Ancestry and somatic profile indicate acral melanoma origin and prognosis

Acral melanoma, which is not ultraviolet-associated, is the type of melanoma reported most commonly in several non-European-descent populations<sup>1-3</sup>, including in Mexican people<sup>4</sup>. Latin American samples are substantially under-represented in global cancer genomics studies<sup>5</sup>, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures<sup>6-8</sup>. To address this, we characterized the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients-a population notable because of its genetic admixture<sup>9</sup>. Compared with other studies of melanoma, we found fewer mutations in classical driver genes such as BRAF, NRAS or NF1. Although most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations. The tumours with activating BRAF mutations had a transcriptional profile more similar to cutaneous non-volar melanocytes, indicating that acral melanomas in these patients may arise from a distinct cell of origin compared with other tumours arising in these locations. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

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Nature
Published
2026-02-18
DOI
https://doi.org/10.1038/s41586-025-09967-z
Primary Topic
Cutaneous Melanoma Detection and Management
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article
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article

Ancestry and somatic profile indicate acral melanoma origin and prognosis

Fernanda Guadalupe Arriaga-González, P. Basurto-Lozada, Richard M. White, Martha Estefania Vázquez‐Cruz et al.
Nature
Cutaneous Melanoma Detection and Management
article

Ancestry and somatic profile indicate acral melanoma origin and prognosis

Fernanda Guadalupe Arriaga-González, P. Basurto-Lozada, Richard M. White, Martha Estefania Vázquez‐Cruz, Peter A. Johansson, Patrícia A. Possik, Rodrigo go Roldán-Marín, Dorian Yarih García-Ortega, Dekker C. Deacon, Dennis Cerrato-Izaguirre, Mireya Cisneros-Villanueva, Carla Daniela Robles Espinoza, Robert L. Judson-Torres, Johana Itzel Ramos-Galguera, Kenya L. Contreras-Ramírez, Jamie Billington, H. Vidaurri de la Cruz, Marcos Díaz-Gay, Mark J Arends, Rebeca Olvera-León, Amanda Jiang, Ingrid Ferreira, Rachel L. Belote, Ludmil Alexandrov, J. Rene C. Wong-Ramirez, D. Timothy Bishop, Eric T. Dawson, Luis Alberto Tavares-de-la-Paz, Christian Molina-Aguilar, Diego Hinojosa-Ugarte, Alethia Álvarez-Cano, Louise van der Weyden, Yesennia Sánchez-Pérez, Irving Simonin-Wilmer, Gino K. In, David J. Adams, O. Isaac García-Salinas, Mark Tullett
article en

Abstract

Acral melanoma, which is not ultraviolet-associated, is the type of melanoma reported most commonly in several non-European-descent populations<sup>1-3</sup>, including in Mexican people<sup>4</sup>. Latin American samples are substantially under-represented in global cancer genomics studies<sup>5</sup>, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures<sup>6-8</sup>. To address this, we characterized the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients-a population notable because of its genetic admixture<sup>9</sup>. Compared with other studies of melanoma, we found fewer mutations in classical driver genes such as BRAF, NRAS or NF1. Although most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations. The tumours with activating BRAF mutations had a transcriptional profile more similar to cutaneous non-volar melanocytes, indicating that acral melanomas in these patients may arise from a distinct cell of origin compared with other tumours arising in these locations. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

NatureVol. 651(8104)
University of Southern California (US), University of Leeds (GB), University of Helsinki (FI), Autonomous University of Queretaro (MX), The University of Queensland (AU), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), Huntsman Cancer Institute (US), Hospital General de México (MX), Wellcome Sanger Institute (GB), Edinburgh Cancer Research (GB), University of California San Diego (US), University of Oxford (GB), Spanish National Cancer Research Centre (ES), Hospital do Câncer III (BR), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX), Ludwig Cancer Research (GB), St Richard's Hospital (GB), National Institute of Genomic Medicine (MX), USC Norris Comprehensive Cancer Center (US), La Jolla Bioengineering Institute (US), Instituto Nacional de Câncer - INCA (BR), Hospital Regional de Alta Especialidad del Bajío (MX), Instituto Nacional de Cancerología (MX), The Ohio State University (US), University of Monterrey (MX), Universidad Nacional Autónoma de México (MX), Bryan College (US)
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Cutaneous Melanoma Detection and Management
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