A novel highly frequent single‑nucleotide polymorphism site of cadherin 23 in clear cell renal cell carcinoma with sarcomatoid differentiation based on whole exome sequencing.

Clear cell renal cell carcinoma (CCRCC) with sarcomatoid differentiation (CCRCCS) displays invasive behavior, poor prognosis, and poor therapeutic response. The present study was aimed to gain new insights into the molecular mechanisms of sarcomatoid transformation, and identify new prognostic and therapeutic targets for CCRCCS. Whole exome sequencing was performed on matched carcinomatous and sarcomatoid elements from five specimens with CCRCCS. A non‑synonymous single‑nucleotide polymorphism (SNP) of cadherin 23 (CDH23) was further studied through Sanger sequencing in expanded 40 specimens with CCRCCS and 50 specimens with CCRCC. Carcinomatous and sarcomatoid elements shared most somatic single‑nucleotide variants (SSNVs) as revealed through whole exome sequencing. Sarcomatoid element had higher overall SSNVs than carcinomatous element. A highly frequent mutation of CDH23 (rs3802711) was observed in CCRCCS that resulted in an alteration in the highly conserved calcium‑binding site in the three‑dimensional (3D) structure mediating the functions of cadherins. In the expanded 90 specimens, CDH23 SNP (rs3802711) was a highly frequent mutation in CCRCCS than that in all CCRCC samples and even high grade CCRCC. Cox multivariate analysis indicated that CDH23 (rs3802711) genotype was an independent prognostic factor affecting the overall survival of the cohort. CDH23 gene and protein were negatively or weakly expressed in most CCRCCS specimens with CDH23 mutation. The present study revealed, for the first time, that the CDH23 (rs3802711) was a highly genetic risk factor for CCRCCS. It was associated with the decreased expression of CDH23 protein, resulting in the absence of cadherin function of CDH23, indicating that the CDH23 mutation may be involved in the sarcomatoid transformation in CCRCCS. Collectively, a novel and specific SNP of CDH23 was identified in CCRCCS and a new candidate cadherin involved in EMT was revealed. Furthermore, a new prognostic evaluation factor and potential therapeutic target for CCRCCS was identified.