{"doi":"10.1101/2025.08.08.25332963","title":"Modelling Acral Melanoma in Admixed Brazilians Uncovers Genomic Drivers and Targetable Pathways","abstract":"ABSTRACT Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like those residing in Latin America, AM accounts for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing revealed low mutation burden and predominance of copy number alterations, including high-amplitude focal amplifications termed hailstorms. These hailstorms frequently affected chromosomes 11, 5 and 22 and key oncogenes such as CCND1 , GAB2 , CDK4 , and TERT . The presence of hailstorms in the long arms of chromosomes 11 and 22 was associated with higher focal copy number burden and loss of DNA damage response genes ( ATM , CHEK1 ), suggesting a permissive genomic environment driving structural instability. To explore the unique genomic context of AM, we established a comprehensive collection of patient-derived xenograft (AM-PDX) models that faithfully retain the histopathological and genomic features of the original tumours. Functional exploration of AM-specific vulnerabilities through pharmacological and CRISPR/Cas9 knockout screenings identified strong sensitivity to targeting MAPK, CDK4/6, MDM2, and WEE1 pathways. Notably, the pan-RAS(ON) inhibitor RMC-7977 effectively reduced viability in NRAS -, KRAS -, and KIT -mutant AM cell lines. Finally, CRISPR screens revealed dependencies selectively essential in AM, including CRKL and SF3B4 , highlighting previously unrecognized vulnerabilities. Our findings emphasize the distinct biology of AM compared to other subtypes of melanoma, provide a valuable resource of models reflective of Latin American ancestry, and identify potential drivers and therapeutic targets.","journal":"medRxiv","year":2025,"id":572270,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8451,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1478467,"name":"Sara Santos Bernardes","orcid":"0000-0001-6700-2447","position":1,"is_corresponding":false},{"id":1478468,"name":"Flavia C. Aguiar","orcid":"0000-0001-7149-6531","position":2,"is_corresponding":false},{"id":1478909,"name":"Antonio C. Facciolo","orcid":null,"position":3,"is_corresponding":false},{"id":1334473,"name":"Martín del Castillo Velasco Herrera","orcid":null,"position":4,"is_corresponding":false},{"id":1334468,"name":"J. Rene C. Wong-Ramirez","orcid":null,"position":5,"is_corresponding":false},{"id":931324,"name":"Patricia Basurto‐Lozada","orcid":null,"position":6,"is_corresponding":false},{"id":1478469,"name":"Aretha Brito Nobre","orcid":"0000-0002-7177-9838","position":7,"is_corresponding":false},{"id":1478910,"name":"Geethanjali Annamalai","orcid":null,"position":8,"is_corresponding":false},{"id":1478911,"name":"Rebecca Martins Cadimo do Nascimento","orcid":null,"position":9,"is_corresponding":false},{"id":942112,"name":"Jacqueline Marcia Boccacino","orcid":"0000-0001-6813-5217","position":10,"is_corresponding":false},{"id":1478912,"name":"Rafaela Fagundes","orcid":null,"position":11,"is_corresponding":false},{"id":1478913,"name":"Pedro Barros","orcid":null,"position":12,"is_corresponding":false},{"id":1478914,"name":"Mariana de Moraes Pitombo","orcid":null,"position":13,"is_corresponding":false},{"id":1206357,"name":"Rebeca Olvera-León","orcid":null,"position":14,"is_corresponding":false},{"id":915723,"name":"Larissa Satiko Alcântara Sekimoto Matsuyama","orcid":"0000-0002-5610-0030","position":15,"is_corresponding":false},{"id":1334467,"name":"Jamie Billington","orcid":null,"position":16,"is_corresponding":false},{"id":1032939,"name":"Ian Vermes","orcid":null,"position":17,"is_corresponding":false},{"id":1334463,"name":"Irving Simonin-Wilmer","orcid":null,"position":18,"is_corresponding":false},{"id":1478915,"name":"Danielle Gonçalves de Carvalho","orcid":null,"position":19,"is_corresponding":false},{"id":1478916,"name":"João Pedro Cavalcante Simoes","orcid":null,"position":20,"is_corresponding":false},{"id":1478470,"name":"Priscila Valverde Fernandes","orcid":"0000-0002-0196-4755","position":21,"is_corresponding":false},{"id":1478471,"name":"Luíz Fernando Nunes","orcid":"0000-0003-2835-6597","position":22,"is_corresponding":false},{"id":679967,"name":"Andréia Cristina de Melo","orcid":"0000-0002-1201-4333","position":23,"is_corresponding":false},{"id":1478472,"name":"Jadivan Leite de Oliveira","orcid":"0000-0003-2035-9910","position":24,"is_corresponding":false},{"id":35706,"name":"Meenhard Herlyn","orcid":"0000-0003-0839-0739","position":25,"is_corresponding":false},{"id":336530,"name":"Andrew E. Aplin","orcid":"0000-0002-2734-3244","position":26,"is_corresponding":false},{"id":467223,"name":"Carla Daniela Robles‐Espinoza","orcid":"0000-0003-3277-7466","position":27,"is_corresponding":false},{"id":13189,"name":"David J. Adams","orcid":"0000-0001-9490-0306","position":28,"is_corresponding":false},{"id":915725,"name":"Patrícia A. Possik","orcid":"0000-0003-2899-0969","position":29,"is_corresponding":false},{"id":1478466,"name":"Annie Cristhine Moraes Sousa‐Squiavinato","orcid":"0000-0003-0345-1571","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":"40832384","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":[]}