Overexpression of REG4 confers an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy

[[abstract]]Background and Objectives: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is the standard treatment for locally advanced rectal cancer. Through data mining from published transcriptomic database, we identified Regenerating Gene Type IV (REG4) as the most significantly associated gene with resistance to CCRT. This study examined the prognostic impact of REG4 expression in patients with rectal cancer receiving neoadjuvant CCRT. Methods: REG4 immunohistochemistry was retrospectively assessed for pre-treatment biopsy specimens from 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery without initial distant metastasis. The results were correlated with the clinicopathological variables, disease-specific survival (DSS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS), as well as g-H2AX expression in post-treatment tumor samples. Results: High expression of REG4 was associated with advanced pre-treatment nodal status (P.0.026), advanced post-treatment tumor status (P.0.006), advanced post-treatment nodal status (P.0.001), advanced post-treatment tumor stage (P 0.001), and inferior tumor regression grade (P.0.001). Of note, high expression of REG4 emerged as an adverse prognosticator for DSS (P.0.0004), LRFS (P.0.0009), and MeFS (P.0.0254). After multivariate comparisons, it remained independently prognostic for worse DSS (hazard ratio [HR].2.731; P.0.025) and LRFS (HR.2.676; P.0.029). High expression of REG4 was also negatively associated with g-H2AX expression (P 0.0001, r.-0.708). Conclusions: High expression of REG4 is associated with poor therapeutic response, adverse outcome and an aggressive phenotype in rectal cancer patients treated with neoadjuvant CCRT, justifying REG4 is a surrogate marker to predict CCRT resistance