Browsing by Author "Rivas, Solange"
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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 El cáncer de pulmón de células no pequeñas en la era de la medicina de precisión(2022) Rivas, Solange; Armisén, RicardoEl cáncer se origina por mutaciones conductoras que entregan ventajas en el crecimiento celular, por medio de la inhibición de los puntos de control y la activación exacerbada de vías de señalización involucradas en la sobrevivencia y la proliferación. El cáncer de pulmón es la principal causa de muerte por cáncer en 89/185 países, y la medicina de precisión ha mejorado el diagnóstico y tratamiento de esta enfermedad, considerando la importancia del perfil mutacional del tumor. Los inhibidores de tirosina quinasa (TKIs) dirigidos a mutaciones conductoras en EGFR, uno de los genes más mutado en cáncer de pulmón de células no pequeñas (NSCLC), han demostrado una disminución significativa en la mortalidad al ser drogas más específicas y menos tóxicas. Los genes accionables en NSCLC son EGFR, ALK, ROS1, ERBB2, MET, MAP2K1, BRAF, KRAS, NTRK1/2/3 y RET, y combinados impactan al 64% de los pacientes. Sin embargo, el acceso a NGS (secuenciación de próxima generación por sus siglas en inglés) y a las drogas dirigidas es desigual por país y la ausencia de mutaciones en genes accionables y el desarrollo de mutaciones de resistencia a la terapia dirigida, son desafíos a nivel mundial. La incorporación de nuevos biomarcadores como PD-L1, la validación del DNA circulante en plasma, la medición de la carga mutacional del tumor, y el desarrollo de ensayos clínicos con combinación de terapias, son parte de las estrategias actuales en investigación. Esta revisión está enfocada en entregar a lectores de lengua española el estado actual de la medicina de precisión en NSCLC.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.Item MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies(2022) Rivas, Solange; Marín, Arnaldo; Samtani, Suraj; González, Evelin; Armisén, RicardoThe MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and β-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient’s mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapiesPublication Neutralizing antibodies induced by homologous and heterologous boosters in CoronaVac vaccines in Chile(2023) Acevedo, Johanna; Acevedo, Mónica L.; Gaete-Argel, Aracelly; Araos, Rafael; González, Cecilia; Espinoza, Daniela; Rivas, Solange; Pizarro, Pablo; Jarpa, Stephan; Soto-Rifo, Ricardo; Jara, Alejandro; Valiente-Echeverría, FernandoObjectives:To determine the impact of a booster dose on the humoral response in individuals inoculated with a complete schedule of any SARS-CoV-2 vaccine, we evaluated the neutralizing antibody (NAb) titres of homologous or heterologous booster doses over a 90-days period in CoronaVac vaccinees from 3 centres in Santiago, Chile. Methods:Individuals previously inoculated with 2 doses of CoronaVac (N = 523) were recruited in the context of the REFUERZO clinical trial (NCT04992182) and received either placebo (N = 129), or a booster dose of CoronaVac (N = 134), BNT162b2 (N = 133), or ChAdOx1 (N = 127). Pseudovirus neutralizing antibody titres (pVNT) were determined at baseline (day 0) as well as at days 14, 30, 60, and 90 after booster dose administration. Results:Inoculating a booster dose increases the pVNTs titres at days 14 and 30 in all groups, (13.5- and 12.0-fold increase for the CoronaVac group; 247.0- and 212.3-fold increase for the BTN162b2 group; and 89.1- and 128.1-fold increase for ChAdOx1 at each time point, respectively) with a decline observed at days 60 and 90. However, although pVNTs remained significantly higher for the BTN162b2 and ChAdOx1 groups at days 60 and 90, NAb titres reached baseline levels in the CoronaVac group at 90 days after inoculation. Discussion: A single heterologous booster (BTN162b2 or ChAdOx1) in individuals who completed the CoronaVac primary series resulted in an important increase in NAb titres remaining significantly higher at least for 90 days. These data may directly impact middle- and low-income countries currently using CoronaVac as the