

Machine learning identifies ac4C-related prognostic signature and TUBA1C as therapeutic target in COAD.

To explore the role of N4-acetylcytidine (ac4C)-related genes (acRGs) in colon adenocarcinoma (COAD) and identify reliable prognostic biomarkers and potential therapeutic targets. Multi-source transcriptomic datasets (TCGA-COAD, GSE39582, GSE17536) and single-cell RNA-seq data were analyzed. Ten machine learning algorithms were integrated to construct an acRG-based prognostic signature (acRGBS). Immune microenvironment (TME) and genomic profiling were performed, with in vitro functional experiments validating TUBA1C's role. acRGBS, comprising four hub genes (SARAF, CDC42SE2, TSPYL2, TUBA1C), effectively stratified COAD patients into high- and low-risk groups with distinct survival outcomes and was an independent prognostic factor. High-risk patients exhibited increased genomic instability and immunosuppressive TME, while low-risk patients had favorable immunotherapy response. TUBA1C was overexpressed in COAD cells, and its knockdown inhibited proliferation/migration and induced apoptosis. The acRGBS is a robust prognostic tool for COAD, and TUBA1C serves as a candidate therapeutic target, providing new insights for personalized COAD management.

Humans↗

PubMed2026

Development and Validation of a Prognostic Signature Based on Transcription Factors Associated with Endoplasmic Reticulum Stress in Pancreatic Adenocarcinoma.

BACKGROUND: Endoplasmic reticulum stress (ER stress) plays a crucial role in influencing the malignant behaviors of various tumors. Targeting the expression or degradation of transcription factors (TFs) offers a promising avenue for cancer treatment. However, a detailed understanding of how ER stress affects TF function and their interactions remains limited. This study aims to develop a prognostic model and identify TFs associated with ER stress in pancreatic ductal adenocarcinoma (PDAC). METHODS: We obtained gene expression profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA). To develop a prognostic signature, we performed several analyses, including unsupervised clustering, enrichment analysis, immune infiltration assessment, as well as univariate, LASSO, and multivariate Cox regression analyses. Four transcription factors-STAT1, IRF6, NRF1, and RXRA-were incorporated into a risk model, which was subsequently validated using the GSE dataset. Additionally, we examined IRF6 through quantitative PCR, western blotting, flow cytometry, and immunohistochemistry in vitro using pancreatic cancer cell lines and a tissue microarray. RESULTS: The high-risk group identified by the model exhibited significant associations with immune cell infiltration and poorer survival outcomes, though there was no significant correlation with tumor purity (p = 0.19). Furthermore, IRF6 downregulation in vitro was found to inhibit pancreatic cancer cell proliferation and promote apoptosis. IRF6 depletion also increased the expression of key molecules involved in ER stress at both the transcriptional and translational levels. Immunohistochemical analysis revealed marked differences in IRF6 expression between tumor and adjacent non-tumor tissues (59.29±29.88 vs. 95.22±40.80, p<0.001). CONCLUSION: This study provides evidence that the constructed risk model can effectively predict prognosis in PDAC patients. Transcription factors related to ER stress, such as IRF6, show promise as both prognostic biomarkers and potential therapeutic targets for PDAC.

Humans↗

PubMed2026

Age-Associated Four-Gene Prognostic Signature in Breast Cancer.

BACKGROUND: Young-onset breast cancer is associated with inferior disease-free survival (DFS), but the contribution of additional molecular heterogeneity remains unclear. AIMS: To identify an exploratory age-associated gene expression signature linked to recurrence-related outcomes and evaluate its prognostic association. METHODS AND RESULTS: We analyzed clinicopathological and RNA-sequencing data from 821 patients with Stages I-III invasive ductal or lobular carcinoma in The Cancer Genome Atlas, including 142 patients aged ≤ 45 years. Genes associated with both age and DFS were screened, followed by LASSO-Cox and stepwise multivariable Cox regression. A four-gene signature (Sig4: C4orf14 [NOA1], LINC01124, ZNF704, and AGFG2) was identified. Young patients had significantly worse DFS than older patients, whereas overall and disease-specific survival did not differ significantly. After adjustment for clinicopathological factors, young age remained associated with worse DFS. Following inclusion of the continuous Sig4 score, the age association was attenuated and no longer statistically significant, while Sig4 remained independently associated with worse DFS. Sig4-high tumors were enriched for proliferation, cell-cycle, DNA-repair, metabolic, and stress-response pathways. In METABRIC, the fixed TCGA-derived Sig4 score was associated with worse relapse-free survival in the overall cohort but not in patients aged ≤ 45 years. CONCLUSION: Sig4 is an exploratory age-associated four-gene signature with potential general prognostic relevance in breast cancer. Its utility for risk stratification specifically in young-onset breast cancer was not externally validated and requires confirmation in independent prospective cohorts enriched for young patients.

