Liu Weisi, Fu Qiang, An Huimin, Chang Yuan, Zhang Weijuan, Zhu Yu, Xu Le, Xu Jiejie
From the Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (WL, QF, JX); Department of Urology, Shanghai Cancer Center, Fudan University, Shanghai (HA, YZ); Department of Urology, Zhongshan Hospital (YC); Department of Immunology, School of Basic Medical Sciences, Fudan University (WZ); and Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China (LX).
Medicine (Baltimore). 2015 Nov;94(45):e2004. doi: 10.1097/MD.0000000000002004.
DNA sequencing revealed that mutations in SETD2 occur in 3% to 12% of clear-cell renal cell carcinoma (ccRCC) cases and are associated with poor clinical outcome. In this study, we used an immunohistochemistry (IHC) assay to evaluate the impact of SETD2 loss, with expression of H3K36me3, a nonredundantly histone modification by SETD2, on recurrence and survival of nonmetastatic ccRCC patients after nephrectomy.SETD2 and H3K36me3 were assessed in 192 nonmetastatic ccRCC patients enrolled retrospectively from a single institution. Kaplan-Meier and Cox regression analysis were used to associate prespecified SETD2/H3K36me3 score with overall survival (OS) and recurrence-free survival (RFS). And a nomogram was constructed to predict OS at 10 years.Patients with low expression of SETD2 were prone to possess large tumor size and advanced pT stage. And low H3K36me3 expression was associated with larger tumor size. A prespecified combined score based on SETD2 and H3K36me3 expression remained an independent prognosticator for OS and RFS, which was associated with tumor size, pT stage, and sarcomatoid. Furthermore, using prespecified SETD2/H3K36me3 score could stratify nonmetastatic ccRCC patients into different risk subgroups, especially in patients dichotomized by pT stage and Fuhrman grade, respectively. Finally, the C-index for predicting OS increased from 0.727 to 0.747, after adding SETD2/H3K36me3 score to pT stage and Fuhrman grade.The combined score based on expression of SETD2 and H3K36me3 using IHC could predict poor clinical outcomes in nonmetastatic ccRCC patients, and it may benefit preoperative risk stratification and guide treatment planning in the future.
DNA测序显示，3%至12%的透明细胞肾细胞癌（ccRCC）病例中存在SETD2突变，且这些突变与不良临床预后相关。在本研究中，我们采用免疫组织化学（IHC）检测方法，评估SETD2缺失以及SETD2特异性的组蛋白修饰H3K36me3的表达对肾切除术后非转移性ccRCC患者复发和生存的影响。对从单一机构回顾性纳入的192例非转移性ccRCC患者进行SETD2和H3K36me3评估。采用Kaplan-Meier法和Cox回归分析将预先设定的SETD2/H3K36me3评分与总生存期（OS）和无复发生存期（RFS）相关联。并构建列线图预测10年OS。SETD2低表达的患者倾向于具有较大肿瘤大小和较高的pT分期。而H3K36me3低表达与较大肿瘤大小相关。基于SETD2和H3K36me3表达的预先设定的综合评分仍然是OS和RFS的独立预后因素，其与肿瘤大小、pT分期和肉瘤样变相关。此外，使用预先设定的SETD2/H3K36me3评分可将非转移性ccRCC患者分层为不同风险亚组，特别是分别按pT分期和Fuhrman分级二分法分组的患者。最后，在将pT分期和Fuhrman分级加入SETD2/H3K36me3评分后，预测OS的C指数从0.727提高到0.747。基于IHC的SETD2和H3K36me3表达的综合评分可预测非转移性ccRCC患者的不良临床结局，未来可能有助于术前风险分层并指导治疗计划。
