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Armisen, Ricardo

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Armisen

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Ricardo

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2024 - 20252
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Author: González, Evelin ×

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    MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients
    (2024) Rivas, Solange; Sepúlveda, Romina V.; Tapia, Ignacio; Estay, Catalina; Soto, Vicente; Blanco, Alejandro; González, Evelin; Armisen, Ricardo
    Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients. This study utilized a 52-genes next-generation sequencing (NGS) panel to analyze 1560 tumor biopsies from NSCLC patients in Chile, Brazil, and Peru. The RNA sequencing reads and DNA coverage were correlated to improve the detection of the actionable MET exon 14 skipping variant (METex14). The pathogenicity of MET variants of uncertain significance (VUSs) was assessed using bioinformatic methods, based on their predicted driver potential. The effects of the predicted drivers VUS T992I and H1094Y on c-MET signaling activation, proliferation, and migration were evaluated in HEK293T, BEAS-2B, and H1993 cell lines. Subsequently, c-Met inhibitors were tested in 2D and 3D cell cultures, and drug affinity was determined using 3D structure simulations. The prevalence of MET variants in the South American cohort was 8%, and RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis. The novel actionable T992I and H1094Y variants induced proliferation and migration through c-Met/Akt signaling. Both variants showed sensitivity to crizotinib and savolitinib, but the H1094Y variant exhibited reduced sensitivity to capmatinib. These findings highlight the importance of RNA-based METex14 diagnosis and reveal the drug sensitivity profiles of novel actionable MET variants from an understudied patient population
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    The mutational landscape and actionable targets of gallbladder cancer: an ancestry-informed and comparative analysis of a Chilean population
    (2025) Erices, José; González, Evelin; Salgado, Marcela; Barahona, Carol; Freire, Matías; Sepúlveda, Gonzalo; Ampuero, Diego; Blanco, Alejandro; Gárate, Valentina; Báez, Pablo; Tapia, Camilo; Toro, Jessica; Gallegos, Iván; Barajas, Olga; Ahumada, Mónica; Sanhueza, Verónica; Spencer, Loreto; De Toro, Gonzalo; Morales, Erik; Gutiérrez, Lorena; Morales, Fernanda; Marin, Arnaldo; Varela, Nelson; Bermejo, Justo; Armisen, Ricardo; Marcelain, Katherine
    Introduction: Gallbladder cancer (GBC) is a highly aggressive malignancy with one of the highest incidence rates reported in Chile. Despite its clinical impact, molecular characterization of GBC in Latin American populations remains limited, and the absence of effective targeted therapies underscores the urgent need for new therapeutic strategies. Methods: We collected 118 tumor samples, of which 56 passed sequencing quality control using the Oncomine™ Comprehensive Assay v1. Somatic variants were identified with ANNOVAR and Cancer Genome Interpreter, and ancestry was inferred using ADMIXTURE and PCA with ancestry-informative markers. Comparative analyses were performed with Japanese, Singaporean, and U.S. cohorts. Results: A total of 535 somatic mutations were detected in 43 genes, with TP53 (30%), TSC2 (29%), and NOTCH1 (27%) being the most frequently mutated. We identified 121 clinically actionable variants in ATM, BRCA1/2, EGFR, ERBB2, and other genes. Exploratory analysis suggested an association between higher Mapuche ancestry and TP53 mutations. Comparative analyses revealed distinct mutational patterns in the Chilean cohort relative to Asian and U.S. datasets. Conclusion: This ancestry-informed genomic analysis provides the first comprehensive landscape of Chilean GBC, identifying actionable alterations with potential therapeutic relevance and supporting the development of population-specific precision oncology strategies.

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