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

Jian Wan; Shizhen Chen; Anqin Zhang; Yiting Liu; Yangyang Zhang; Qinghua Li; Ziqi Yu; Yuwei Wan; Lei Yang; Qi Wang

doi:10.3389/fonc.2022.861439

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

Front Oncol. 2022 Apr 12:12:861439. doi: 10.3389/fonc.2022.861439. eCollection 2022.

Authors

Jian Wan^{1

2}, Shizhen Chen³, Anqin Zhang², Yiting Liu², Yangyang Zhang², Qinghua Li², Ziqi Yu³, Yuwei Wan³, Lei Yang³, Qi Wang^{1

2}

Affiliations

¹ The First Affiliated Hospital, Jinan University, Guangzhou, China.
² Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China.
³ The State Key Lab of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China.

Abstract

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.

Keywords: A-to-I RNA editing; breast cancer; disease-free survival; nomogram; overall survival.