Abstract 3148: Identification and establishment of an 18-gene redox signature for recurrence prediction in colorectal cancer

Abstract

Abstract Purpose: Colorectal cancer (CRC) is the third most common cancers worldwide. The immediate clinical challenge is the identification of high-risk CRC patients, particularly stage II and III, who are genuine candidates for adjuvant chemotherapy, while sparing the low-risk patients from the toxicity and expense of such treatment modalities. According to ASCO guidelines, the high-risk stage II CRC patients are currently defined by specific clinicopathological risk factors. However, the prognosis of patients, even with similar clinicopathological features varies significantly; highlighting their inadequacy in identifying true high-risk CRC patients. Accumulating evidence shows that redox adaptation provides survival benefit to cancer cells and enhances resistance to conventional chemotherapy. Therefore, in this study we performed a comprehensive evaluation of the clinical potential of redox-related genes as recurrence prediction biomarkers in CRC patients. Experimental Design: We undertook a rigorous biomarker discovery effort (GSE33113, n=90), followed by validation of a redox gene signature for recurrence prediction in two datasets (GSE39582, n=461 and GSE14333, n=185) of stage II and III CRC patients. The 18-gene signature discovered from the genome wide discovery effort was subsequently validated in an independent in-house clinical cohort (n=128) by qRT-PCR assays. Univariate and multivariate analyses were performed using CoxPH regression by including various clinicopathological features. Results: A systematic analysis of 312 redox-related genes in three public datasets of 736 CRC patients led to the identification of an 18-gene panel for predicting recurrence free survival (RFS) in stage II and III CRC patients. This gene signature could successfully discriminate high vs. low risk patients in the discovery cohort (AUC=0.88, HR=17.0, p<0.0001), as well as two validation cohorts (GSE39582: AUC=0.70; HR=3.1, p<0.0001; GSE14333: AUC=0.63; HR=3.8, p<0.0001). Subsequent validation in an independent CRC clinical cohort (n=128) confirmed that this gene signature was significantly associated with RFS (AUC=0.81; HR=9.3, CI=3.8 to 22.5, p<0.0001). Univariate analysis identified tumor stage, tumor infiltration, and TNM stage as significant predictors of RFS, and multivariate analysis further confirmed that our gene signature was a significant predictor of RFS in stage II/III CRC patients (p<0.0001). A risk-assessment model by combining the 18-gene signature and the three clinical factors exhibited an even superior prediction for RFS (AUC = 0.877; HR=10.34, CI=4.2 to 25.6, p<0.0001). Conclusions: We identified and established a novel 18-gene redox signature for the prediction of tumor recurrence in high-risk stage II/III CRC patients, which has the potential for translation into the clinic for improved risk-assessment and stratification in CRC patients. Citation Format: Priyanka Sharma, Jasjit K. Banwait, Luis Bujanda, Ajay Goel. Identification and establishment of an 18-gene redox signature for recurrence prediction in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3148.