Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited.,Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms.,We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients.,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.,In contrast 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.,These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.
The detection of V600E BRAF mutations has fundamental clinical consequences as the treatment option with BRAF inhibitors such as vemurafenib or dabrafenib yields response rates of ∼48%.,Heterogeneity with respect to BRAF mutation in different metastases has been described in single cases.,As this has important implications for the determination of BRAF status and treatment of patients, it is essential to acquire more data.,A total of 300 tumour samples from 187 melanoma patients were analysed for BRAF mutations by pyrosequencing.,Equivocal results were confirmed by capillary sequencing.,Clinical data with respect to melanoma type, tumour site and survival were summarised for 53 patients with multiple analysed tumour samples (2-13 per patient).,BRAF mutations were found in 84 patients (44.9%) and 144 tumour samples (48%) with BRAF mutations in 45.5% of primary tumours and 51.3% of metastases, respectively.,In 10 out of 53 patients (18.9%) where multiple samples were analysed results were discordant with respect to mutation findings with wild-type and mutated tumours in the same patient.,Mutations did not appear more frequently over the course of disease nor was its occurrence associated with a specific localisation of metastases.,As heterogeneity with respect to BRAF mutation status is detected in melanoma patients, subsequent testing of initially wild-type patients can yield different results and thus make BRAF inhibitor therapy accessible.,The role of heterogeneity in testing and for clinical response to therapy with a BRAF inhibitor needs to be further investigated.