Background
Chemotherapy resistance is one of the major reasons for treatment failure and tumour recurrence in colorectal cancer. Recent studies indicate that cancer stem cells (CSCs) are responsible for chemotherapy resistance. This study aims to establish a stemness-related gene signature for predicting the prognosis of colorectal cancer patients with adjuvant chemotherapy.
Methods
Two independent cohorts with complete gene expression profiles, adjuvant chemotherapy and survival information were included. GSE39582 (n = 566) was used as the training cohort and TCGA (n = 624) as the validation cohort. 233 patients from GSE39582 and 231 patients from TCGA with complete gene expression profiles, adjuvant chemotherapy and survival information were finally included in our study, respectively. Nine widely recognized CSC markers were used to identify stemness-related genes from the protein-protein interaction database (BioGRID). Candidate genes were further filtered by Cox regression with bootstrap and then LASSO Cox was used to construct the prognostic model. Univariate and multivariate analyses were conducted to evaluate the prognostic value of the model. Pathway analysis was conducted between the risk groups for functional study.
Results
We constructed a 10-gene signature and divided patients into two groups using an optimal cut-off determined using time-dependent ROC analysis. The Kaplan-Meier curves showed that patients in the high-risk group had a significantly poorer 5-year disease-free survival (DFS) than those in the low-risk group (training cohort: hazard ratio (HR)=2.41[1.58-3.66], P < 0.001; validation cohort: HR=1.82[1.17-2.83], P < 0.001). More importantly, the 10-gene signature could also robustly stratify stage II and III patients into high- and low-risk groups (training cohort: HR=2.61[1.62-4.23], P < 0.001; validation cohort: HR=1.87[1.03-3.40], P=0.037). Multivariate analysis showed that the 10-gene signature was an independent prognostic factor for colorectal cancer patients with adjuvant therapy (training cohort: HR=1.94[1.23-3.08], P < 0.001; validation cohort: HR=1.66[1.06-2.61], P = 0.027). Functional analysis showed that several pathways were dysregulated in the high-risk group, including EMT, myogenesis and KRAS signalling.
Conclusions
The stemness-related gene signature is a robust predictive tool for colorectal cancer. Patients in the high-risk group may not be suitable for chemotherapy due to a higher risk of chemotherapy resistance.