摘要目的:探讨透明细胞性肾细胞癌（clear cell renal cell carcinoma，CCRCC）伴肉瘤样分化（CCRCCS）的分子机制，以筛选新的治疗靶标。方法:收集2017年1月至2018年10月诊断的5例CCRCCS石蜡包埋标本，对癌和肉瘤样成分分别进行全外显子组测序。选择全外显子组测序筛选到的一个钙黏蛋白23（CDH23）基因的高频错义突变位点进一步研究，收集2008年1月至2018年10月诊断的40例CCRCCS和50例CCRCC石蜡包埋标本，通过Sanger测序检测CDH23基因该位点序列信息，并行免疫组织化学检测90例扩大样本CDH23蛋白表达。结果:全外显子组测序结果显示，同一样本癌和肉瘤样成分具有大部分相同的体细胞突变，肉瘤样成分总的体细胞突变高于癌成分。筛选到一个在癌和肉瘤样成分中共同高频突变的CDH23基因的错义突变（p.Arg1804Gln），该位点突变导致介导CDH23功能的钙离子结合域蛋白序列发生改变。在扩大的90例样本中，CDH23（p.Arg1804Gln）突变在CCRCCS中的发生频率明显高于所有CCRCC。CDH23基因突变的CCRCCS病例中，CDH23蛋白多呈阴性或弱阳性表达，CDH23基因突变与蛋白表达呈正相关性（ r=0.598， P<0.01）。 结论:CDH23（p.Arg1804Gln）突变是CCRCCS的高危遗传因素，与肿瘤细胞中CDH23蛋白水平降低有关，进而影响CDH23蛋白功能发挥，表明CDH23突变可能与CCRCCS的肉瘤样转化有关，可能是CRCCCS潜在的治疗靶标。

abstractsObjective: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.