Browsing by Author "Blanco, Alejandro"
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Publication A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer(2024) Bernal, Yanara; Blanco, Alejandro; Sagredo, Eduardo; Oróstica, Karen; Alfaro, Ivan; Marcelain, Katherine; Armisén, RicardoDysregulated 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.Item ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response(Elsevier B.V., 2020) Sagredo, Eduardo; Sagredo, Alfredo; Blanco, Alejandro; Rojas, Pamela; Rivas, Solange; Assar, Rodrigo; Pérez, Paola; Marcelain, Katherine; Armisén, RicardoRNA editing has emerged as a novel mechanism in cancer progression. The double stranded RNA-specific adenosine deaminase (ADAR) modifies the expression of an important proportion of genes involved in cell cycle control, DNA damage response (DDR) and transcriptional processing, suggesting an important role of ADAR in transcriptome regulation. Despite the phenotypic implications of ADAR deregulation in several cancer models, the role of ADAR on DDR and proliferation in breast cancer has not been fully addressed. Here, we show that ADAR expression correlates significantly with clinical outcomes and DDR, cell cycle and proliferation mRNAs of previously reported edited transcripts in breast cancer patients. ADAR's knock-down in a breast cancer cell line produces stability changes of mRNAs involved in DDR and DNA replication. Breast cancer cells with reduced levels of ADAR show a decreased viability and an increase in apoptosis, displaying a significant decrease of their DDR activation, compared to control cells. These results suggest that ADAR plays an important role in breast cancer progression through the regulation of mRNA stability and expression of those genes involved in proliferation and DDR impacting the viability of breast cancer cells.Publication Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers(2024) Garrido, Javiera; Bernal, Yanara; González, Evelin; Blanco, Alejandro; Sepúlveda, Gonzalo; Freire, Matías; Oróstica, Karen; Rivas, Solange; Marcelain, Katherine; Owen, Gareth; Ibañez, Carolina; Corvalan, Alejandro; Garrido, Marcelo; Assar, Rodrigo; Lizana, Rodrigo; Cáceres, Javier; Ampuero, Diego; Ramos, Liliana; Pérez, Paola; Aren, Osvaldo; Chernilo, Sara; Fernández, Cristina; Spencer, María; Flores, Jacqueline; Bernal, Giuliano; Ahumada, Mónica; Rasse, Germán; Sánchez, Carolina; De Amorim, Maria; Bartelli, Thais; Noronha, Diana; Dias, Emmanuel; Freitas, Helano; Armisén, RicardoBackground: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. Methods: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. Results: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. Conclusions: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.Item Concordance analysis of ALK gene fusion detection methods in patients with Non– Small-Cell Lung Cancer from Chile, Brazil, and Peru(2021-06) Sepúlveda-Hermosilla, Gonzalo; Freire, Matías; Blanco, Alejandro; Cáceres, Javier; Lizana, Rodrigo; Ramos, Liliana; Assar, Rodrigo; Ampuero, Diego; Aren, Osvaldo; Chernilo, Sara; Spencer, María Loreto; Bernal, Giuliano; Flores, Jacqueline; Rasse, Germán; Sánchez, Carolina; Marcelain, Katherine; Rivas, Solange; Pereira Branco, Gabriela; Galli de Amorim, María; Noronha Nunes, Diana; Dias-Neto, Emmanuel; Freitas, Helano C.; Fernández, Cristina; Pérez, Paola; NIRVANA team; Armisén, RicardoAbout 4 to 7 % of the Non-small cell lung cancer patients have ALK rearrangements and specific target therapies improve patients’ outcomes significantly. ALK gene fusions are detected by immunohistochemistry (IHC) or Fluorescent in situ Hybridization (FISH) as gold standards in South America. Next Generation Sequencing (NGS) based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4,240 Non-small cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru; where ALK rearrangements were determined as part of their standard of care (SofC) using either IHC or FISH. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a qPCR EML4-ALK fusion detection kit. ALK fusion prevalence is very similar for Chile (3.67%, N=2142), Brazil (4.05%, N=1013) and Peru (4.59%, N=675). Whereas a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements.Publication Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis(2024) Tapia, Camilo; Valenzuela, Guillermo; González, Evelin; Maureira, Ignacio; Toro, Jessica; Freire, Matías; Sepúlveda, Gonzalo; Ampuero, Diego; Blanco, Alejandro; Gallegos, Iván; Morales, Fernanda; Erices, José; Barajas, Olga; Ahumada, Mónica; Contreras, Héctor; González, Jaime; Armisén, Ricardo; Marcelain, KatherineColorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10-5) and MSK-IMPACT cohorts (p-value = 3.062 × 10-2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.Item Immune-related IncRNA LINC00944 responds to variations in ADAR1 levels and it is associated with breast cancer prognosis(Elsevier Inc., 2020) Blanco, Alejandro; Morales, Fernanda; Marcelain, Katherine; Harismendy, Olivier; Sjöberg, Marcela; Armisén, Ricardo; de Santiago, PamelaAims: Breast cancer is one of the leading causes of woman deaths worldwide, being a major public health problem. It has been reported that the expression of the RNA-editing enzyme Adenosine Deaminase Acting on RNAs 1 (ADAR1) is upregulated in breast cancer, predicting poor prognosis in patients. A few reports in literature examine ADAR1 and long non-coding RNAs (lncRNAs) interplay in cancer and suggest key roles in cancer-related pathways. This study aimed to investigate whether ADAR1 could alter the expression levels of lncRNAs and explore how those changes are related to breast cancer biology. Main methods: ADAR1 overexpression and knockdown studies were performed in breast cancer cell lines to analyze the effects over lncRNAs expression. Guilt-by-Association correlation analysis of the TCGA-BRCA cohort was performed to predict the function of the lncRNA LINC00944. Key findings: Here, we show that LINC00944 is responsive to ADAR1 up- and downregulation in breast cancer cells. We found that LINC00944 expression has a strong relationship with immune signaling pathways. Further assessment of the TCGA-BRCA cohort showed that LINC00944 expression was positively correlated to tumor-infiltrating T lymphocytes and pro-apoptotic markers. Moreover, we found that LINC00944 expression was correlated to the age at diagnosis, tumor size, and estrogen and progesterone receptor expression. Finally, we showed that the low expression of LINC00944 is correlated to poor prognosis in breast cancer patients. Significance: Our study provides further evidence of the effect of ADAR1 over lncRNA expression levels, and on the participation of LINC00944 in breast cancer, suggesting to further investigate its potential role as prognostic biomarker.