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^1-3, including in Mexican people⁴. Latin American samples are substantially under-represented in global cancer genomics studies⁵, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures^6-8. 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 admixture⁹. 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.