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

Abstract

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.

E26 transformation-specific transcription variant 5 in development and cancer: modification, regulation and function

“…In colon cancer, 5-fluorouracil (5-FU)-based adjuvant chemotherapy is recommended for high-risk stage II patients as well as stage III patients, but its application is hampered by considerable toxicity and economic cost [ 152 ]. ETV5 expression is associated with the overall survival of patients treated with 5-FU-based adjuvant chemotherapy and affects the survival response of 5-FU treated stage III patients, suggesting that ETV5 can be used as a predictive biomarker for 5-FU-based adjuvant chemotherapy responses in stage II/III patients [ 153 ]. Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is currently used in patients with wild-type (WT) KRAS [ 154 ].…”

Identification and Validation of an Immune Evasion Molecular Subgroup of Patients With Colon Cancer for Implications of Immunotherapy

“…Moreover, activation of β-catenin signaling promotes T cell exclusion from the melanoma microenvironment (Spranger et al, 2015), and LSD1 expression prevents antitumor immunity (Sheng et al, 2018). Several studies recently revealed that the signatures based on gene expression of tumor immune infiltration cells manifest potentially better prognostic values (Wu et al, 2019;Bao et al, 2020;Giri, 2020;Gao et al, 2021;Wang et al, 2022). However, studies to evaluate the value of immune evasion-related genes (IEVGs) in the prediction of the prognosis of patients with colon cancer are lacking.…”