WRN Promoter CpG Island Hypermethylation Does Not Predict More Favorable Outcomes for Patients with Metastatic Colorectal Cancer Treated with Irinotecan-Based Therapy.
WRN Promoter CpG Island Hypermethylation Does Not Predict More Favorable Outcomes for Patients with Metastatic Colorectal Cancer Treated with Irinotecan-Based Therapy.
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WRN 启动子 CpG 岛高甲基化并不预示接受伊立替康治疗的转移性结直肠癌患者会获得更有利的结果
DOI：
10.1158/1078-0432.ccr-15-2703
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发表时间：
2016-09-15
期刊：
影响因子：
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通讯作者：
Grady WM
中科院分区：
文献类型：
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作者：
Bosch LJ;Luo Y;Lao VV;Snaebjornsson P;Trooskens G;Vlassenbroeck I;Mongera S;Tang W;Welcsh P;Herman JG;Koopman M;Nagtegaal ID;Punt CJ;van Criekinge W;Meijer GA;Monnat RJ Jr;Carvalho B;Grady WM
目的：据报道，结直肠癌中WRN启动子CpG岛高甲基化会增加对伊立替康治疗的敏感性。我们的目的是表征WRN启动子的甲基化，确定WRN启动子超甲基化对表达的影响，并验证先前的报道，即WRN启动子超甲基化预测伊立替康治疗转移性结直肠癌（mCRC）患者的预后改善。实验设计：使用甲基化特异性PCR和亚硫酸盐测序法评估WRN甲基化状态。采用qRT-PCR和Western blotting检测WRN的表达。在183例mCRC患者中，WRN甲基化状态与总生存期（OS）和无进展生存期（PFS）相关。在这些患者中，90例接受卡培他滨单药治疗作为一线治疗，93例接受卡培他滨加伊立替康（CAPIRI）治疗作为CAIRO III期临床试验的一部分。结果：在结直肠癌细胞系和原发性结直肠癌中，WRN mRNA和WRN蛋白的表达水平较低，且在很大程度上与WRN甲基化状态无关。与未甲基化的WRN结直肠癌患者相比，甲基化的WRN结直肠癌患者的OS较短（HR = 1.6； 95%可信区间[CI]， 1.2-2.2; P = 0.003）。与单独使用卡培他滨相比，未甲基化WRN患者在接受CAPIRI治疗时的PFS明显更长（HR = 0.48; 95% CI, 0.32-0.70; P = 0.0001）。相比之下，当WRN甲基化时，患者没有从伊立替康加入卡培他滨中获益（HR = 1.1; 95% CI, 0.69-1.77; P = 0.7）。结论：结直肠癌中WRN的表达在很大程度上独立于WRN启动子超甲基化。此外，我们无法验证先前的发现，即WRN启动子高甲基化预测伊立替康治疗mCRC的临床结果改善，而是发现相反的结果。临床癌症研究；22 (18);4612 - 22所示。AACR©2016。
Purpose: WRN promoter CpG island hypermethylation in colorectal cancer has been reported to increase sensitivity to irinotecan-based therapies. We aimed to characterize methylation of the WRN promoter, determine the effect of WRN promoter hypermethylation upon expression, and validate a previous report that WRN promoter hypermethylation predicts improved outcomes for patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based therapy. Experimental Design: WRN methylation status was assessed using methylation-specific PCR and bisulfite sequencing assays. WRN expression was determined using qRT-PCR and Western blotting. WRN methylation status was correlated with overall survival (OS) and progression-free survival (PFS) in 183 patients with mCRC. Among these patients, 90 received capecitabine monotherapy as first-line therapy, and 93 received capecitabine plus irinotecan (CAPIRI) therapy as part of the CAIRO phase III clinical trial. Results: WRN mRNA and WRN protein expression levels were low in colorectal cancer cell lines and in primary colorectal cancer and were largely independent of WRN methylation status. Patients with methylated WRN colorectal cancer had a shorter OS compared with patients who had unmethylated WRN colorectal cancer (HR = 1.6; 95% confidence interval [CI], 1.2–2.2; P = 0.003). Patients with unmethylated WRN showed a significantly longer PFS when treated with CAPIRI compared with capecitabine alone (HR = 0.48; 95% CI, 0.32–0.70; P = 0.0001). In contrast, patients did not benefit from adding irinotecan to capecitabine when WRN was methylated (HR = 1.1; 95% CI, 0.69–1.77; P = 0.7). Conclusions: WRN expression is largely independent of WRN promoter hypermethylation in colorectal cancer. Moreover, we could not validate the previous finding that WRN promoter hypermethylation predicts improved clinical outcomes of mCRC treated with irinotecan-based therapy and found instead the opposite result. Clin Cancer Res; 22(18); 4612–22. ©2016 AACR.