{"doi":"10.3389/fonc.2025.1658528","title":"The mutational landscape and actionable targets of gallbladder cancer: an ancestry-informed and comparative analysis of a Chilean population","abstract":"<jats:sec><jats:title>Introduction</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 535 somatic mutations were detected in 43 genes, with <jats:italic>TP53</jats:italic> (30%), <jats:italic>TSC2</jats:italic> (29%), and <jats:italic>NOTCH1</jats:italic> (27%) being the most frequently mutated. We identified 121 clinically actionable variants in <jats:italic>ATM, BRCA1/2, EGFR, ERBB2</jats:italic>, and other genes. Exploratory analysis suggested an association between higher Mapuche ancestry and <jats:italic>TP53</jats:italic> mutations. Comparative analyses revealed distinct mutational patterns in the Chilean cohort relative to Asian and U.S. datasets.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec>","journal":"Frontiers in Oncology","year":2025,"id":621117,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1603648,"name":"Evelin González","orcid":null,"position":1,"is_corresponding":false},{"id":1603650,"name":"Marcela Salgado","orcid":null,"position":2,"is_corresponding":false},{"id":1603652,"name":"Carol Barahona-Ponce","orcid":null,"position":3,"is_corresponding":false},{"id":1603654,"name":"Matías Freire","orcid":null,"position":4,"is_corresponding":false},{"id":1603656,"name":"Gonzalo Sepúlveda-Hermosilla","orcid":null,"position":5,"is_corresponding":false},{"id":1603658,"name":"Diego Ampuero","orcid":null,"position":6,"is_corresponding":false},{"id":1339369,"name":"Alejandro Blanco","orcid":null,"position":7,"is_corresponding":false},{"id":1603661,"name":"Valentina Gárate-Calderón","orcid":null,"position":8,"is_corresponding":false},{"id":1603663,"name":"Pablo Báez-Benavides","orcid":null,"position":9,"is_corresponding":false},{"id":1603665,"name":"Camilo Tapia-Valladares","orcid":null,"position":10,"is_corresponding":false},{"id":293560,"name":"Jessica Toro","orcid":null,"position":11,"is_corresponding":false},{"id":1603667,"name":"Iván Gallegos","orcid":null,"position":12,"is_corresponding":false},{"id":1603668,"name":"Olga Barajas","orcid":null,"position":13,"is_corresponding":false},{"id":1603669,"name":"Mónica Ahumada","orcid":null,"position":14,"is_corresponding":false},{"id":1603670,"name":"Verónica Sanhueza","orcid":null,"position":15,"is_corresponding":false},{"id":1603671,"name":"Loreto Spencer","orcid":null,"position":16,"is_corresponding":false},{"id":1603672,"name":"Gonzalo De Toro","orcid":null,"position":17,"is_corresponding":false},{"id":1603673,"name":"Erik Morales","orcid":null,"position":18,"is_corresponding":false},{"id":1603674,"name":"Lorena Gutiérrez","orcid":null,"position":19,"is_corresponding":false},{"id":1603675,"name":"Fernanda Morales","orcid":null,"position":20,"is_corresponding":false},{"id":1603676,"name":"Arnaldo Marin","orcid":null,"position":21,"is_corresponding":false},{"id":1603677,"name":"Nelson M. Varela","orcid":null,"position":22,"is_corresponding":false},{"id":53250,"name":"Justo Lorenzo Bermejo","orcid":"0000-0002-6568-5333","position":23,"is_corresponding":false},{"id":1338895,"name":"Ricardo Armisén","orcid":"0000-0003-2567-0521","position":24,"is_corresponding":false},{"id":1044165,"name":"Katherine Marcelain","orcid":"0000-0003-4018-6623","position":25,"is_corresponding":false},{"id":1603647,"name":"José Ignacio Erices","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The mutational landscape and actionable targets of gallbladder cancer: an ancestry-informed and comparative analysis of a Chilean population","abstract":"<jats:sec><jats:title>Introduction</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 535 somatic mutations were detected in 43 genes, with <jats:italic>TP53</jats:italic> (30%), <jats:italic>TSC2</jats:italic> (29%), and <jats:italic>NOTCH1</jats:italic> (27%) being the most frequently mutated. We identified 121 clinically actionable variants in <jats:italic>ATM, BRCA1/2, EGFR, ERBB2</jats:italic>, and other genes. Exploratory analysis suggested an association between higher Mapuche ancestry and <jats:italic>TP53</jats:italic> mutations. Comparative analyses revealed distinct mutational patterns in the Chilean cohort relative to Asian and U.S. datasets.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41114336","pmcid":"PMC12531073","openalex_id":"https://openalex.org/W4414771294","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"825741","title":"Establishment and Exploitation of a European-Latin American Research Consortium towards Eradication of Preventable Gallbladder Cancer"}],"total_grants":1,"fwci":3.2831,"citation_percentile":0.92687003,"influential_citations":0,"citation_trend":[{"year":2025,"count":1},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1658528/pdf","host_type":"journal"},{"url":"https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1658528/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fonc.2025.1658528/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fonc.2025.1658528","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41114336","host_type":"repository"},{"url":"https://doaj.org/article/b83b2362b75a47b89418cec97b2ede16","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12531073","host_type":"repository"},{"url":"https://repositorio.uchile.cl/handle/2250/210997","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12531073","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12531073?pdf=render","host_type":"Europe_PMC"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41114336/","host_type":""},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12531073/","host_type":""},{"url":"http://dx.doi.org/10.3389/fonc.2025.1658528","host_type":""}],"fields_of_study":["Cholangiocarcinoma and Gallbladder Cancer Studies","Cancer Genomics and Diagnostics","Gallbladder and Bile Duct Disorders","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":[],"keywords":["Population","Relevance (law)","Precision medicine","Gallbladder","Genomics","Gallbladder cancer","Personalized Therapies","Driver Mutations","Genetic Ancestry","Next-generation Sequencing (Ngs)","Oncology"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T13:17:01.807801Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}