长链非编码RNA ReCAL作为肾透明细胞癌预后标志物和靶向治疗反应预测因子的研究

LncRNA ReCAL as aprognostic biomarker and targeted-therapy response predictor in clear cell renal cell carcinoma

目的分析肾透明细胞癌(ccRCC)患者队列转录组数据,寻找一种可靠的长链非编码RNA(lncRNA)作为预测ccRCC患者预后的生物标记物,对患者个体化治疗方案的有效制订和改善预后提供参考。方法开发一种综合数据挖掘策略来识别3个筛选队列中的预测候选lncRNA。在2004年至2012年间收集的多中心的1908例ccRCC患者中,对所选lncRNA的预后价值进行验证,中位随访时间为96个月(IQR 46-105)。对98例接受舒尼替尼或索拉非尼治疗的患者进行lncRNA表达与临床预后的关系分析。主要临床终点是总生存期(OS)。采用单变量和多变量Cox回归、Kaplan-Meier曲线评估lncRNA表达与临床终点的相关性。结果ReCAL(与肾癌相关的lncRNA)被认为是研究队列中与OS相关最显著的lncRNA。多中心队列验证证实ReCAL的预后价值。在多变量模型中,较高的ReCAL表达与低OS相关(长海队列:HR:3.391;95%CI:2.741~4.386;P=1.344E-14。长征队列:HR:2.473;95%CI:1.062~3.251;P=0.044。东总队列:HR:2.409;95%CI:1.097~3.210;P=0.037)。ReCAL在低危Mayo Clinic SSIGN评分肿瘤患者中尤其具有预后价值。低表达ReCAL的肾癌患者表现出对舒尼替尼(HR:0.157;95%CI:0.033~0.744;P=0.020)或索拉非尼(HR:0.470;95%CI:0.229~0.646;P=0.031)靶向治疗较好的反应性。结论高表达ReCAL是ccRCC患者预后不良的独立生物标志物,也是靶向治疗反应不良的预测性生物标志物。

Objective To analyze the transcriptome data of patients with renal clear cell carcinoma(ccRCC)and to identify a robust long noncoding RNA(lncRNA)biomarker to predict the prognosis of patients with ccRCC,and to provide a reference for the effective formulation of individualized treatment and improvement of prognosis.Methods An integrative data-mining strategy was developed to identify prognostic candidate lncRNA in three discovery cohorts.The prognostic value of selected lncRNA was validated in 1908 ccRCC patients from multi-institutional cohorts collected between 2004 and 2012,with median follow-up of 96 months(IQR 46-105).A total of 98 patients who underwent sunitinib or sorafenib treatment with matched patients were analyzed for the relationship between lncRNA expression and clinical outcomes.The primary clinical endpoint was overall survival(OS).Univariable and multivariable Cox regression,Kaplan-Meier curves and Harrell′s C-index were used to evaluate the association of lncRNA expression with these end-points.Results Renal Cancer Associated LncRNA(ReCAL)was identified as the most significant lncRNA associated with OS in discovery cohorts.Validation in multi-institutional cohorts confirmed the prognostic value of ReCAL.In multivariable models,higher ReCAL expression was associated with poor OS(Changhai,HR,3.391;95%CI,2.741-4.386;P=1.344E-14;Changzheng,HR,2.473;95%CI,1.062-3.251;P=0.044;Nanjing,HR,2.409;95%CI,1.097-3.210;P=0.037).ReCAL was particularly prognostic among patients with low-risk Mayo Clinic SSIGN score tumors.Patients with low ReCAL expression showed improved response after sunitinib(HR,0.157;95%CI,0.033-0.744;P=0.020)or sorafenib(HR,0.470;95%CI,0.229-0.646;P=0.031)treatment.Conclusion High ReCAL is an independent prognostic biomarker for poor outcome and a predictive biomarker for poor targeted therapy response in ccRCC patients.