Humans↗

PubMed2026

Identification of a necroptosis-related lncRNA prognostic signature and the hub RBP HNRNPK in esophageal squamous cell carcinoma.

ObjectiveEsophageal squamous cell carcinoma (ESCC) is a malignant tumor with poor prognosis. Necroptosis is important for tumor immunity, but its role in ESCC remains unclear. This retrospective bioinformatics study aimed to investigate the prognostic value of necroptosis-related long non-coding RNAs (lncRNAs) and to identify key lncRNA-binding proteins (RBPs) in ESCC patients.MethodsRNA transcriptome and clinical data of ESCC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Necroptosis-related lncRNAs were identified through correlation analysis with necroptosis-related genes, subjected to consensus cluster analysis, and used to construct a prognostic risk model via least absolute shrinkage and selection operator (LASSO) regression. The hub RBP was experimentally validated by quantitative polymerase chain reaction (qPCR) using 30 pairs of ESCC and adjacent normal tissues from patients who underwent surgical resection.ResultsA total of 30 necroptosis-related lncRNAs were significantly correlated with overall survival (OS). The upregulated lncRNAs in the risk model were associated with high immune scores, innate immune cell infiltration, cluster 2 classification, and advanced T-stage disease (p < 0.05). Three hub RBPs (HNRNPA1, HNRNPC, and HNRNPK) were identified through protein-protein interaction network analysis. qPCR confirmed that HNRNPK was significantly overexpressed in ESCC tissues compared to adjacent normal tissues (p < 0.05).ConclusionsThe necroptosis-related lncRNA risk model is an independent prognostic factor for ESCC patients. HNRNPK was identified as a hub RBP significantly overexpressed in ESCC tissues. We hypothesize that HNRNPK may promote tumor progression through regulating proto-oncogene expression or modulating the immune microenvironment, though this requires further mechanistic validation.

Humans↗

PubMed2025

Identification and external validation of a prognostic signature based on myeloid-derived suppressor cells-related LncRNAs to evaluate survival prognosis and treatment efficacy in invasive breast carcinoma.

BACKGROUND: Originating in the hematopoietic tissue, myeloid-derived suppressor cells (MDSCs) significantly contribute to tumor-related immunological processes. However, their relationship with long noncoding RNAs (lncRNAs) and breast cancer remains incompletely understood. In this study, we introduced MDSCs-associated lncRNAs as novel prognostic biomarkers to assess outcomes in patients with invasive breast carcinoma (BRCA). METHODS: Information regarding BRCA cases, including clinical and genomic details, was obtained from the TCGA repository. Predictive indicators were discovered, and their reliability underwent thorough verification. A clinically useful nomogram was developed following application-based validation. Additional investigations encompassed functional analysis, TMB assessment, TME profiling, immunotherapy efficacy forecasting, and drug sensitivity testing along with target identification. Long non-coding RNA expression was measured using reverse transcription quantitative PCR. RESULTS: A risk stratification model incorporating eight MDSCs-related lncRNAs effectively predicted patient outcomes. Kaplan-Meier (K-M) survival analysis clearly indicated a much worse prognosis among patients classified as high-risk (p < 0.001). The nomogram accurately forecasted overall survival (OS). Analysis of functional enrichment revealed that pathways associated with epithelial cells showed activity among patients at higher risk. Characterization of the tumor microenvironment showed increased immune cell presence in those classified as low-risk. Conversely, individuals with greater risk displayed higher tumor mutational burden. TIDE and IPS analyses indicated superior immunotherapy responsiveness in the low-risk BRCA subgroup. Among 47 drugs with notable IC50 variations, Ribociclib, PD173074, KU-55933, NU7441, and nutlin-3a exhibited lower IC50 values within the low-risk group, whereas Lapatinib demonstrated greater efficacy among the high-risk group. Moreover, 10 potential therapeutic agents and their targets were predicted for high-risk patients. RT-qPCR validation confirmed the robustness of the model. CONCLUSIONS: We successfully verified a new model of molecular markers of MDSCs-related lncRNAs, offering critical insights for predicting outcomes and guiding therapeutic decisions in BRCA cases.

