Hum Genomics. 2026 Feb 3. doi: 10.1186/s40246-026-00927-w. Online ahead of print.

ABSTRACT

BACKGROUND: Extrachromosomal DNA (ecDNA) is an emerging hallmark of cancer that promotes tumor evolution and heterogeneity. However, the molecular characteristics and clinical significance of ecDNA in hepatocellular carcinoma (HCC) remain incompletely understood.

METHODS: The clinical outcomes, genomics, transcriptomics, proteomics, tumor microenvironment, and drug target landscapes of ecDNA-negative and ecDNA-positive HCC in the Cancer Genome Atlas (TCGA) were compared. Next, the least absolute shrinkage and selection operator (LASSO) and random survival forest (RSF) algorithms were used to screen the ecDNA gene signature. A nomogram was constructed and evaluated based on the risk score and clinicopathological features. Finally, the role of DNASE1L3 was validated through in vitro experiments.

RESULTS: EcDNA-positive tumors showed increased vascular invasion, higher AFP levels, and more TP53 mutations. These tumors displayed unique activation of proliferation pathways, decreased stromal infiltration, and heightened immune activation. Our validated six-gene signature (RNF186, BMP6, AOC1, FBLL1, MYBL2, and DNASE1L3) demonstrated strong prognostic value when combined with tumor stage in the nomogram. Notably, DNASE1L3 was downregulated in HCC, showed endothelial cell-specific expression, and suppressed the proliferation and migration of Hep3B2.1-7 cells.

CONCLUSION: Our study characterizes the molecular and clinical distinctions between ecDNA-negative and ecDNA-positive HCC and establishes a clinically applicable gene signature for patient prognosis. These findings advance our understanding of ecDNA-driven tumor heterogeneity and provide potential strategies for personalized HCC management.

PMID:41634868 | DOI:10.1186/s40246-026-00927-w

Gut. 2026 Jan 30:gutjnl-2025-337247. doi: 10.1136/gutjnl-2025-337247. Online ahead of print.

ABSTRACT

BACKGROUND: Gastric cancer, with disproportionately higher incidence in East Asia, arises from complex host-microbiome-environment interactions beyond Helicobacter pylori (HP) infection. However, the molecular architecture linking environmental carcinogens, microbial succession and host response remains unclear.

OBJECTIVE: To delineate multifactorial aetiologies and clinically actionable subtypes/biomarkers of gastric cancer through integrative proteogenomic, microbial and environmental exposure profiling.

DESIGN: We established a multiomics atlas of paired tumour, adjacent mucosa tissues and blood from 154 treatment-naïve Taiwanese patients, integrating whole-exome sequencing, RNA-seq, proteome and phosphoproteome profiling with carcinogen signatures, HP status, microbiome composition and refined anatomical mapping. Cell-based functional assays tested carcinogen effects. Microbial subtype was assessed in an independent cohort.

RESULTS: A polycyclic-aromatic-hydrocarbon signature, dibenz[a,h]acridine, emerged as a high-risk exposure promoting invasion, immune suppression and poor survival, significantly exceeding nitrosamine-linked risk in this cohort. Multilayer integration defined three initiation ecologies: HP-driven inflammatory, non-HP microbiome-enriched immune-silent and HP-free microbially depleted states. Among HP-negative tumours, a Streptococcus-enriched subtype associated with tight-junction (CLDN18.2/ZO-1/OCLN) disruption and epithelial-mesenchymal transition, whereas a subset of clinically aggressive cases retained CLDN18.2-high epithelial-stable subtype for therapeutic accessibility. An independent cohort revealed gastric juice-derived Streptococcus anginosus abundance inversely correlated with tight-junction proteins. Anatomical mapping reveals location-specific, sex-specific, subtype-specific oncogenic networks and kinase activity, including CDK4 activation in clinical biomarker-negative tumours. Decision-tree models combining exposure and proteome-immune states refined recurrence and survival prediction beyond stage.

CONCLUSION: This proteogenomic framework defines exposure-informed and microbiome-informed gastric cancer subtypes, providing a molecular schema for patient stratification, prevention and actionable therapeutic vulnerabilities.

PMID:41617485 | DOI:10.1136/gutjnl-2025-337247

Discov Oncol. 2026 Jan 29;17(1):178. doi: 10.1007/s12672-025-03646-1.

ABSTRACT

Pulmonary nodules are a common radiological finding that can be classified as either benign or Malignant, with significant clinical implications. The early detection of malignant nodules is critically important for improving the prognosis of lung cancer, which remains the leading cause of cancer-related mortality worldwide. Traditional imaging techniques have Limitations in accurately classifying pulmonary nodules. Liquid biopsy, a minimally invasive method that evaluates circulating components in the Blood, presents promising diagnostic potential in this context. This study aims to evaluate the diagnostic capacity of multiple liquid biopsy biomarkers for early and accurate differentiation between benign and Malignant pulmonary nodules. Accordingly, we conducted a comprehensive study involving a meta-analysis, selecting 16 eligible studies that utilised liquid biopsy to assess various circulating biomarkers in the diagnostic yield. The most significant results were linked to circulating free DNA (cfDNA). However, other components, including circulating tumour cells (CTCs), microRNAs/pfeRNAs, extracellular vesicles (EVs), serological markers, and imaging techniques, also provided valuable information. Similarly, integrating multi-omics data with machine learning models has been shown to enhance the ability to differentiate between benign and malignant pulmonary nodules, thereby supporting early diagnosis and improved management for patients with lung cancer.

