Human Mutation最新文献

Colorectal cancer is acknowledged as the fifth most common cause of cancer-related mortality, presenting significant challenges for patient outcomes due to its relatively gradual progression and the subtle nature of its initial symptoms. Carbohydrates, essential nutrients in cellular function, participate in various metabolic processes, including glycolysis, oxidative phosphorylation, and the pentose phosphate pathway. Recent studies have established that irregularities in carbohydrate metabolism play a critical role in tumor cell growth, development, and treatment resistance. Glycolysis serves as a crucial regulatory component of metabolism in cancer cells, influencing cell growth, proliferation, and functionality by modifying carbohydrate utilization. By diminishing oxidative phosphorylation activity and enhancing energy production through glycolysis, tumor cells augment their proliferative capacity and partially evade immune responses. As a result, glycolysis significantly contributes to tumor progression. We have comprehensively outlined the functions of glycolysis and its key enzymes concerning the diagnosis, treatment strategies, and immune microenvironment of colorectal cancer, with the goal of delivering innovative insights and perspectives for the clinical management and diagnosis of this condition.

Glucokinase regulatory protein (GCKR) is a metabolic regulator implicated in glucose homeostasis, but its genetic and functional roles in cancer remain poorly understood. Through integrated pan-cancer multiomics and experimental analyses, we mapped the expression and mutational landscape of GCKR with a focus on gastric cancer. GCKR expression was downregulated in most tumors but upregulated in subsets such as kidney renal papillary carcinoma (KIRP) and lung adenocarcinoma (LUAD). Genomic profiling revealed recurrent alterations, with the highest mutation frequencies observed in sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC), and missense mutations representing the predominant variant type, particularly in breast cancer (BRCA). Functionally, reduced GCKR expression in gastric cancer was associated with an immune-cold phenotype characterized by diminished cytotoxic T cell infiltration, impaired antigen presentation, and metabolic reprogramming. Spatial transcriptomics and single-cell analyses highlighted compartment-specific heterogeneity and links with cancer-associated fibroblasts and macrophages. Clinically, low GCKR expression predicted poorer survival and reduced immunotherapy benefit, while higher expression indicated selective sensitivity to MEK inhibitors including refametinib and PD0325901. These findings define GCKR as both a mutation- and expression-driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.

Head and neck squamous cell carcinoma (HNSCC) ranks second among men and sixth globally, with a notable increase in HPV-associated cases. However, the molecular underpinnings and immune landscape of HPV+ HNSCC remain incompletely understood. In this study, we first retrieved and harmonized single-cell RNA sequencing (RNA-Seq), bulk RNA-Seq, and spatial transcriptomic profiles from public repositories. We then applied high-dimensional weighted gene coexpression network analysis (hdWGCNA) and gene nonnegative matrix factorization (GeneNMF) to dissect HPV+ epithelial subpopulations, their extracellular matrix (ECM)–interacting ligand programs, and CXCL/complement immune circuits. Furthermore, we mapped the spatial niches of malignant and immune cells and constructed a consensus prognostic index using 101 machine learning algorithms. Our findings revealed transcriptionally distinct HPV+ epithelial clusters that activate viral oncogenesis, inflammatory pathways, and ECM-sensing pathways. These cells communicate with stromal and immune compartments via CXCL axes and complement cascades, yet they are spatially segregated from lymphocytes. A high-risk signature, identified as HPV-related risk genes including TRMT112, stratified the TCGA-HNSC and GSE65858 cohorts into patients with markedly worse 1-, 2-, and 3-year survival rates (ROC–AUC 0.934, 0.968, and 0.973) and poor responses to immunotherapy. Notably, TRMT112 expression inversely correlated with cytotoxic T-cell infiltration, mechanistically linking it to the formation of “cold” tumors. Our integrative analysis defines HPV-driven epithelial subpopulations whose TRMT112-enriched, immune-excluded microenvironment contributes to therapeutic resistance, thus providing robust prognostic biomarkers and actionable targets for precision immunotherapy in HPV+ HNSCC.