FOXI1 expression in chromophobe renal cell carcinoma and renal oncocytoma: a study of The Cancer Genome Atlas transcriptome-based outlier mining and immunohistochemistry.

FOXI1 is a forkhead family transcription factor that plays a key role in differentiation and functional maintenance for the renal intercalated cell (IC). The diagnostic utility of FOXI1 is rarely studied thus far. Comparative analyses of FOXI1 mRNA expression in normal kidney tissue and different renal neoplasms including chromophobe renal cell carcinoma (chRCC), renal oncocytoma (RO), and other renal cell carcinomas were conducted using transcriptomic data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, and single-cell RNA-seq datasets, in combination with integrative analyses using mutant data, karyotype data, and digital slides for cases with anomalous FOXI1 expression in TCGA. Formalin-fixed, paraffin-embedded whole-tissue slides of varied primary renal neoplasms (n = 367) were subjected to FOXI1 staining for validating FOXI1 transcription levels. We confirmed that FOXI1 was significantly upregulated at mRNA levels in ICs, chRCCs, and ROs compared with other renal tubule cell and renal cell carcinoma subtypes. Furthermore, most of the cases with FOXI1 expression outliers were misclassified in the TCGA kidney cancer project. An underlying novel entity with frequent mutations involved in the mTOR pathway was also found. FOXI1 immunoreactivity was consistently noted in ICs of the distal nephron. FOXI1 staining was positive in 85 of 93 chRCCs and 13 of 18 ROs, respectively. FOXI1 staining was not seen in renal neoplasms (n = 254) derived from non-ICs. In conclusion, FOXI1 expression in normal kidney tissue is restricted to ICs. This cell type-specific expression is retained during neoplastic transformation from ICs to chRCCs or ROs. FOXI1 is thereby a potential biomarker of IC-related tumors.