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.,Acral melanoma occurs on the soles of the feet, palms of the hands and in nail beds.,Here, the authors reports the genomic landscape of 87 acral melanomas and find that some tumors harbor a UV signature and that the tumors are diverse at the levels of mutational signatures, structural aberrations and copy number signatures.
Melanoma is currently divided on a genetic level according to mutational status.,However, this classification does not optimally predict prognosis.,In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology.,Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes.,We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group.,Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes.,We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response.,In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02).,In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.