Introduction: Due to its aggressiveness, cutaneous melanoma (CM) is responsible for most skin cancer-related deaths worldwide. The origin of CM is closely linked to the appearance of UV-induced somatic mutations in melanocytes present in normal skin or in CM precursor lesions (nevi or dysplastic nevi). In recent years, new NGS studies performed on CM tissue have increased the understanding of the genetic somatic changes underlying melanomagenesis and CM tumor progression. Methods: We reviewed the literature using all important scientific databases. All articles related to genomic mutations in CM as well as normal skin and nevi were included, in particular those related to somatic mutations produced by UV radiation. Conclusions: CM development and progression are strongly associated with exposure to UV radiation, although each melanoma subtype has different characteristic genetic alterations and evolutionary trajectories. While BRAF and NRAS mutations are common in the early stages of tumor development for most CM subtypes, changes in CDKN2A, TP53 and PTEN, together with TERT promoter mutations, are especially common in advanced stages. Additionally, large genome duplications, loss of heterozygosity, and copy number variations are hallmarks of metastatic disease. Finally, the mutations driving melanoma targeted-therapy drug resistance are also summarized. The complete sequential stages of clonal evolution leading to CM onset from normal skin or nevi are still unknown, so further studies are needed in this field to shed light on the molecular pathways involved in CM malignant transformation and in melanoma acquired drug resistance.

Melanocytic tumorigenesis is thought to occur through stepwise genomic evolution from normal skin to nevi and, ultimately, melanoma. To investigate this progression, we performed targeted deep sequencing of a 46-gene panel in matched healthy skin, nevus, and melanoma samples from 15 patients, including 14 complete tissue trios. Mutation burden increased progressively across tissues, with median mutation counts rising from benign skin to nevi and showing the highest levels in melanoma, consistent with cumulative somatic alterations. Canonical MAPK pathway mutations were common: BRAF V600E and NRAS Q61 variants were detected in many nevi and melanomas and were shared between lesions in 8 of 15 patients, providing direct evidence of clonal continuity. Variant allele frequencies for driver and nonsynonymous mutations were higher than those of passenger and synonymous mutations, reflecting selective expansion of functionally relevant clones. UV-signature substitutions were abundant, particularly among synonymous variants, suggesting background mutagenesis without clonal advantage. Melanoma-private mutations in genes such as ARID1A, ARID2, PIK3CA, and CDKN2A indicated additional late events contributing to malignant progression. Overall, this study supports a model in which many melanomas evolve from pre-existing nevi through sequential acquisition and clonal amplification of somatic mutations, while also revealing heterogeneous evolutionary trajectories.

Lupus erythematosus panniculitis or lupus erythematosus profundus is characterized by inflammation of the deep dermis and subcutaneous tissue. It can occur in isolation or associated with chronic systemic or discoid lupus erythematosus. It usually consists of nodules and hardened subcutaneous plaques on the forehead, cheeks, proximal extremities, and buttocks. Periorbital and parotid involvement are rare and can lead to misdiagnosis. We present the case of a patient with lupus erythematosus panniculitis who presented with palpebral edema and involvement of the periocular fat and parotid gland.