Integration of <scp>scRNA</scp> ‐Seq and <scp>scATAC</scp> ‐Seq Reveals Malignant Characteristics of Sarcomatoid Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) with sarcomatoid differentiation is a rare histological type of ccRCC, characterized by aggressive clinical behavior and poor prognosis. However, the malignant characteristics of this disease have yet to be fully elucidated. Here, we performed single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), and WES analysis on a single patient with sarcomatoid ccRCC. By integrating scRNA-seq and scATAC-seq data from 19 previous classical ccRCC samples (19,819 tumor cells and 21,684 nuclei), we firstly identified the transcriptional regulatory features of sarcomatoid differentiated tumor cells by scATAC-seq, primarily evidenced by active binding with FOS/JUND, FOSL1/JUN, and FOSL2. In addition, we identified DST, FRMD4A, and PREX2 as tumor markers for ccRCC with sarcomatoid differentiation, which were validated in a cohort study. Moreover, we determined that PREX2 played a malignant role in ccRCC with sarcomatoid differentiation in vitro and in vivo, facilitating tumor progression by inhibiting PTEN and activating the PI3K/AKT pathway. This study demonstrated the comprehensive gene expression and DNA regulation information of ccRCC with sarcomatoid differentiation, highlighting its malignant characteristics, thereby offering novel insights for the diagnosis and treatment of sarcomatoid ccRCC.