PMID:41612093 | PMC:PMC12855667 | DOI:10.1007/s12672-025-03646-1

Front Mol Biosci. 2026 Jan 12;12:1708518. doi: 10.3389/fmolb.2025.1708518. eCollection 2025.

ABSTRACT

Liquid biopsy has emerged as a transformative tool in precision oncology, offering a minimally invasive approach for cancer detection, monitoring, and treatment guidance. Unlike traditional tissue biopsies, which are invasive and limited by tumor accessibility and sampling bias, liquid biopsy enables real-time tumor assessment through the analysis of circulating biomarkers in blood and other biofluids. This review provides a comprehensive overview of recent advances in liquid biopsy, with a focus on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), non-coding RNAs, extracellular vesicles (exosomes), and secreted proteins. These biomarkers offer valuable insights into tumor biology, supporting applications in early diagnosis, prognosis, treatment response monitoring, and minimal residual disease detection across various cancer types. We also discuss state-of-the-art methodologies, including next-generation sequencing, digital PCR, microfluidics, proteomics, and emerging artificial intelligence-based approaches that enhance the sensitivity, specificity, and scalability of liquid biopsy assays. Clinical studies demonstrate the potential of liquid biopsy for tailoring targeted therapies, predicting resistance mechanisms, and identifying tumor recurrence earlier than conventional methods. Furthermore, FDA-approved assays and ongoing phase III and IV clinical trials highlight its growing integration into routine clinical practice. Beyond technical innovations, this review examines the global landscape of liquid biopsy, emphasizing opportunities and challenges for implementation across diverse healthcare settings. Disparities in access, particularly between high-income and low- and middle-income countries, underscore the need for strategies that ensure equitable adoption of liquid biopsy technologies worldwide. In summary, liquid biopsy represents a paradigm shift in oncology, bridging innovations in cancer diagnostics with clinical applications. By enabling dynamic, personalized, and less invasive cancer management, it holds great promise for improving patient outcomes and advancing precision medicine.

PMID:41602544 | PMC:PMC12832364 | DOI:10.3389/fmolb.2025.1708518

Discov Oncol. 2026 Jan 27. doi: 10.1007/s12672-026-04515-1. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic neuroendocrine tumor (pNET) is a heterogeneous tumor originating from pancreatic endocrine cells. Emerging evidence suggests that oxidative stress plays a crucial role in pNET pathogenesis, yet the precise molecular mechanisms and their interplay with the tumor microenvironment remain unclear. This study aims to systematically elucidate how oxidative stress-related pathways drive pNET progression through an integrated multi-omics approach.

METHODS: We designed a three-tier analytical strategy to address interconnected scientific questions. First, to identify which oxidative stress-related genes are dysregulated in pNET, we performed differential expression analysis and weighted gene co-expression network analysis (WGCNA) on the GSE73338 dataset (63 pNET samples, 5 controls), intersecting the. results with oxidative stress gene sets to obtain 71 candidate genes. Second, to understand the functional implications of these genes, we conducted GO/KEGG enrichment analysis and constructed protein-protein interaction (PPI) networks, from which we identified BCL2L1 and PHGDH as key hub genes using three independent algorithms. We then assessed their diagnostic value through ROC analysis and built a prognostic nomogram model. Third, to explore how these key genes influence the tumor microenvironment, we performed immune infiltration analysis using CIBERSORTx. Fourth, to reveal upstream regulatory mechanisms, we constructed ceRNA networks and predicted transcription factors. Fifth, to identify potential therapeutic interventions, we conducted drug prediction and molecular docking analyses. Finally, to validate our findings at cellular resolution and understand cellular heterogeneity, we analyzed single-cell RNA sequencing data from GSE256136 (20 samples), identifying cell types, quantifying cell-cell communications, and confirming key gene expression patterns across different cell populations.

RESULTS: Our systematic analysis revealed that oxidative stress-related genes in pNET were significantly enriched in the PI3K-Akt signaling pathway, cysteine and methionine metabolism, and HIF-1 signaling pathway. BCL2L1 and PHGDH emerged as central regulators with excellent diagnostic performance (AUC > 0.9). Immune infiltration analysis demonstrated significant alterations in activated dendritic cells, memory B cells, and resting NK cells, which correlated strongly with BCL2L1 and PHGDH expression, suggesting these genes link oxidative stress to immune dysfunction. The ceRNA network centered on KCNQ1OT1 and hsa-miR-15a-5p revealed multi-layered transcriptional and post-transcriptional regulation. Drug prediction identified sertindole and cabozantinib as promising therapeutic candidates. Single-cell analysis identified 11 cell types and confirmed that endocrine cells are the primary site of BCL2L1 and PHGDH dysregulation, with extensive crosstalk between endocrine cells and T cells potentially mediating immune evasion.

CONCLUSION: Through integrated multi-omics analysis, we established that oxidative stress pathways may drive pNET progression through a coordinated mechanism involving metabolic reprogramming (via BCL2L1 and PHGDH downregulation), immune microenvironment remodeling (through altered dendritic cell and NK cell function), and complex regulatory networks. BCL2L1 and PHGDH represent potential diagnostic biomarkers and candidate therapeutic targets that require experimental validation, providing new directions for precision medicine in pNET.

PMID:41591671 | DOI:10.1007/s12672-026-04515-1