Abstract
To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.
Highlights
We have described the largest whole-genome analysis of acral melanoma to date
Subungual tumors were characterized by higher numbers of mutations per megabase, and were more aneuploid than those in other sites, harboring a higher proportion of CNS1 and chromosome 6 isochromosomes
It would be of interest to explore the UVR signature and other genomic features of subungual tumors in a series of tumors from different ethnicities
Summary
The study involved WGS of 87 fresh-frozen tumor specimens and matched germline DNA (Supplementary Data 1 and 2). In a multivariable Cox regression survival model based on SPRED1 mutation status, overall stage, age, gender and specimen type (primary or recurrence/metastasis), SPRED1 aberrations co-occurring with NRAS/NF1/KIT mutations were associated with increased risk of melanoma-specific mortality (p = 0.006) (Fig. 6c). A BRAF V600E subclassification for acral melanomas has been previously proposed, and in our cohort, these tumors appeared similar to CM, with low rearrangement burden and fewer samples with complex chromosomes (Fisher’s exact test, p = 0.011). AM cell lines and PDX with CDK4 pathway aberrations have been reported to be sensitive to CDK4/6 inhibitors, indicating these drugs may have utility in a large proportion of AMs. Other potential treatments for tumors, in the Triple WT subtype subgroup include KIT inhibitors, PARP inhibitors for ATM LoF mutations, and in the one tumor with a ROS1 fusion, treatment with the tropomyosin receptor kinase inhibitor entrectinib
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