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[Whole exome sequencing reveals molecular mechanisms of clear cell renal cell carcinoma with sarcomatoid
1Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao 266003, China.
Abstract:
Objective: To investigate the molecular mechanisms of clear cell renal cell carcinoma (CCRCC) with sarcomatoid differentiation (CCRCCS) and to explore new therapeutic targets for CCRCCS. Methods: Whole exome sequencing was performed on the carcinomatous and sarcomatoid components of five CCRCCS cases collected from January 2017 to October 2018. A highly frequent non-synonymous mutation of cadherin 23 (CDH23) was revealed by whole exome sequencing and further studied in additional samples. The sequencing of CDH23 in 40 specimens with CCRCCS and 50 specimens with CCRCC collected from January 2008 to October 2018 were conducted using Sanger sequencing. Immunohistochemistry was carried out to detect the protein expression of CDH23 in the additional 90 cases. Results: Carcinomatous and sarcomatoid components of CCRCCS shared most of the somatic single-nucleotide variants (SSNVs) as revealed through whole exome sequencing, while the sarcomatoid component had higher overall SSNVs than carcinomatous component. A highly frequent non-synonymous mutation of CDH23 (p.Arg1804Gln) was observed both in carcinomatous and sarcomatoid components of CCRCCS that resulted in the alteration in the highly conserved calcium-binding site mediating the functions of cadherins. In the additional 90 specimens, CDH23 mutation was much frequently detected in CCRCCS than that in CCRCC samples and even the high grade CCRCC. CDH23 protein was not or weakly expressed in most CCRCCS specimens with CDH23 mutation. There was an correlation between CDH23 gene mutation and negative expression of its protein (r=0.598, P<0.01). Conclusions: The present study reveals, for the first time, that the mutation of CDH23 (p.Arg1804Gln) is a genetic risk factor for CCRCCS. It is associated with the decreased expression of CDH23 protein, resulting in the absence of cadherin function of CDH23, indicating that CDH23 mutation may be involved in the sarcomatoid transformation in CCRCCS. Thus, CDH23 might be a potential therapeutic target for CCRCCS.
Insights
A mutation in the cadherin 23 (CDH23) gene is a significant risk factor for clear cell renal cell carcinoma with sarcomatoid differentiation (CCRCCS). This CDH23 mutation leads to decreased protein expression, suggesting it
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (CCRCC) is a common kidney cancer.
- Sarcomatoid differentiation (CCRCCS) is associated with aggressive tumor behavior and poor prognosis.
- The molecular mechanisms underlying CCRCCS remain incompletely understood.
Purpose of the Study:
- To investigate the molecular underpinnings of CCRCCS.
- To identify potential therapeutic targets for CCRCCS.
Main Methods:
- Whole exome sequencing (WES) of carcinomatous and sarcomatoid components from CCRCCS cases.
- Targeted sequencing of the cadherin 23 (CDH23) gene in a larger cohort.
- Immunohistochemistry to assess CDH23 protein expression.
Main Results:
- A recurrent non-synonymous mutation (p.Arg1804Gln) in the CDH23 gene was identified in both components of CCRCCS.
- This CDH23 mutation was significantly more frequent in CCRCCS compared to CCRCC, including high-grade CCRCC.
- CDH23 gene mutation correlated with decreased or absent CDH23 protein expression, impacting its cadherin function.
Conclusions:
- CDH23 (p.Arg1804Gln) mutation is a novel genetic risk factor for CCRCCS.
- CDH23 mutation-associated loss of protein function may drive sarcomatoid transformation.
- CDH23 represents a potential therapeutic target for CCRCCS.
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