A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer

Journal
Biomedicines
ISSN
2227-9059
Date Issued
2024
Author(s)
Yanara A. Bernal
Alejandro Blanco
Eduardo A. Sagredo
Katherine Marcelain
Type
journal-article
Scopus ID
2-s2.0-85191460341
WoS ID
WOS:001211300100001
DOI
URL
Abstract
Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.
Cite this document
Bernal, Y. A., Blanco, A., Sagredo, E. A., Oróstica, K., Alfaro, I., Marcelain, K., & Armisén, R. (2024). A comprehensive analysis of the effect of a>i(G) rna-editing sites on genotoxic drug response and progression in breast cancer. Biomedicines, 12(4), 728. https://doi.org/10.3390/biomedicines12040728
Project(s)
Dataset(s)
Subjects
breast cancer

; 

rna editing

; 

rna-edited sites

; 

adar1

; 

drug sensitivity

; 

parp inhibitors

; 

anthracyclines

; 

alkylating agents

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cancer therapy