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.

Wenjuan Yu,Xiaohui Wang,Wei Zhang,Yuewei Wang,Yanxia Jiang,Hailei Shi,Yujun Li

doi:10.3892/or.2020.7613

Abstract

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 cadherin23 (CDH23) was further studied through Sanger sequencing in expanded 40specimens with CCRCCS and 50specimens 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.

Highlights

Renal cell carcinoma (RCC) with sarcomatoid differentiation is a relatively rare renal tumor, and clear cell renal cell carcinoma (CCRCC) with sarcomatoid differentiation accounts for approximately 79% [1]
Somatic single nucleotide variants (SSNVs) in CCRCC with sarcomatoid differentiation (CCRCCS) were first screened in the five groups through whole exome sequencing
With the advent of generation sequencing (NGS), few researchers have applied this technology to the research of CCRCCS

Summary

Introduction

Renal cell carcinoma (RCC) with sarcomatoid differentiation is a relatively rare renal tumor, and clear cell renal cell carcinoma (CCRCC) with sarcomatoid differentiation accounts for approximately 79% [1]. According to the World Health Organization (WHO) 2016 classification system, RCC with sarcomatoid differentiation was not classified into a distinct subtype, it is considered to be a specific histological characteristic of RCC [2,3]. CCRCC with sarcomatoid differentiation (CCRCCS) is of Fuhrman IV grade, its prognosis is worse in comparison to other high‐grade RCCs. Approximately 80% of patients have been reported to be prone to distant meta stasis with a median overall survival of only 5.8 months, and 38% of patients had a survival of one year. Frequently reduced expression of epithelial adhesion molecules, such as E‐cadherin and aberrant expression of YU et al: A Novel HighLY Frequent SNP of CDH23 in CCRCCS

Methods

Results

Conclusion