Armisen Yañez, RicardoBernal Gómez, Yanara Alejandra2025-03-042025-03-042025https://hdl.handle.net/11447/9894Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Science in Science and Innovation in Medicine from Faculty of Medicine, Clínica Alemana de Santiago, Universidad del Desarrollo.Breast cancer (BC) is the most common malignancy among women and a leading cause of cancer-related mortality. While advancements in genomic technologies have improved the understanding of BC biology, therapeutic resistance remains a significant challenge, particularly to genotoxic drugs. This study explores the association of A>I(G) RNA editing, a post-transcriptional modification mediated by ADAR enzymes, in drug response and resistance in BC. A>I(G) RNA editing modifies adenosine to inosine in double-stranded RNA, potentially altering RNA stability, splicing, and protein function. The results identified ADAR1-mediated A>I(G) RNA editing sites associated with sensitivity or resistance to genotoxic drugs in BC cell lines. These sites, predominantly located in non-coding regions, were functionally linked to genes involved in DNA damage repair, immune response, and cancer progression. Furthermore, RNA editing levels in genes such as LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 were significantly associated with progression-free survival in BC patients, highlighting their potential as prognostic biomarkers. In addition, multi-omics data were integrated using machine learning tools to predict the risk of therapy non-response in BC. This approach identified ADAR1 mediated RNA-edited sites, such as those in KDM4B, miRNA200/TTLL10-AS1, and BEST1, as key predictive variables alongside clinically relevant features. These sites, primarily in non-coding regions, were associated with genes involved in histone demethylation, DNA damage repair (DDR), epithelial-mesenchymal transition (EMT), and cell proliferation. The predictive models demonstrated acceptable performance in distinguishing responder and non-responder patients, emphasizing the utility of combining transcriptomic, epitranscriptomic, and clinical data to predict therapy response and their potential as predictive biomarkers. This study advances the understanding of A>I(G) RNA editing as a contributor to drug resistance in BC and underscores its potential as a biomarker and therapeutic target. The findings highlight the importance of post-transcriptional modifications in precision medicine, offering new avenues for the development of personalized treatment strategies.171 p., art.enBreast cancerDrug responseRNA editing090036SA>I(G) RNA Editing in genotoxic drug response in breast cancerThesis