Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma.
Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma.
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DOI：
10.1200/jco.2017.73.3238
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发表时间：
2017-11-10
期刊：
影响因子：
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通讯作者：
Parker AS
中科院分区：
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作者：
Ho TH;Kapur P;Eckel-Passow JE;Christie A;Joseph RW;Serie DJ;Cheville JC;Thompson RH;Homayoun F;Panwar V;Brugarolas J;Parker AS
zeste增强子同源物2（EZH 2）是一种染色质重塑物，与透明细胞肾细胞癌（ccRCC）的发病机制有关。然而，EZH 2对局部ccRCC结局的影响尚不清楚，分子生物标志物目前尚未整合到预后模型或辅助治疗试验中。我们进行了考克斯回归分析，以评估基于肿瘤的EZH 2基因和蛋白表达与三个独立队列中生存率的相关性：来自癌症基因组图谱的队列（n = 532），来自德克萨斯大学西南医学中心的队列（n = 122）和来自马约诊所的队列（n = 1，338）。对预后分期、大小、分级和坏死（SSGN）评分以及低、中、高风险SSGN组进行了调整。癌症基因组图谱队列中EZH 2高基因表达的患者发生总体死亡的可能性是EZH 2低表达患者的1.5倍（95% CI，1.1至2.3; P = 0.028）。德克萨斯大学西南医学中心队列中EZH 2高蛋白表达的患者总体死亡的可能性是EZH 2低表达患者的两倍（95% CI，1.1至4.4; P = 0.034）。同样，马约诊所队列中EZH 2蛋白高表达的患者发生总体死亡的可能性是其他患者的1.4倍（95%CI，1.2 - 1.7; P <0.001）。马约诊所队列中EZH 2蛋白高表达的患者发生RCC特异性死亡的可能性增加近两倍（95% CI，1.5至2.6; P < .001）; EZH 2蛋白表达在低风险SSGN肿瘤患者中具有特别的预后（HR，6.1; 95% CI，3.4至11.1; P < .001）。EZH 2表达准确预测RCC死亡风险，超出现有临床病理模型，特别是在低风险和中等风险SSGN肿瘤中。需要进一步的研究将分子生物标志物纳入监测指南和辅助临床试验。
Enhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials. We performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups. Patients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001). EZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.