Tong Kuo, Hu Zhongliang
Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410078, Hunan, China.
Department of Pathology, The Bishan Hospital of Chongqing, Bishan District, Chongqing, 402760, China.
Virchows Arch. 2021 Apr;478(4):647-658. doi: 10.1007/s00428-020-02900-x. Epub 2020 Aug 19.
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.
FOXI1是一种叉头框家族转录因子，在肾闰细胞（IC）的分化和功能维持中起关键作用。迄今为止，FOXI1的诊断效用很少被研究。利用来自癌症基因组图谱（TCGA）、基因表达综合数据库（Gene Expression Omnibus）和单细胞RNA测序数据集的转录组数据，结合对TCGA中FOXI1表达异常病例的突变数据、核型数据和数字切片进行综合分析，对正常肾组织以及包括嫌色肾细胞癌（chRCC）、肾嗜酸细胞瘤（RO）和其他肾细胞癌在内的不同肾肿瘤中FOXI1 mRNA表达进行了比较分析。对多种原发性肾肿瘤（n = 367）的福尔马林固定、石蜡包埋全组织切片进行FOXI1染色，以验证FOXI1转录水平。我们证实，与其他肾小管细胞和肾细胞癌亚型相比，FOXI1在闰细胞、嫌色肾细胞癌和肾嗜酸细胞瘤的mRNA水平上显著上调。此外，大多数FOXI1表达异常的病例在TCGA肾癌项目中被错误分类。还发现了一个涉及mTOR通路且频繁发生突变的潜在新实体。在远端肾单位的闰细胞中始终观察到FOXI1免疫反应性。FOXI1染色在93例嫌色肾细胞癌中的85例以及18例肾嗜酸细胞瘤中的13例中呈阳性。在源自非闰细胞的肾肿瘤（n = 254）中未观察到FOXI1染色。总之，FOXI1在正常肾组织中的表达仅限于闰细胞。这种细胞类型特异性表达在从闰细胞向嫌色肾细胞癌或肾嗜酸细胞瘤的肿瘤转化过程中得以保留。因此，FOXI1是IC相关肿瘤的潜在生物标志物。
