Comprehensive Genomic Profiling of Acral Melanoma: Insights From the AACR Project GENIE Database

BACKGROUND: Acral melanoma (AM) is a rare but aggressive melanoma subtype that arises on palmoplantar surfaces and nail units. It disproportionately affects individuals with darker skin tones and is frequently diagnosed at advanced stages. Limited genomic data have hindered the development of effective targeted therapies. METHODS: A retrospective genomic analysis of AM was conducted using the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange repository, evaluating 212 tumor samples from 203 patients for somatic mutations, copy number alterations, and mutational patterns across demographic and clinical variables. Co-occurrence, mutual exclusivity, and survival analyses were also performed. RESULTS: NRAS (21.2%), BRAF (18.3%), and KIT (9.0%) were the most common mutations. CDKN2A and CDKN2B deletions occurred in over 20% of the samples, along with recurrent amplifications in CDK4 , CCND1 , and TERT . Significant comutation patterns included NF1 - PTPRT and KRAS - TERT . Mutation frequencies varied across sex and racial groups, and NAB2 mutations were exclusive to metastatic tumors. CONCLUSION: This study provides a comprehensive genomic overview of AM, highlighting recurrent alterations in the MAPK and cell cycle pathways, and potential demographic-specific molecular signatures. These findings support the need for expanded molecular profiling to improve prognostic accuracy and identify targets for future therapy.