Bioinformatics↗

PubMed2025

Identification of a prognostic signature consisting of three macrophage-related genes for glioblastoma based on bulk and single-cell transcriptomes analyses.

BACKGROUND: Tumor-associated macrophages have been implicated in the progression and treatment resistance of glioblastoma (GBM). This study aimed to identify macrophage-related genes associated with prognosis and therapeutic response in GBM. MATERIALS AND METHODS: Bulk RNA-seq data from 533 patients with GBM were downloaded from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Bioinformatic tools were used to detect the co-expression gene modules associated with the infiltration of immune cells, identify a prognostic macrophage-related gene signature, and explore their association with sensitivity to chemotherapeutic drugs and immune checkpoint blockade. Single-cell RNA-seq data and multiplexed immunofluorescence were used to validate ISG20 expression (a member of the identified gene signature) in macrophages. RESULTS: We detected gene modules associated with macrophages and identified a signature consisting of three macrophage-related genes (ISG20, PARP12 and IFIT5) in the discovery set (TCGA-GBM, n = 159), and validated its prognostic value in the validation set (CGGA-GBM, n = 374). This gene signature demonstrated favorable accuracy in predicting prognosis and resistance of immuno- and chemo-therapy. The co-expression of ISG20 and PD-1 in macrophages was verified by single-cell RNA-seq data and multiplex immunofluorescence. CONCLUSIONS: This study presents a macrophage-related gene signature to predict prognosis and therapeutic response in GBM. ISG20, PARP12 and IFIT5 are interferon-stimulated genes, and further investigations may provide new insights into the interplay between macrophages and interferon signaling in GBM.

Humans↗

PubMed2025

A prognostic signature for lung adenocarcinoma in people who have never smoked.

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes' alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings.

Journal Article↗

PubMed2026

LLPS-based classification and a novel prognostic signature reveal NRF1 as a therapeutic target in pancreatic cancer.

BACKGROUND: Aberrant liquid-liquid phase separation (LLPS) can alter biomolecular condensate functions and may influence pancreatic tumorigenesis and progression, but the specific role of LLPS regulators in prognosis and the tumor immune microenvironment (TIME) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: We integrated transcriptome data of LLPS regulator-related differentially expressed genes (DEGs; n = 298) in a cohort of 176 PDAC patients from TCGA. Three LLPS regulator subtypes (LS1-LS3) were identified through multi-omics analyses, and a prognostic LLPS subtype-related risk model (LRRPC) was developed and validated. Chromatin immunoprecipitation confirmed NRF1 binding to promoters of key risk genes, and in vitro and in vivo experiments assessed the effects of NRF1 targeting on tumor growth. RESULTS: The three LLPS regulator subtypes exhibited significant differences in prognosis, clinical features, genomic alterations, TIME patterns and predicted immunotherapy response. The LRRPC signature predicted prognosis and immunotherapy efficacy across cohorts and was associated with tumor biomarkers and immune infiltration. Nuclear Respiratory Factor 1 (NRF1) directly regulated hub genes such as FAM83A, RHOV and ITGB6, promoting PDAC cell proliferation, while its inhibition induced apoptosis and reduced tumor growth. CONCLUSIONS: This study proposes an LLPS-based stratification framework for PDAC, and the LRRPC model provides an LLPS subtype-related risk score that may assist personalized prognostic assessment and immunotherapy stratification. NRF1 emerges as a promising therapeutic candidate whose targeting can inhibit tumor progression in PDAC experimental models and warrants further evaluation.

Immunotherapy↗

PubMed2026

Machine learning-based integration develops a novel lysosome-related prognostic signature associated with prognosis and immune infiltration landscape in acute myeloid leukemia.

