Comprehensive Genomic Profiling Reveals Distinct Patterns Of Driver Mutations And Chromosomal Alterations In Acral And Mucosal Melanomas.

9576 Background: The incidence of melanoma subtypes differs significantly among ethnicities. Ultraviolet (UV) radiation-driven melanomas are common in Caucasians, while non-cutaneous melanomas including acral and mucosal melanomas are more frequent in Asians. It will be of great interest and clinical relevance to decipher the molecular pathogenesis of different melanoma subtypes. Methods: We retrospectively studied a cohort of 89 Chinese melanoma patients who underwent surgical resection of their primary tumors followed by chemotherapy. Genomic profiling of primary melanomas was performed using next generation sequencing by targeting 422 cancer-relevant genes. The Kaplan-Meier method and logrank test were used for survival analysis, and a cox model was used for multivariate survival analysis. Results: Acral melanomas (54/89, 60%) were the most common subtype of this cohort, while cutaneous and mucosal subtypes accounted for 25% and 15%, respectively. Mutation profiling revealed that BRAF was most frequently mutated in cutaneous melanomas, but aberrant BRAF, RAS, KIT, and NF1 were almost evenly represented in acral and mucosal melanomas; of note, mucosal melanomas had a propensity for concurrent driver mutations. Chromosomal alterations were detected across all subtypes, and chr7p amplification significantly correlated with poor prognosis while independently of melanoma subtypes. Furthermore, acral and mucosal melanomas demonstrated higher rates of focal copy number variations (CNVs) than cutaneous melanomas. The amplification of CDK4/CCND1 and NOTCH2 was observed predominantly in acral melanomas , and RAD51 loss was significantly enriched in mucosal melanomas correlating with poor survival. In addition, the tumor mutation burden (TMB) was significantly lower in acral or mucosal melanomas than in cutaneous melanomas. Conclusions: Our findings revealed distinct patterns of driver mutations and chromosomal alterations in acral and mucosal melanomas in contrast to cutaneous melanoma, and highlighted the association of chromosome 7p amplification and RAD51 deletion with unfavourable survival in melanoma patients treated with standard chemotherapy.