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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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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Major Histocompatibility Complex Class I-Related Chain A (MICA) Allelic Variants Associate With Susceptibility and Prognosis of Gastric Cancer

2021 , Karen Toledo-Stuardo , Carolina H. Ribeiro , Andrea Canals , Marcela Morales , Valentina Gárate , Jose Rodríguez-Siza , Samantha Tello , Marco Bustamante , ARMISEN YAÑEZ, RICARDO AMADO , Douglas J. Matthies , Gerald Zapata-Torres , Patricio González-Hormazabal , María Carmen Molina

Gastric cancer (GC) is the fifth most prevalent type of cancer worldwide. Gastric tumor cells express MICA protein, a ligand to NKG2D receptor that triggers natural killer (NK) cells effector functions for early tumor elimination. MICA gene is highly polymorphic, thus originating alleles that encode protein variants with a controversial role in cancer. The main goal of this work was to study MICA gene polymorphisms and their relationship with the susceptibility and prognosis of GC. Fifty patients with GC and 50 healthy volunteers were included in this study. MICA alleles were identified using Sanger sequencing methods. The analysis of MICA gene sequence revealed 13 MICA sequences and 5 MICA-short tandem repeats (STR) alleles in the studied cohorts We identified MICA*002 (*A9) as the most frequent allele in both, patients and controls, followed by MICA*008 allele (*A5.1). MICA*009/049 allele was significantly associated with increased risk of GC (OR: 5.11 [95% CI: 1.39–18.74], p = 0.014). The analysis of MICA-STR alleles revealed a higher frequency of MICA*A5 in healthy individuals than GC patients (OR = 0.34 [95% CI: 0.12–0.98], p = 0.046). Survival analysis after gastrectomy showed that patients with MICA*002/002 or MICA*002/004 alleles had significantly higher survival rates than those patients bearing MICA*002/008 (p = 0.014) or MICA*002/009 (MICA*002/049) alleles (p = 0.040). The presence of threonine in the position MICA-181 (MICA*009/049 allele) was more frequent in GC patients than controls (p = 0.023). Molecular analysis of MICA-181 showed that the presence of threonine provides greater mobility to the protein than arginine in the same position (MICA*004), which could explain, at least in part, some immune evasion mechanisms developed by the tumor. In conclusion, our findings suggest that the study of MICA alleles is crucial to search for new therapeutic approaches and may be useful for the evaluation of risk and prognosis of GC and personalized therapy.

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171P An unwelcome guest: P. gingivalis intratumoral infection and immune evasion in gastric cancer

2021 , I.N. Retamal , M. Muñoz Medel , M. Cáceres , K. Cereceda , F. Villarroel-Espíndola , P. Manque , A. Berkovits , J.A. Ríos , B. García-Bloj , M.P. Rodríguez , A.H. Corvalán , G.I. Owen , ARMISEN YAÑEZ, RICARDO AMADO , M. Garrido , A. Chaparro

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

2023 , RIVAS VERA, SOLANGE VERÓNICA , GONZÁLEZ, EVELYN , BLANCO MARTÍNEZ, ALEJANDRO , Carolina Ibáñez , Alejandro Corvalán , Marcelo Garrido , Gareth Owen , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

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?

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Abstract 5293: A molecular classification of gastric cancer in Chilean patients

2020 , Mauricio P. Pinto , Matias Muñoz-Medel , Miguel Cordova-Delgado , Ignacio N. Retamal , Gareth Owen , Maria Loreto Bravo , ARMISEN YAÑEZ, RICARDO AMADO , Marcelo Garrido , POLI HARLOWE, MARIA CECILIA BERTA

