Background: Olfactory receptors (ORs) are G protein-coupled receptors that are aberrantly expressed in various cancers, including clear cell renal cell carcinoma (KIRC). However, the roles of ORs in KIRC are unknown. This study aimed to comprehensively analyze the expression profiles of OR genes in KIRC and evaluate their potential as diagnostic and prognostic biomarkers. Methods: We analyzed RNA-seq data from The Cancer Genome Atlas KIRC dataset, which contains 72 normal and 530 tumor samples. We selected OR genes with median transcripts per million (TPM) values of 1 or higher in at least one group (normal or tumor). Differential expression analysis was performed using the Student's t-test or Wilcoxon rank-sum test. The diagnostic potential of OR genes was evaluated using receiver operating characteristic (ROC) curve analysis. Kaplan-Meier analysis was employed to assess the association between OR gene expression and patient survival. Sex-based differences in OR gene expression were also examined. Results: We identified 11 OR genes with significant changes in KIRC expression. Among them, OR2A4, OR51E1, and OR7E14P showed high diagnostic performance, with AUC values of 0.951, 0.924, and 0.910, respectively. Combining these three genes improved the AUC to 0.972. High OR2A20P expression was significantly associated with poorer prognosis, whereas high OR7E7P expression was associated with better prognosis. We also found sex-based differences in the expression of OR2A7, OR2I1P, and OR7E14P, with females exhibiting significantly higher expression. Conclusions: Our findings suggest that ORs, especially OR2A4, OR51E1, and OR7E14P, could serve as potential diagnostic markers for KIRC. OR2A20P and OR7E7P may represent promising prognostic markers. The observed sex-based differences in OR gene expression highlight the need for personalized treatment of KIRC. Further studies are warranted to validate these findings and elucidate the functional roles of ORs in the pathogenesis of KIRC.

The authors have declared no competing interest.

This work was supported by JSPS KAKENHI Grant Numbers JP23K27975 and JP24K22277, and by Takahashi Industrial and Economic Research Foundation Grant Number 112 (2024).

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The study used ONLY openly available human data that were originally located at: The Cancer Genome Atlas Program (TCGA) - NCI.

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