BACKGROUND: Lysosomes are essential for intracellular degradation and recycling, and changes in their function significantly contribute to tumor growth. Nonetheless, the exact role of lysosome-related genes (LRGs) in the pathogenesis of acute myeloid leukemia (AML) is still inadequately comprehended. METHODS: Differentially expressed LRGs (DE-LRGs) between AML and control groups were identified using AML-related data extracted from the Gene Expression Omnibus (GEO). The LRGs-related prognostic genes were identified and the risk model was established using univariate COX regression analysis and machine learning algorithms, based on the data obtained from The Cancer Genome Atlas (TCGA). Subsequently, we performed comprehensive analyses regarding clinical features, functional pathways, immune microenvironment, and chemotherapeutic drugs sensitivity between the high- and low-risk groups. Reverse transcription Quantitative polymerase chain reaction (RT-qPCR) and western blot were adopted to validate the expression of prognostic genes in human bone marrow-derived cell line HS-27 A and human AML cell line MOLM-13. RESULTS: Through comprehensive analysis, a risk model was developed utilizing ten LRGs (ATP6V0E2, CALCRL, TMEM165, GZMB, HCK, TCIRG1, CD1D, GPRASP1, ABCA1, and NAGA), and this model was further validated using GEO datasets. Significant differences in clinical characteristics, functional pathways, immune microenvironment characteristics, and chemotherapeutic drug sensitivity were observed between the two risk groups In vitro validation experiment illustrated that the expression trends of ATP6V0E2, TMEM165, and ABCA1 were consistent with our bioinformatics analysis. CONCLUSION: Our study demonstrates that lysosome-associated signature might forecast the prognosis of AML patients and offer guidance for subsequent immunotherapy and chemotherapy strategies.

Acute myeloid leukemia↗

PubMed2026

Systematic characterization of neurotransmitter receptor dysregulation identifies a neural-related prognostic signature associated with biochemical recurrence in prostate cancer.

BACKGROUND: The nervous system is increasingly recognized to play a critical role in tumor initiation and progression. Central to this complex relationship are the interactions between neurotransmitters secreted by neurons and their receptors (neurotransmitter receptors, NTRs) expressed on cancer cells, which activate multiple intracellular signaling pathways. However, the spectrum of NTR dysregulation and its association with biochemical recurrence (BCR) in prostate cancer (PCa) has not been explored. Therefore, the aim of this study was to fill this gap. METHODS: We systematically characterized the expression profiles of 130 NTR genes by integrating bulk and single-cell transcriptomic data. Consistently dysregulated NTR (cdNTR) genes were identified and used to construct a PCa signature (PCaSig) using elastic-net regression. The robustness of PCaSig was evaluated across three independent cohorts. In addition, the associations of PCaSig with clinicopathological characteristics, genomic alterations, tumor immune-related characteristics, and biological pathways were comprehensively investigated. RESULTS: Thirteen cdNTR genes with strong cell-type specificity, particularly in luminal epithelial cells, were identified. PCaSig robustly stratified patients into distinct BCR risk groups across multiple independent cohorts and remained an independent predictor after adjustment for clinicopathological factors. High PCaSig scores were associated with aggressive clinicopathological features, elevated tumor mutation burden (TMB), suppression of neurotransmitter-related signaling, and activation of cell-cycle and immune-related pathways. Notably, PCaSig refined prognostic stratification regardless of TMB status and was associated with distinct immune-related characteristics, including immune checkpoint expression and immune cell infiltration. Incorporation of PCaSig into a clinical nomogram significantly improved prognostic accuracy and clinical net benefit. CONCLUSIONS: These findings establish NTR dysregulation as a previously underappreciated dimension of PCa and support PCaSig as a clinically relevant tool for personalized management.

Neurotransmitter receptor (NTR)↗

PubMed2026

Identification of a novel signature for prognostic stratification and integrative analyses in lung adenocarcinoma.

BACKGROUND: Recently, research has revealed that the Golgi apparatus is involved in the development process of cancer; however, the specific effect of Golgi apparatus-related genes (GAGs) in lung adenocarcinoma (LUAD) remains unclear. This study aims to construct a more concise and practical risk model in LUAD using GAG. METHODS: The gene expression profiles of patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and GAGs were downloaded from the Gene Set Enrichment Analysis (GSEA) database. Univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses were performed to identify the prognostic GAG signature. Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to validate the predictive effect of the prognostic signatures. The correlation between the risk model and the immune landscape was examined using CIBERSORT and TIDE analyses. Also, the genes in the signature were assessed by single-cell RNA sequencing (scRNA-seq). RESULTS: A prognostic signature comprising 5 GAG genes (GNPNAT1, RGS20, CAV3, NTSR1, and FURIN) was established after LASSO and multi-Cox analyses. Both the Kaplan-Meier analysis and the ROC curves supported the strong predictive utility of the risk model. Specifically, the former yielded significant stratification in all three validation datasets (P=1.2001e-05, P=0.006, and P=0.04), while the latter provided further evidence of its predictive precision through the area under the curve. In addition, we found that the low-risk group responded better to immunotherapy than the high-risk group (P<0.0001). scRNA-seq analysis revealed the distribution patterns of the 5 GAG genes in cells. Finally, we assessed the situation of tumor mutation burden (TMB) and performed functional analysis based on the risk model of GAGs. CONCLUSIONS: The risk model based on GAGs can effectively stratify the prognosis of patients and predict immunotherapy responses in LUAD.

