Genetic Analysis of Acral Melanomas From Southern African Patients

While the molecular characteristics of cutaneous melanomas (CMs) in individuals with light skin have been extensively studied, less is known about acral melanoma (AM), a non-ultraviolet radiation-induced melanoma more frequently found in individuals with darker skin. Exome and whole genome sequencing of 25 AMs from South African patients with a range of ancestral backgrounds were performed. While close to 50% in CMs, only one AM in a patient of European ancestry harbored an alteration at p.V600 in BRAF. 76% of tumors were triple wild-type. There were hotspot mutations in KIT, mutations in genes encoding components of the MAPK pathway (K57N in MAP2K1 and Y71H in HRAS), and novel candidate driver mutations in genes including PROS1, RGPD3, and SF3A3. Copy number gains included regions with TERT, CDK4, PAK1/GAB2, and DAD1 (chr14q11.2). Gain of chr17q25.1 harboring CDK3 was seen in samples with African ancestry. Eleven significantly deleted regions included chr1q43 (MAP1LC3C) and homozygous deletions of HLA-DRB1, PHF10 (chr6q27), and ATMIN (chr16q23). Mutational signatures included chromosomal instability and chromothripsis. There was a robust ancestry-related difference in tumor evolutionary dynamics where African ancestry was correlated with more genome doubling and clonality with less evolutionary branching.