ARMISEN YAÑEZ, RICARDO AMADO
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ARMISEN YAÑEZ, RICARDO AMADO
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rarmisen@udd.cl
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22956957700

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Abstract C018: Disparities in the access to non-small cell lung cancer´s target therapies in Chile

2023 , Solange V. Rivas , Evelin González , Alejandro Blanco , Carolina Ibáñez , Alejandro Corvalán , Marcelo Garrido , Gareth Owen , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

Abstract Comprehensive next-generation sequencing (NGS) panels designed to identify the tumor mutational profile are becoming the standard care to prescribe target therapies in developed countries. In non-small cell lung cancer (NSCLC), this approach significantly impacts the patient´s clinical results, measured as progression-free survival and/or overall survival, compared to conventional chemotherapies. However, as Latin American patients tend to experience more significant health disparities because of structural, sociodemographic, and psychosocial factors, in this work, our purpose is to measure the disparities in the access to NSCLC´s target therapies, specifically in Chile. DNAs and RNAs from 1643 NSCLC samples from Chile, Brazil, and Peru were sequenced to assess the mutational status in fifty-two cancer genes. After an NGS quality control, variants were called and annotated using the Variant Effect Predictor, Annovar, COSMIC, and OncoKB, to categorize somatic mutations. The following analysis focused on today’s actionable genes in NSCLC, with FDA-approved target therapies (EGFR, KRAS, ALK, MET, ERBB2, BRAF, ROS1, and RET). In this analysis, 46.5% of tumors evidenced driver mutations (764/1643); interestingly, from this subset, 86.9% showed one driver variant, 11.2% two drivers, 1.4% three drivers, and 0.5% evidenced between 4-6 driver mutations. However, 19.4% (495/1643) evidenced actionable variants. The most mutated genes and the most common actionable variants were 15.3% EGFR (37% EGFR L858R), followed by 4.9% KRAS (100% KRAS G12C), 4.5% ALK (95.4% EML4-ALK fusion), 3% MET (100% MET exon 14 skipping), and 2.3% ERBB2. Finally, 1.5% BRAF, 1% ROS1 gene fusions and 0.9% RET gene fusions. Considering the target therapies approved by Chile´s Instituto de Salud Publica until October 2021, and if all these patients were diagnosed in Chile, only 64% would receive a targeted drug. EGFR is the gene with more target therapies validated in Chile, although drugs against exon twenty insertion have not been approved yet. Chile does not account for any targeted treatment for patients with alterations in KRAS, MET, RET and ERBB2; although the FDA approved a specific drug against KRAS G12C very recently (May 28, 2021), different is the case of MET because the first inhibitor, crizotinib, was FDA approved four years ago. Interestingly, in 2021, two inhibitors against the most common MET alteration were FDA approved, but none have been approved in Chile yet. In Chile, almost all target therapies have been validated against EGFR, ALK, and BRAF; however, patients with KRAS, MET, RET, and ERBB2 cannot access specific drugs, so in these cases, the recommended therapeutic option is chemotherapy. It is important to note that the target drugs approval only ensures the availability of the drug in Chile. Still, few of the target drugs are part of financed drugs by the Chilean health system, so the question is, how could we increase the national access to existing target therapies? Citation Format: Solange V. Rivas, Evelin González, Alejandro Blanco, Carolina Ibáñez, Alejandro Corvalán, Marcelo Garrido, Gareth Owen, Katherine Marcelain, Ricardo Armisén. Disparities in the access to non-small cell lung cancer´s target therapies in Chile [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C018.

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Immune-related IncRNA LINC00944 responds to variations in ADAR1 levels and it is associated with breast cancer prognosis

2021 , Pamela R. de Santiago , Alejandro Blanco , Fernanda Morales , Katherine Marcelain , Olivier Harismendy , Marcela Sjöberg Herrera , ARMISEN YAÑEZ, RICARDO AMADO

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ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response

2020 , Eduardo A. Sagredo , Alfredo I. Sagredo , Alejandro Blanco , Pamela Rojas De Santiago , RIVAS VERA, SOLANGE VERÓNICA , Rodrigo Assar , Paola Pérez , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

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Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers

2024 , GARRIDO MANRIQUEZ, JAVIERA NICOLE , Yanara Bernal , Evelin González , Alejandro Blanco , Gonzalo Sepúlveda-Hermosilla , Matías Freire , Karen Oróstica , RIVAS ARENA, SOLANGE , Katherine Marcelain , Gareth Owen , Carolina Ibañez , Alejandro Corvalan , Marcelo Garrido , Rodrigo Assar , Rodrigo Lizana , Javier Cáceres-Molina , Diego Ampuero , Liliana Ramos , Paola Pérez , Osvaldo Aren , Sara Chernilo , Cristina Fernández , María Loreto Spencer , Jacqueline Flores Aguila , Giuliano Bernal Dossetto , Mónica Ahumada Olea , Germán Rasse , Carolina Sánchez , Maria Galli de Amorim , Thais F. Bartelli , Diana Noronha Nunes , Emmanuel Dias-Neto , Helano C. Freitas , Ricardo Armisén

