Development and Validation of a Four Adenosine-to-Inosine RNA Editing Site-Relevant Prognostic Signature for Assessing Survival in Breast Cancer Patients

BACKGROUND: Adenosine-to-inosine RNA editing (ATIRE) is increasingly being used to characterize cancer. However, no studies have been conducted to identify an ATIRE signature for predicting cancer survival. METHODS: Breast cancer (BRCA) samples with ATIRE profiles from The Cancer Genome Atlas were divided into training (n = 452) and internal validation cohorts (n = 311), and 197 additional BRCA patients were recruited as an external validation cohort. The ATIRE signature for BRCA overall survival (OS) and disease-free survival (DFS) were identified using forest algorithm analysis and experimentally verified by direct sequencing. An ATIRE-based risk score (AIRS) was established with these selected ATIRE sites. Significantly prognostic factors were incorporated to generate a nomogram that was evaluated using Harrell’s C-index and calibration plot for all cohorts. RESULTS: Seven ATIRE sites were revealed to be associated with both BRCA OS and DFS, of which four sites were experimentally confirmed. Patients with high AIRS displayed a higher risk of death than those with low AIRS in the training (hazard ratio (HR) = 3.142, 95%CI = 1.932–5.111), internal validation (HR = 2.097, 95%CI = 1.123–3.914), and external validation cohorts (HR = 2.680, 95%CI = 1.000–7.194). A similar hazard effect of high AIRS on DFS was also observed. The nomogram yielded Harrell’s C-indexes of 0.816 (95%CI = 0.784–0.847), 0.742 (95%CI = 0.684–0.799), and 0.869 (95%CI = 0.835–0.902) for predicting OS and 0.767 (95%CI = 0.708–0.826), 0.684 (95%CI = 0.605–0.763), and 0.635 (95%CI = 0.566–0.705) for predicting DFS in the three cohorts. CONCLUSION: AIRS nomogram could help to predict OS and DFS of patients with BRCA.