Acral lentiginous melanoma (ALM) is a rare sun-shielded melanoma subtype associated with worse survival than cutaneous melanoma (CM), a more common form of skin cancer linked to exposure to ultra-violet (UV) light. In order to better understand the genomic landscape of ALM with the goal of identifying novel therapeutic strategies, we performed comprehensive genomic and transcriptomic analysis of 37 tumors from 34 clinically well-annotated, histopathologically qualified ALM patients. For all samples with available analytes, whole exome sequencing, long insert whole genome and mRNA sequencing was performed. Bioinformatics tools and workflows were used to identify somatic point mutations, indels, copy number alterations, structural variants, and to perform gene expression analyses. The overall mutation burden (SNV) was variable, with a median of 123 SNVs (range of 2-2449), including 16 samples with < 100. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. Our study thus demonstrates the value of implementing a comprehensive sequencing and informatics strategy to understand the genomics of a disease and how such integrated analyses have the power to lead to identifying therapeutic strategies for patients.
Research And Development
Medical Laboratory Technician50%
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