main vaccination strategy.Item Ski Is Required for Tri-Methylation of H3K9 in Major Satellite and for Repression of Pericentromeric Genes: Mmp3, Mmp10 and Mmp13, in Mouse Fibroblasts(Elsevier Ltd., 2020) Capelli, Claudio; Sepúlveda, Hugo; Rivas, Solange; Víctor, Paola; Urzúa, Ulises; Donoso, Gerardo; Sagredo, Eduardo; Carrero, David; Casanova-Ortiz, Emmanuel; Sagredo, Alfredo; González, Marisel; Manterola, Marcia; Nardocci, Gino; Armisén, Ricardo; Montecino, Martín; Marcelain, KatherineSeveral mechanisms directing a rapid transcriptional reactivation of genes immediately after mitosis have been described. However, little is known about the maintenance of repressive signals during mitosis. In this work, we address the role of Ski in the repression of gene expression during M/G1 transition in mouse embryonic fibroblasts (MEFs). We found that Ski localises as a distinct pair of dots at the pericentromeric region of mitotic chromosomes, and the absence of the protein is related to high acetylation and low tri-methylation of H3K9 in pericentromeric major satellite. Moreover, differential expression assays in early G1 cells showed that the presence of Ski is significantly associated with repression of genes localised nearby to pericentromeric DNA. In mitotic cells, chromatin immunoprecipitation assays confirmed the association of Ski to major satellite and the promoters of the most repressed genes: Mmp3, Mmp10 and Mmp13. These genes are at pericentromeric region of chromosome 9. In these promoters, the presence of Ski resulted in increased H3K9 tri-methylation levels. This Ski-dependent regulation is also observed during interphase. Consequently, Mmp activity is augmented in Ski −/− MEFs. Altogether, these data indicate that association of Ski with the pericentromeric region of chromosomes during mitosis is required to maintain the silencing bookmarks of underlying chromatin.Item Total mutational load and clinical features as predictors of the metastatic status in lung adenocarcinoma and squamous cell carcinoma patients(2022) Oróstica, Karen; Saez, Juan; De Santiago, Pamela; Rivas, Solange; Contreras, Sebastián; Navarro, Gonzalo; Asenjo, Juan; Olivera, Álvaro; Armisén, RicardoAbstract Background: Recently, extensive cancer genomic studies have revealed mutational and clinical data of large cohortsof cancer patients. For example, the Pan-Lung Cancer 2016 dataset (part of The Cancer Genome Atlas project), sum‑marises the mutational and clinical profles of diferent subtypes of Lung Cancer (LC). Mutational and clinical signa‑ tures have been used independently for tumour typifcation and prediction of metastasis in LC patients. Is it then possible to achieve better typifcations and predictions when combining both data streams? Methods: In a cohort of 1144 Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LSCC) patients, we studied the number of missense mutations (hereafter, the Total Mutational Load TML) and distribution of clinical variables, for diferent classes of patients. Using the TML and diferent sets of clinical variables (tumour stage, age, sex, smoking status, and packs of cigarettes smoked per year), we built Random Forest classifcation models that calculate the likelihood of developing metastasis. Results: We found that LC patients diferent in age, smoking status, and tumour type had signifcantly diferent mean TMLs. Although TML was an informative feature, its efect was secondary to the "tumour stage" feature. However, its contribution to the classifcation is not redundant with the latter; models trained using both TML and tumour stage performed better than models trained using only one of these variables. We found that models trained in the entire dataset (i.e., without using dimensionality reduction techniques) and without resampling achieved the highest perfor‑mance, with an F1 score of 0.64 (95%CrI [0.62, 0.66]). Conclusions: Clinical variables and TML should be considered together when assessing the likelihood of LC patients progressing to metastatic states, as the information these encode is not redundant. Altogether, we provide new evi‑ dence of the need for comprehensive diagnostic tools for metastasis.