Identification of hub genes associated with sensitivity to neoadjuvant chemoradiation in locally advanced rectal cancer

Abstract

Abstract: Preoperative neoadjuvant chemoradiation (NACR) can reduce tumor size and clinical stage in most locally advanced rectal cancer (LARC) patients, enhance local disease control, promote anal preservation, and decrease the rate of local recurrence. However, there is still a scarcity of confirmed biomarkers that identify individuals who are susceptible to NACR. The goal of this study was to find potential biomarkers to assess therapy response, and to aid risk stratify individuals. Differentially expressed genes (DEGs) were obtained from GEO database among NACR-sensitive and resistant patients. STRING and Cytoscape were utilized to construct PPI networks and identify hub genes. Based on CIBERSORT, TCGA, GTEx, GSEA and Roc curves, the connections between hub genes and specific signaling pathways, immune cell infiltration, prognosis value and miRNA-transcription factor (TF)-target network were investigated. HPA was used to visualize hub gene expression in clinical samples. We identified 512 up- and 349 down-regulated genes in GSE119409; 1,171 up- and 1,355 down-regulated genes in GSE123390; and 936 up- and 762 down-regulated genes in GSE150082. The up-regulated DEGs were searched for highly expressed genes in the NACR-resistant, TCGA and GTEx-related datasets compared to the NACR-sensitive group, yielding a total of six hub genes (RRM2, HNRNPL, EZH2, METTL1, NHP2L1 and ASF1B). ROC curves for the six genes revealed their utility in predicting NACR sensitivity. Immune infiltration research revealed no significant relationship between LARC neoadjuvant chemoradiation sensitivity and immune cell infiltration extent. The miRNA-TF-target network was established. Finally, HPA online database results showed that six genes were expressed at variable levels in rectal cancer patients. This study convincingly identified RRM2, HNRNPL, EZH2, METTL1, NHP2L1 and ASF1B were up-regulated in LARC and involved in many pathways in tumor cell biology. These biomarkers had a high potential for predicting patients' susceptibility to NACR and benefit from this therapy.