AUTHOR=Ke Yumin , Liang Meili , Zhou Zhimei , Xie Yajing , Huang Li , Sheng Liying , Wang Yueli , Zhou Xinyan , Wu Zhuna 

TITLE=Recognition of pivotal immune genes NR1H4 and IL4R as diagnostic biomarkers in distinguishing ovarian clear cell cancer from high-grade serous cancer

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 12 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1600808

DOI=10.3389/fmolb.2025.1600808

ISSN=2296-889X

ABSTRACT=ObjectiveOvarian clear cell carcinoma (OCCC) is characterized by poor prognosis and limited early diagnostic markers. Identifying molecular distinctions between OCCC and the more common high-grade serous ovarian cancer (HGSC) is critical to developing targeted diagnostic and therapeutic strategies for improved clinical outcomes.MethodsWe retrieved the mRNA expression profiles of OCCC and HGSC from the Gene Expression Omnibus (GEO) database. To identify differentially immune-related genes (DIRGs) linked to OCCC. We assessed DIRGs functional enrichment and built a protein-protein interaction (PPI) to explore DIRGs interactions. Least Absolute Shrinkage and Selection Operator (LASSO) regression model and Multiple Support Vector Machine Recursive Feature Elimination (mSVM-RFE) methods were applied to identify predictive genes. The diagnostic performance of these candidate genes was evaluated using receiver operating characteristic (ROC) curves. A nomogram was constructed to predict OCCC. We further validated key DIRGs’ diagnostic ability via a validation set and immunohistochemistry (IHC). The CIBERSORT algorithm was used to analyze correlations between DIRGs and immune cell types in OCCC.ResultsWe detected 10 DIRGs in OCCC compared to HGSC. These genes were mainly linked to collagen-rich extracellular matrix, Phosphoinositide-3 Kinase- Protein Kinase B (PI3K-AKT) pathway, and transcriptional dysregulation in cancer. Nuclear receptor subfamily 1 group H member 4 (NR1H4) and Interleukin-4 Receptor (IL4R) emerged as potential biomarkers for OCCC (AUCNR1H4 = 0.809; AUCIL4R = 0.840). In the validation cohort, AUCNR1H4 = 0.848 and AUCIL4R = 0.821, respectively. IHC revealed higher expression levels of NR1H4 and IL4R in OCCC (P < 0.05). Additionally, NR1H4 correlated positively with resting memory T cells and neutrophils, while IL4R correlated with resting Natural Killer (NK) cells and neutrophils.ConclusionNR1H4 and IL4R are promising immune-related diagnostic biomarkers for OCCC, with potential roles in neutrophil-mediated tumor microenvironment modulation. These findings enhance understanding of OCCC pathogenesis and provide a foundation for developing targeted diagnostic tools and immunotherapeutic strategies.