Golgi apparatus↗

PubMed2026

Construction of molecular signatures based on the co-expression network of NECSO-related gene TRPM4 and its prognostic value in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) demonstrates significant prognostic variability that is not entirely accounted for by traditional staging systems. Necrosis by sodium overload (NECSO) is an emerging programmed cell death pathway, but its clinical relevance in HCC remains undefined. Therefore, this study aimed to identify TRPM4-associated core genes, develop and validate a prognostic signature, and investigate its relationship with the tumor immune microenvironment, tumor mutational burden, and single-cell expression patterns in HCC. METHODS: We integrated transcriptomic, clinical, and mutational datasets from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (n=421) and Gene Expression Omnibus (GEO) cohorts (n=115) to identify genes co-expressed with TRPM4-a key NECSO mediator-and those differentially expressed in HCC. A prognostic signature was developed using least absolute shrinkage and selection operator (LASSO)-Cox regression and validated through survival analysis, time-dependent receiver operating characteristic (ROC) curves, and multivariate Cox regression analysis. The immune landscape was characterized using CIBERSORT, somatic mutation data were used to calculate tumor mutational burden (TMB) and assess its correlation with the risk score, and single-cell RNA sequencing (scRNA-seq) resolved cell-type-specific expression patterns. RESULTS: From 294 TRPM4-associated core genes, we identified an 11-gene signature (BRSK1, MMP1, GRIN2D, GP6, MYOM2, N4BP3, CCDC112, TSEN54, MAP3K9, SPP1, B3GNT4) that independently predicted overall survival (OS) (hazard ratio =5.419, P<0.001) with areas under the curve (AUCs) of 0.779, 0.693, and 0.701 at 1, 3, and 5 years. These values were superior or comparable to conventional clinicopathologic variables after direct comparison. High-risk patients exhibited an immunosuppressive microenvironment, characterized by enrichment of M0 macrophage, a higher M2/M1 ratio (P<0.001) and distinct immune checkpoint profiles. When integrated with TMB, the prognostic stratification was further refined: high-TMB/high-risk patients had poorest outcomes (median OS, 15.3 months), while low-TMB/low-risk patients had the most favorable survival (median OS, 68.7 months). Single-cell analysis revealed that MMP1 was induced in cancer-associated fibroblasts (CAFs) and SPP1 was downregulated in macrophages, single-cell risk scores confirmed TAFs and macrophages as the main contributors to the prognostic model. CONCLUSIONS: The TRPM4-centered 11-gene signature provides robust and independent prognostic stratification in HCC by integrating immune, mutational, and single-cell features. This signature serves as a potential tool for prognostic evaluation and may help inform immunotherapeutic strategies for HCC.

Hepatocellular carcinoma (HCC)↗

PubMed2025

A novel glycogene-related signature for prognostic prediction and immune microenvironment assessment in kidney renal clear cell carcinoma.

BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is a prevalent urinary malignancies worldwide. Glycosylation is a key post-translational modification that is essential in cancer progression. However, its relationship with prognosis, tumour microenvironment (TME), and treatment response in KIRC remains unclear. METHOD: Expression profiles and clinical data were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering, Cox regression, and LASSO regression analyses were conducted to develop an optimal glycogene-related signature. The prognostic relevance of this molecular signature was rigorously analyzed, along with its connections to tumour microenvironment (TME), tumour mutation burden, immune checkpoint activity, cancer-immunity cycle regulation, immunomodulatory gene expression patterns, and therapeutic response profiles. Validation was performed using real-world clinical specimens, quantitative PCR (qPCR), and immunohistochemistry (IHC), supported by cohort analyses from the Human Protein Atlas (HPA) database. RESULTS: A glycogene-associated prognostic scoring system was established to categorize patients into risk-stratified subgroups. Patients in the high-risk cohort exhibited significantly poorer survival outcomes (p < 0.001). By incorporating clinicopathological variables into this framework, we established a predictive nomogram demonstrating strong calibration and a concordance index (C-index) of 0.78. The high-risk subgroup displayed elevated immune infiltration scores (p < 0.001), upregulated expression of immune checkpoint-related genes (p < 0.05), and an increased frequency of somatic mutations (p = 0.043). The risk score positively correlated with cancer-immunity cycle activation and immunotherapy-related signals. The high-risk groups also showed associations with T cell exhaustion, immune-activating genes, chemokines, and receptors. Drug sensitivity analysis revealed that low-risk patients were more sensitive to sorafenib, pazopanib, and erlotinib, whereas high-risk individuals responded better to temsirolimus (p < 0.01). qPCR and IHC analyses consistently revealed distinct expression patterns of MX2 and other key genes across the risk groups, further corroborated by the HPA findings. CONCLUSION: This glycogene-based signature provides a robust tool for predicting prognosis, TME characteristics, and therapeutic responses in KIRC, offering potential clinical utility in patient management.

