ETV5 expression positively correlates with promoter methylation and predicts response for 5-FU-based adjuvant therapy response in proximal 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 colorectal cancer (CRC) is necessary for early identification of potential responders as only 20-65% of CRC patients benefit from the treatment. 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 and their role in predicting therapy response in colon cancer is 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 ({rho}= -0.17, p=5.6x10-3) and positively correlates with ETV5 expression ({rho}= 0.22, p=1.43x10-4) in colon cancer tissue. Further, our analysis in 662 colon cancer patients treated with 5-FU-based-adjCTX revealed that higher ETV5 expression associated with shorter relapse-free survival (RFS) of treated patients with proximal tumors (Hazard ratio = 3.30 - 6.22, p=0.005-0.02). We also observed higher expression of signaling molecules involved in cellular proliferation (e.g. GNB5, DUSP4, FYN) in patients with high ETV5 level, suggesting that the increased cellular proliferation due to overexpression of these genes could drive the therapy resistance. The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CRC patients with proximal tumors.