Abstract
Rectal cancer is a heterogeneous malignancy with different clinical responses to preoperative concurrent chemoradiotherapy (CCRT). To discover the significant genes associated with CCRT response, we performed data mining of a transcriptomic dataset (GSE35452), including 46 rectal cancer patients who received preoperative CCRT and underwent standardized curative resection. We identified ARHGEF28 as the most significantly upregulated gene correlated with resistance to CCRT among the genes related to Rho guanyl-nucleotide exchange factor activity (GO:0005085). We enrolled 172 patients with rectal cancer receiving CCRT with radical surgery. The expression of ARHGEF28 encoded protein, Rho guanine nucleotide exchange factor (RGNEF), was assessed using immunohistochemistry. The results showed that upregulated RGNEF immunoexpression was considerably correlated with poor response to CCRT (p = 0.018), pre-CCRT positive nodal status (p = 0.004), and vascular invasion (p < 0.001). Furthermore, high RGNEF expression was significantly associated with worse local recurrence-free survival (p < 0.0001), metastasis-free survival (MeFS) (p = 0.0029), and disease-specific survival (DSS) (p < 0.0001). The multivariate analysis demonstrated that RGNEF immunoexpression status was an independent predictor of DSS (p < 0.001) and MeFS (p < 0.001). Using Gene Ontology enrichment analysis, we discovered that ARHGEF28 overexpression might be linked to Wnt/β-catenin signaling in rectal cancer progression. In conclusion, high RGNEF expression was related to unfavorable pathological characteristics and independently predicted worse clinical prognosis in patients with rectal cancer undergoing CCRT, suggesting its role in risk stratification and clinical decision making.