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Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis

2024 , Camilo Tapia-Valladares , Guillermo Valenzuela , Evelin González Feliú , Ignacio Maureira , Jessica Toro , Matías Freire , Gonzalo Sepúlveda-Hermosilla , Diego Ampuero , Alejandro Blanco , Iván Gallegos , Fernanda Morales , José I. Erices , Olga Barajas , Mónica Ahumada , Héctor R. Contreras , Jaime González , ARMISEN YAÑEZ, RICARDO AMADO , Katherine Marcelain

Colorectal 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.

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Ski Is Required for Tri-Methylation of H3K9 in Major Satellite and for Repression of Pericentromeric Genes: Mmp3, Mmp10 and Mmp13, in Mouse Fibroblasts

2020 , Claudio Cappelli , Hugo Sepulveda , Solange Rivas , Víctor Pola , Ulises Urzúa , Gerardo Donoso , Eduardo Sagredo , David Carrero , Emmanuel Casanova-Ortiz , Alfredo Sagredo , Marisel González , Marcia Manterola , Gino Nardocci , ARMISEN YAÑEZ, RICARDO AMADO , Martin Montecino , Katherine Marcelain

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Validation of an NGS Panel Designed for Detection of Actionable Mutations in Tumors Common in Latin America

2021 , Mauricio Salvo , Evelin González-Feliú , Jessica Toro , Iván Gallegos , Ignacio Maureira , Nicolás Miranda-González , Olga Barajas , Eva Bustamante , Mónica Ahumada , Alicia Colombo , ARMISEN YAÑEZ, RICARDO AMADO , Camilo Villamán , Carolina Ibañez , María Loreto Bravo , Verónica Sanhueza , M. Loreto Spencer , Gonzalo de Toro , Erik Morales , Carolina Bizama , Patricia García , Ana María Carrasco , Lorena Gutiérrez , Justo Lorenzo Bermejo , Ricardo A. Verdugo , Katherine Marcelain

Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.

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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 , Karen Oróstica , Ivan Alfaro , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

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.

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NTRK genomic alterations in Latin-American cancer patients.

2021 , CARVAJAL HAUSDORF, DANIEL EDUARDO , Claudio Salas , Katherine Marcelain , Francisco Perez , Evelin Feliu , Kurt Schalper , Solange Rivas , ARMISEN YAÑEZ, RICARDO AMADO

e15088 Background: The neurotrophic receptor tyrosine kinase genes NTRK1-3 encode the tropomyosin receptor kinase proteins TRKA, TRKB, and TRKC, respectively. TRK fusions lead to overexpression of the chimeric protein, resulting in constitutively active, ligand-independent downstream signaling. NTRKs act as oncogenes, they can be targeted, and it is estimated that they are present in up to 0.3% of tumors. The incidence of actionable alterations in these genes is currently unknown in Latin-American patients. We investigated the presence of NTRK1-3 mutations/rearrangements in 3 independent patient series from several tertiary hospitals from Chile, Brazil and Peru. Methods: 1795 FFPE tumor samples from multiple institutions divided in 3 series were analyzed using 2 NGS panels: Oncomine Focus Assay (OFA; 52 genes) and Oncomine Comprehensive Assay (OCA; 161 genes. Data on NTRK1-3 SNVs, indels, CNVs and fusions was obtained. Bioinformatic workflows were used to study the biologic significance of these alterations. Results: Using OCA (series 1-2), 31 somatic variants were found in gastric, CRC, gallbladder, lung and pancreatic cases out of 300 patients. From these, 13 were located in the tyrosine kinase domain. Using OFA, no NTRK alteration were detected (series 3, 1495 NSCLC cases). Conclusions: NTRK alterations are rare events in Latin-American cancer patients. In 3 series including 1,795 patients, 31 somatic variants were detected. No NTRK fusions or CNVs were identified. The presence of NTRK mutations in the tyrosine kinase domain warrants further research into their potential to benefit from FDA/EMA-approved targeted therapies. [Table: see text]

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Increase in ADAR1p110 activates the canonical Wnt signaling pathway associated with aggressive phenotype in triple negative breast cancer cells

2022 , Fernanda Morales , Paola Pérez , Julio C. Tapia , Lorena Lobos-González , José Manuel Herranz , Francisca Guevara , Pamela Rojas de Santiago , Esteban Palacios , Rodrigo Andaur , Eduardo A. Sagredo , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

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