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    Integration of RNA Editing into Multiomics Machine Learning Models for Predicting Drug Responses in Breast Cancer Patients
    Background: The integration of multi-omics data, such as genomics and transcriptomics, into artificial intelligence models has advanced precision medicine. However, their clinical applicability remains limited due to model complexity. We integrated DNA mutation, RNA expression, and A>I(G) RNA editing data to develop a predictive model for drug response in breast cancer. Methods: We analyzed 104 patients from the Breast Cancer Genome-Guided Therapy Study (ClinicalTrials.gov: NCT02022202). Clinical variables, gene expression, tumor and germline DNA variants, and RNA editing features were integrated into machine learning models to predict therapy response. Generalized linear models (GLM), random forest (RF), and support vector machines (SVM) were trained and evaluated across multiple random 70/30 train-test splits. Feature selection was performed exclusively within the training set using LASSO regularization. Model performance was assessed using the F1-score on independent test sets. The additive effect of RNA editing was evaluated using paired comparisons across identical train/test splits. Results: We characterized the cohort using clinical, mutational, transcriptomic, and RNA editing profiles in 69 non-responders and 35 responders. Across repeated splits, adding RNA editing frequently maintained or modestly improved predictive performance, particularly in expression-based models, with paired analyses showing a statistically significant increase in F1-score. Conclusions: RNA editing represents a complementary molecular layer that can enhance multi-omic models for therapy response prediction in breast cancer, supporting further investigation of epitranscriptomic features in precision oncology.
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    Scopus© Citations 1  6
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    Item type:Publication,
    Advances in machine learning for tumour classification in cancer of unknown primary: A mini-review
    (2025) ;
    Felipe Mardones
    ;
    Yanara A. Bernal
    ;
    Samuel Molina
    ;
    Marcos Orchard
    Scopus© Citations 3  8
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    A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer
    (2024)
    Yanara A. Bernal
    ;
    Alejandro Blanco
    ;
    Eduardo A. Sagredo
    ;
    ;
    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.
    Scopus© Citations 4  7
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    ADAR-Mediated A>I(G) RNA Editing in the Genotoxic Drug Response of Breast Cancer
    (2024)
    Yanara A. Bernal
    ;
    Eduardo Durán
    ;
    Isidora Solar
    ;
    Eduardo A. Sagredo
    ;
    <jats:p>Epitranscriptomics is a field that delves into post-transcriptional changes. Among these modifications, the conversion of adenosine to inosine, traduced as guanosine (A&gt;I(G)), is one of the known RNA-editing mechanisms, catalyzed by ADARs. This type of RNA editing is the most common type of editing in mammals and contributes to biological diversity. Disruption in the A&gt;I(G) RNA-editing balance has been linked to diseases, including several types of cancer. Drug resistance in patients with cancer represents a significant public health concern, contributing to increased mortality rates resulting from therapy non-responsiveness and disease progression, representing the greatest challenge for researchers in this field. The A&gt;I(G) RNA editing is involved in several mechanisms over the immunotherapy and genotoxic drug response and drug resistance. This review investigates the relationship between ADAR1 and specific A&gt;I(G) RNA-edited sites, focusing particularly on breast cancer, and the impact of these sites on DNA damage repair and the immune response over anti-cancer therapy. We address the underlying mechanisms, bioinformatics, and in vitro strategies for the identification and validation of A&gt;I(G) RNA-edited sites. We gathered databases related to A&gt;I(G) RNA editing and cancer and discussed the potential clinical and research implications of understanding A&gt;I(G) RNA-editing patterns. Understanding the intricate role of ADAR1-mediated A&gt;I(G) RNA editing in breast cancer holds significant promise for the development of personalized treatment approaches tailored to individual patients’ A&gt;I(G) RNA-editing profiles.</jats:p>
    Scopus© Citations 2  2
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    Item type:Publication,
    Chronic Stress and Ovulatory Dysfunction: Implications in Times of COVID-19
    (2022)
    Pilar Vigil
    ;
    Jaime Meléndez
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    Hugo Soto
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    Grace Petkovic
    ;
    Yanara A. Bernal
    <jats:p>Stress is known to be associated with adverse health outcomes. The COVID-19 pandemic and its associated lockdowns are examples of chronic stressors. Lockdown measures inadvertently caused significant psychological distress and became a powerful source of anxiety/stress, sleep disturbances, nutritional changes and weight gain. Stress is known to impact women's health specifically, through hypothalamic-pituitary-gonadal (HPG) axis dysfunction and resultant ovulatory dysfunction. Such dysfunction may manifest in menstrual irregularities and/or infertility due to hypothalamic hypogonadism. Here, we review the key physiological mediators of stress and associated ovulatory dysfunction. The kisspeptinergic system is comprised of sets of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and the arcuate nucleus (ARC). This system links nutrition, reproductive signals and stress. It plays a key role in the function of the HPG axis. During chronic stress, the kisspeptinergic system affects the HPG axis, GnRH pulsatility, and, therefore, ovulation. Leptin, insulin and corticotrophin-releasing hormone (CRH) are thought to be additional key modulators in the behavioral responses to chronic stress and may contribute to stress-related ovulatory dysfunction. This mini-review also summarizes and appraises the available evidence on the negative impact of chronic stress as a result of the COVID-19 pandemic lockdowns. It proposes physiological mechanisms to explain the observed effects on women's reproductive health and well-being. The review suggests areas for future research.</jats:p>
    Scopus© Citations 19  1