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Melanoma is a major public health concern that is responsible for significant morbidity and mortality, particularly in countries such as New Zealand and Australia where it is the commonest cause of cancer death in young adults. Until recently, there were no effective drug therapies for patients with advanced melanoma however significant advances in our understanding of the biological and molecular basis of melanoma in recent decades have led to the development of revolutionary treatments, including targeted molecular therapy and immunotherapy. This review summarizes our current understanding of the key events in the pathway of melanomagenesis and discusses the role of genomic analysis as a potential tool for improved diagnostic evaluation, prognostication and treatment strategies. Ultimately, it is hoped that a continued deeper understanding of the mechanisms of melanomagenesis will lead to the development of even more effective treatments that continue to provide better outcomes for patients with melanoma.

Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22). Immunohistochemistry was performed on all biopsies to detect CD8, FOXP3, PD-1 and VISTA expression on T-cells and PTEN, β-catenin, PD-L1, HLA-A, and HLA-DPB1 expression in the tumor. The majority of patients showed significantly increased density of VISTA+ lymphocytes from PRE to PROG (12/18) (P=0.009) and increased expression of tumor PD-L1 from PRE to PROG (11/18). Intratumoral expression of FOXP3+ lymphocytes significantly increased (P=0.018) from PRE to PROG (10/18). Loss of tumor PTEN and downregulation of tumor HLA-A from PRE to PROG were each identified in 5/18 and 4/18 PROG biopsies, respectively. Downregulation of HLA-DPB1 from PRE to PROG was present in 3/18 PROG biopsies, whereas nuclear β-catenin activation was only identified in 2/18 PROG biopsies. Negative immune checkpoint regulation by VISTA represents an important potential mechanism of acquired resistance in melanoma patients treated with anti-PD-1. Downregulation of HLA-associated antigen presentation also occurs with acquired resistance. Augmentation of the VISTA immune checkpoint pathway may hold promise as a therapeutic strategy in metastatic melanoma patients, particularly those failing anti-PD-1 therapy, and warrants assessment in clinical trials.

Blue nevi are melanocytic tumors originating in the cutaneous dermis. Malignant tumors may arise in association with or resembling blue nevi, so called 'blue nevus-like melanoma', which can metastasize and result in patient death. Identifying which tumors will behave in a clinically aggressive manner can be challenging. Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication. Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations). In this study, we analyzed a large cohort (n=301) of various morphologic variants of blue nevi and related tumors including tumors diagnosed as atypical blue nevi (n=21), and blue nevus-like melanoma (n=12), screening for all gene mutations known to occur in uveal melanoma. Similar to published reports, we found the majority of blue nevi harbored activating mutations in GNAQ (53%) or GNA11 (15%). In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified. EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n=3) of blue nevus-like melanoma, respectively). In sequencing data from a larger cohort of cutaneous melanomas, this genetic profile was also identified in tumors not originally diagnosed as blue nevus-like melanoma. Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas. Future studies will need to further elucidate the prognostic implications and appropriate clinical management for patients with tumors harboring these mutation profiles.

Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n=61), followed by less frequent mutations in GNA11 (16%, n=17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T>A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.