Humans↗

PubMed2026

Construction and validation of a β-hydroxybutyrylation-related molecular model for predicting prognosis of papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) usually has a favorable prognosis, yet a subset of patients develops persistent, recurrent, or biologically aggressive disease. The clinical relevance of lysine β-hydroxybutyrylation (Kbhb)-related transcriptional programs in PTC remains unclear. Accordingly, this study aimed to characterize Kbhb-related molecular heterogeneity in PTC, construct a prognostic signature, and explore its association with the tumor microenvironment (TME). METHODS: Transcriptomic and clinical data from PTC samples within The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) cohort were analyzed to identify Kbhb-related differentially expressed genes (DEGs), define molecular subtypes, construct a prognostic signature, and characterize tumor microenvironmental features. Single-cell RNA-sequencing data from PTC were further used to explore the cellular distribution of representative genes. RESULTS: We identified 51 Kbhb-related DEGs in PTC and defined two Kbhb molecular subtypes. The Kbhb_C2 subtype showed shorter progression-free interval (PFI) and a more immune- and stroma-enriched microenvironment. A six-gene prognostic signature comprising TARID, CDSN, PIMREG, KLRC1, SYT13, and NPR3 was then established. High-risk patients had significantly worse PFI in the full, training, and testing cohorts, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.715, 0.793, and 0.771, respectively, in the full cohort. High-risk tumors also exhibited higher stromal, immune, and ESTIMATE scores, altered immune infiltration, and increased expression of multiple immune checkpoint molecules. Single-cell analysis confirmed distinct cell-type-specific expression patterns of representative genes. CONCLUSIONS: Kbhb-related transcriptional programs define clinically relevant molecular heterogeneity in PTC and are closely associated with prognosis and TME remodeling. The identified six-gene signature provides a biologically interpretable framework for risk stratification in PTC.

Papillary thyroid carcinoma (PTC)↗

PubMed2026

Discovery and validation of a prognostic SPP1/PLAU signature in HPV-negative oropharyngeal squamous cell carcinoma.

BACKGROUND: This study aimed to identify and validate robust prognostic biomarkers for oropharyngeal squamous cell carcinoma (OPSCC), with a specific focus on the high-risk HPV-negative subtype. METHODS: Integrated bioinformatics analysis was performed on transcriptomic data from four GEO datasets (n = 418 samples). Differentially expressed genes (DEGs) were identified, and a protein-protein interaction (PPI) network was constructed for the most dysregulated genes. Key modules were analyzed via survival analysis and multivariate Cox regression. The top candidate genes were validated at the protein level using immunohistochemistry (IHC) in an independent cohort of 304 OPSCC patients. RESULTS: A 33-gene module related to extracellular matrix organization showed significant prognostic association. It stratified patients into high- and low-risk groups with markedly different overall survival (HR = 2.71, p < 0.001). From this module, SPP1 and PLAU were identified as independent prognostic factors through multi-step screening. Both genes were significantly overexpressed in tumors (approximately 20-fold and 10-fold, respectively, p < 0.001), with high expression strongly correlated with advanced tumor stage (p < 0.01) and, notably, the HPV-negative subtype (p < 0.001). In survival analysis, high expression of either SPP1 or PLAU was associated with poorer overall survival (SPP1: p < 0.001; PLAU: p < 0.001) and progression-free survival (p < 0.001). IHC validation confirmed high protein expression in 69.7% (SPP1) and 54.8% (PLAU) of cancer tissues. A prognostic nomogram integrating the SPP1/PLAU signature with clinical variables was constructed with strong predictive accuracy (C-index = 0.75). CONCLUSION: The SPP1/PLAU dual-gene signature is a robust and independent prognostic biomarker for OPSCC, with particular clinical utility for stratifying high-risk HPV-negative patients.

Humans↗