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.
Highlights
Colorectal cancer (CRC) is heterogeneous and constitutes 10% of all cancer diagnoses.It is the third most prevalent cancer and the second leading cause (9.8%) of cancer death worldwide [1]
The results showed that ARHGEF28 was the most significantly upregulated gene involved in concurrent chemoradiotherapy (CCRT) resistance in rectal cancer
ARHGEF28 was selected for further analysis because it was the most upregulated gene related to CCRT resistance
Summary
Colorectal cancer (CRC) is heterogeneous and constitutes 10% of all cancer diagnoses. It is the third most prevalent cancer and the second leading cause (9.8%) of cancer death worldwide [1]. Rectal cancer, developing within 15 cm of the anal verge, accounts for about. 40% of CRC cases and is associated with worse clinical outcomes [1,2]. According to the GLOBOCAN 2020 data, there were an estimated 732,210 new cases of rectal cancer and. Advanced rectal cancer (LARC) remains a challenging malignancy. Fluoropyrimidine-based neoadjuvant concurrent chemoradiotherapy (CCRT) reduces the risk of local recurrence in patients with LARC [3,4,5]. New predictive biomarkers are needed for better patient stratification to ensure appropriate therapy
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