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.
Supplemental Digital Content is available in the text.,The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) immune checkpoints are negative regulators of T-cell immune function.,Inhibition of these targets, resulting in increased activation of the immune system, has led to new immunotherapies for melanoma, non-small cell lung cancer, and other cancers.,Ipilimumab, an inhibitor of CTLA-4, is approved for the treatment of advanced or unresectable melanoma.,Nivolumab and pembrolizumab, both PD-1 inhibitors, are approved to treat patients with advanced or metastatic melanoma and patients with metastatic, refractory non-small cell lung cancer.,In addition the combination of ipilimumab and nivolumab has been approved in patients with BRAF WT metastatic or unresectable melanoma.,The roles of CTLA-4 and PD-1 in inhibiting immune responses, including antitumor responses, are largely distinct.,CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes, whereas PD-1 suppresses T cells later in an immune response, primarily in peripheral tissues.,The clinical profiles of immuno-oncology agents inhibiting these 2 checkpoints may vary based on their mechanistic differences.,This article provides an overview of the CTLA-4 and PD-1 pathways and implications of their inhibition in cancer therapy.