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Utility of RGNEF in the Prediction of Clinical Prognosis in Patients with Rectal Cancer Receiving Preoperative Concurrent Chemoradiotherapy.

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.

SUBMITTER: Chen CI

PROVIDER: S-EPMC8778573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The incorporation of chemoradiation prior to resection of the tumour has revolutionized the management of locally advanced rectal cancer. However, a large proportion of these patients are resistant to preoperative treatment schedule. We recently reported that c-Myc gene expression correlates negatively with this resistance in patients with rectal cancer. In this study, we carried out integrated analysis of miRNA and mRNA expression profiling in 45 pre-treatment rectal tumour. Further, expression of miRNAs and c-Myc, and their relationship with clinicopathological factors and patient survival was analysed. As a result, we found that 12 miRNAs were differentially expressed between responder and non-responder rectal cancer patients. Functional classification revealed an association between differentially expressed miRNAs and c-Myc. Subsequent quantitative real-time PCR results showed that both, miRNA-148 and miRNA-375 levels were significantly lower in responder compared to non-responder patients. Notably, the higher level of miRNA-375 was significantly negatively correlated with c-Myc. These results suggest that miRNA-375 and its targeted c-Myc play an important role as predictive biomarker of response to neoadjuvant treatment in patients with locally advanced rectal cancer, but still not suitable for prognosis. Pre-treatment biopsies of 22 patients with LARC were prospectively collected and freshly frozen according to an institutional board-approved protocol. Tumour response was assessed in surgical specimens by pathological examination based on the semi-quantitative tumour regression grading (TRG) system described by Mandard in 1994[36]: TRG1 and TRG2 scores were considered responders, whereas TRG3, TRG4, and TRG5 were classified as non-responders. The inclusion criteria were: histologically proven rectal tumour at a clinical stage UICC II-III (cT3-4/and or N positive), following endorectal ultrasound and/or MRI scan. Patients were excluded if they had the tumour located above 13 cm from the anal verge by rigid rectoscopy, synchronic colonic cancer assessed by colonoscopy, distant metastases by 18FDG PET-CT scan, and suspicion of hereditary colorectal cancer. All patients subsequently received a total dose of 50.4Gy of radiation (28 fractions of 1.8Gy) associated with capecitabine (oral form of 5-FU) with or without oxaliplatine, according to our Hospital Clinical Practice Guidelines. Standardized Surgery was performed, including total mesorectal excision, following an interval of 8-10 weeks after completion of CT/RT.

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Utility of RGNEF in the Prediction of Clinical Prognosis in Patients with Rectal Cancer Receiving Preoperative Concurrent Chemoradiotherapy.

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