Abstract Objective: Incidence and mortality rates of gastric cancer (GC) are characterized by their geographical heterogeneity. In Chile, GC is the leading cause of cancer death. To date, GC patients' response to standard therapies remains limited. A molecular classification of GCs may deliver better stratifications. Herein, we obtained clinical data, protein expression and genetic profiles in a cohort of Chilean patients and present a molecular classification that correlated with overall survival (OS) rates. Methods: A total of 71 patients were included. Clinical data were obtained from medical records; protein expression was analyzed by a Tissue MicroArray. We also performed Next Generation Sequencing to assess p53 status (WT or Mut). Supervised clustering was used to generate a molecular classification. Kaplan-Meier method was used to calculate OS. Hazard ratio was calculated by Cox regression. Results: We defined 5 GC subgroups: Epstein-Barr virus+ (EBV, n=9; 13%), Microsatellite Instable (MSI, n=9; 13%), E-cadherin loss (EMT-like, n=12; 17%). The remaining patients (those MSS-/EBV-/not EMT-like) were classified either as p53 WT (n=21; 30%) or p53 Mutated (n=20; 28%). According to subgroups, 5-year survival rates were: MSI=77,8%; EBV=43.2%; p53WT=43.5%; p53Mut=25% and EMT-like=16.7%. Hazard ratios for p53Mut and EMT-like were 5.1 (IC 95%: 1.16-22.41; p=0.031) and 6.81 (IC 95%: 1.48-31.24; p=0.014), respectively against the MSI group used as reference. This association is maintained in a multivariate model using age, gender and stage. Conclusions: Our study defined 5 GC subgroups. These are associated to OS rates. EMT-like and p53Mut subgroups displayed poorer survival. Future studies should explore actionable targets in these subsets in order to improve their survival. Citation Format: Mauricio P. Pinto, Matias Muñoz-Medel, Miguel Cordova-Delgado, Ignacio N. Retamal, Gareth Owen, Maria Loreto Bravo, Ricardo Armisen, Marcelo Garrido. A molecular classification of gastric cancer in Chilean patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5293.

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ALS-linked protein disulfide isomerase variants cause motor dysfunction

2016 , Ute Woehlbier , Alicia Colombo , Mirva J Saaranen , Viviana Pérez , Jorge Ojeda , Fernando J Bustos , Catherine I Andreu , Mauricio Torres , Vicente Valenzuela , Danilo B Medinas , Pablo Rozas , Rene L Vidal , Rodrigo Lopez‐Gonzalez , Johnny Salameh , Sara Fernandez‐Collemann , Natalia Muñoz , Soledad Matus , ARMISEN YAÑEZ, RICARDO AMADO , Alfredo Sagredo , Karina Palma , Thergiory Irrazabal , Sandra Almeida , Paloma Gonzalez‐Perez , Mario Campero , Fen‐Biao Gao , Pablo Henny , Brigitte Zundert , Lloyd W Ruddock , Miguel L Concha , Juan P Henriquez , Robert H Brown , Claudio Hetz

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Concordance Analysis of ALK Gene Fusion Detection Methods in Patients with Non–Small-Cell Lung Cancer from Chile, Brazil, and Peru

2021 , Gonzalo Sepúlveda-Hermosilla , Matías Freire , Alejandro Blanco , Javier Cáceres , Rodrigo Lizana , Liliana Ramos , Rodrigo Assar Cuevas , Diego Ampuero , Osvaldo Aren , Sara Chernilo , María L. Spencer , Giuliano Bernal , Jacqueline Flores , Germán Rasse , Carolina Sánchez , Katherine Marcelain , RIVAS VERA, SOLANGE VERÓNICA , Gabriela P. Branco , María Galli de Amorim , Diana N. Nunes , Emmanuel Dias-Neto , Helano C. Freitas , Cristina Fernández , Paola Pérez , ARMISEN YAÑEZ, RICARDO AMADO , Luiz Araujo , Luis Pires , Nils Skare , Gustavo Girotto , Manuela Zereu , Helano Freitas , Hakaru Tadokoro , Ana Caroline Gelatti , Jose Fernando Moura , Clarissa Mathias , Pedro Rafael De Marchi , Fernando Silva , Mayler Olombrada Nunes de Santos , Marianna Deway Andrade Dracoulakis , Renata Pinho Costa , Luciana Castro , Paulo Guilherme de Oliveira Salles , Clodoaldo Zago Campos , Maria Andrade Livia , Sara Chernilo , Osvaldo Arén Frontera , Eduardo Yanez Ruiz , Monica Ahumada Olea , Giuliano Bernal , Loreto Spencer , Alejandro Ortega Vasquez , German Rasse , Juan Bertoglio , Jose David Zorrilla Silvera , Hernan Moron Escobar , Luis Riva Gonzalez , Luis Alberto Mas Lopez , José Luis Fernando Hurtado De Mendoza Acurio , Giovanna Victoria Abrill Mendoza , Alfredo Aguilar , Gerardo Campos Siccha , Ricardo Sanchez Sevillano , Cristina Fernández , Sylvia Chandía , Pablo Araos , Ana Mejías , Francisca Angulo , Carolina Sánchez , Jessica Troncoso , David Jara , Marcela Astete , María Jesús Galleguillos , Emmanuel Dias-Neto , Helano Carioca Freitas , María Galli de Amorim , Diana Noronha Nunes , Gabriela Branco , Marina Eloi , Melissa Pizzi , Jordana Silva , Thais F. Bartelli , Katherine Marcelain , Jessica Toro , Luciana Oliveira-Cruz , Daniela Diez

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