Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer

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 (ρ = -0.17, p = 5.6 × 10^-3) and positively correlates with ETV5 expression (ρ = 0.22, p = 1.43 × 10^-4) 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, p = 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.