Aim: Resistance to neoadjuvant chemoradiotherapy (NCRT) and tumor recurrence presents a major clinical problem in locally advanced rectal cancer (LARC) patients. This study aimed to explore a genetic risk score related to NCRT response and tumor recurrence in rectal cancer after NCRT.
Materials and Methods: Weighted gene co-expression network analysis was employed to identify hub genes associated with NCRT response from the GSE93375 dataset. Prognostic hub genes were determined using Cox regression analysis and associated with disease-free survival (DFS). A risk score system was constructed and the prognostic significance of the risk score was validated in our patient cohort. A predictive nomogram for DFS was developed and validated internally.
Results: The Tan module had the highest correlations with NCRT response. Ten hub genes (COL15A1, THBS2, ITGB1, MMP2, CD34, SPARC, NOTCH3, PDGFRB , DCN , and SERPINH1 ) were associated with NCRT response. Immunostaining expression of four genes (NOTCH3, SPARC, DCN , and ITGB1 ) was found to be significantly associated with both NCRT response and DFS in our patient cohort and was selected to build a prognostic risk score for DFS as follows: risk score= (0.6188×Exp_NOTCH3 ) + (0.6511×Exp_SPARC ) + (− 0.2976×Exp_DCN ) + (1.0035×Exp_ITGB1 ). Using this risk score, patients could be separated into high- and low-risk groups for tumor recurrence. A nomogram that incorporated the risk score, ypTNM stage, and tumor regression grade (TRG) was constructed and utilized to predict DFS in LARC patients.
Conclusion: The four-gene expression-based risk score system presented here could be potentially used for predicting tumor recurrence in LARC patients after NCRT.
Keywords: rectal cancer, chemoradiotherapy, treatment response, weighted gene co-expression network analysis, risk score