Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC)

Renal cell carcinoma (RCC) is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-scale clear cell renal cell carcinoma (CCRCC) mutation sequencing projects identified a significantly increased mutation frequency of PBRM1 and the X chromosome encoded KDM5C in tumors from male patients and BAP1 in tumors from female patients. Mutation of BAP1 had previously been significantly associated with poorer overall survival; however, when stratified by gender, mutation of BAP1 only significantly affected overall survival in female patients. Mutation of chromatin remodeling genes alters gene regulation, but the overall effect of these alterations may also be modified by the presence of other gender specific factors. Thus, the combination of gender and mutation of a specific gene, such as BAP1, may have implications not only for prognosis but also for understanding the role of chromatin remodeling gene mutations in kidney cancer progression.

肾细胞癌（Renal cell carcinoma, RCC）每年在全球范围内的确诊病例超过20万例，约占所有恶性肿瘤的2%，但该疾病在不同性别间的分布存在显著不均衡性。以美国为例，其男女发病率之比约为2:1。有研究提出一项潜在假说：不同性别患者的肿瘤可能具有差异化的突变谱，例如由X染色体编码的基因突变在男性来源的肿瘤中更为高发。对三项近期开展的大型透明细胞肾细胞癌（clear cell renal cell carcinoma, CCRCC）突变测序项目的数据进行联合分析后发现，男性患者肿瘤中PBRM1以及X染色体编码的KDM5C的突变频率显著升高，而女性患者肿瘤中BAP1的突变频率更高。既往研究已证实，BAP1突变与较差的总生存期显著相关；但按性别分层分析后可见，BAP1突变仅在女性患者中与总生存期缩短存在显著关联。染色质重塑基因的突变会改变基因表达调控，但这类突变的整体效应也可能受到其他性别特异性因素的调控。因此，性别与特定基因（如BAP1）突变的联合作用，不仅可为肾癌预后评估提供参考依据，也有助于进一步阐明染色质重塑基因突变在肾癌进展中的作用机制。