Giri Anil K
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Front Pharmacol. 2021 Feb 9;11:620811. doi: 10.3389/fphar.2020.620811. eCollection 2020.
Discovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colon cancer (CC) is necessary for precise identification of potential therapy responders. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression as well as their role in predicting therapy response in colon cancer are largely unexplored. In this study, using gene expression and methylation data from The Cancer Genome Atlas (TCGA) project, we showed that promoter DNA methylation negatively correlates with ETV4 expression ( = -0.17, = 5.6 × 10) and positively correlates with ETV5 expression ( = 0.22, = 1.43 × 10) in colon cancer tissue. Further, our analysis in 1,482 colon cancer patients from five different cohorts revealed that higher ETV5 expression associates with shorter relapse-free survival (RFS) of adjCTX treated colon cancer patients (Hazard ratio = 2.09-5.43, = 0.004-0.01). The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CC patients.
发现可预测局部晚期II期和III期结肠癌（CC）患者对基于5-氟尿嘧啶（5-FU）的辅助化疗（adjCTX）反应的标志物，对于精确识别潜在的治疗反应者至关重要。ETS转录因子（ETV1、ETV4和ETV5）的PEA3亚家族在包括结肠癌在内的多种癌症中上调。然而，调节其过表达的潜在表观遗传机制以及它们在预测结肠癌治疗反应中的作用在很大程度上尚未被探索。在本研究中，利用来自癌症基因组图谱（TCGA）项目的基因表达和甲基化数据，我们发现启动子DNA甲基化与结肠癌组织中ETV4表达呈负相关（r = -0.17，P = 5.6 × 10⁻⁵），与ETV5表达呈正相关（r = 0.22，P = 1.43 × 10⁻¹⁰）。此外，我们对来自五个不同队列的1482例结肠癌患者的分析表明，较高的ETV5表达与接受adjCTX治疗的结肠癌患者较短的无复发生存期（RFS）相关（风险比 = 2.09 - 5.43，P = 0.004 - 0.01）。本研究表明ETV5表达是II/III期CC患者基于5-FU的adjCTX反应的强预测生物标志物。
