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.
Highlights
Colon cancer (CC) is the fourth most commonly diagnosed cancer (2 million cases in 2018) globally and kills nearly 1 million people annually (Arnold et al, 2017) mostly due to the spread of tumor cells to other secondary organs in the later stage of the disease (Yu et al, 2019)
We compared the expression level of ETV1, ETV4, and ETV5 between the normal and cancerous tissue in The Cancer Genome Atlas (TCGA) data and observed higher expression of only ETV4 (Wilcox test p 4.90 × 10–25) and ETV5 (Wilcox test p 5.17 × 10–9) in tumor suggesting their possible role in tumor biology (Figures 1A,B) Further, our analysis revealed that promoter methylation negatively correlates with ETV4 expression (ρ -0.17, p 5.6 × 10–3) whereas positively correlates with ETV5 expression (ρ 0.22, p 1.43 × 10–4) in cancer tissue suggesting that DNA methylation play a strong role in regulating ETV5 and ETV4 expression in colon cancer tissue (Figures 1C-F)
ETV5 Correlates With Disease Free Survival Of Stage II/III Patients Treated With Adjuvant Chemotherapy
Summary
Colon cancer (CC) is the fourth most commonly diagnosed cancer (2 million cases in 2018) globally and kills nearly 1 million people annually (Arnold et al, 2017) mostly due to the spread of tumor cells to other secondary organs (e.g., liver) in the later stage (stage IV) of the disease (Yu et al, 2019). ETV1, ETV4, and ETV5 are the members of the polyoma enhancer activator 3 (PEA3) subfamily of E26 transformationspecific (ETS) domain-containing transcription factors They promote cancer cell proliferation and survival in solid tumors including gastric (Keld et al, 2011), ovarian (Llaurado et al, 2012), and colon (Cheng et al, 2019) cancers and are being targeted for therapy (Hsing et al, 2020). The available evidence suggests that PEA3 subfamily members could be a potential biomarker for therapy response against CC (Llaurado et al, 2012), and their role in predicting adjCTX response has not been explored in any cancers including CC. Our analysis identified and validated ETV5 expression as a predictive marker for 5-FU-based adjCTX response in stage II and II colon cancer patients
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