Cutaneous melanoma (CM) is the most aggressive type of skin cancer, and it is characterised by high mutational load and heterogeneity. In this study, we aimed to analyse the genomic and transcriptomic profile of primary melanomas from forty-six Formalin-Fixed, Paraffin-Embedded (FFPE) tissues from Greek patients. Molecular analysis for both germline and somatic variations was performed in genomic DNA from peripheral blood and melanoma samples, respectively, exploiting whole exome and targeted sequencing, and transcriptomic analysis. Detailed clinicopathological data were also included in our analyses and previously reported associations with specific mutations were recognised. Most analysed samples (43/46) were found to harbour at least one clinically actionable somatic variant. A subset of samples was profiled at the transcriptomic level, and it was shown that specific melanoma phenotypic states could be inferred from bulk RNA isolated from FFPE primary melanoma tissue. Integrative bioinformatics analyses, including variant prioritisation, differential gene expression analysis, and functional and gene set enrichment analysis by group and per sample, were conducted and molecular circuits that are implicated in melanoma cell programmes were highlighted. Integration of mutational and transcriptomic data in CM characterisation could shed light on genes and pathways that support the maintenance of phenotypic states encrypted into heterogeneous primary tumours.

Background/Objectives: Cutaneous melanoma is predominantly sporadic, although a subset of patients presents clinical features suggestive of inherited susceptibility. We introduced the pragmatic concept of genetically enriched (GE) melanoma, defined by the presence of early-onset melanoma, familial melanoma, or multiple primary melanomas. Methods: Its clinicopathological characteristics and prognosis were compared with those of sporadic melanoma. Demographic, clinicopathological, and survival data were analyzed using descriptive statistics, survival analysis, and Cox regression models. Results: In this retrospective single-center study, 1,874 patients were classified as having GE (n = 796, 42.5%) or sporadic melanoma (n = 1,078, 57.5%). Patients with GE melanoma were significantly younger at diagnosis (median age, 37 years [IQR 32–43] vs 57 years [IQR 50–66], p < 0.001) and were more frequently females than those with sporadic melanoma (56.8% vs. 51.4%, p = 0.024). The GE cohort also showed a distinct clinicopathological profile, with a higher proportion of melanoma in situ (20.2% vs. 15.2%), lower proportions of acral lentiginous (3.5% vs. 1.1%) and lentigo maligna (5.2% vs. 1.4%) melanoma, and a lower prevalence of previous malignancies. After a median follow-up of 8 years, disease-free survival did not differ significantly between the two cohorts (log-rank p = 0.23). Within the GE cohort, older age and male sex were associated with a higher risk of recurrence. Conclusions: Overall, patients fulfilling clinical criteria suggestive of inherited melanoma susceptibility appear to represent a distinct clinicopathological subgroup without evidence of poorer prognosis. The concept of GE melanoma may offer a pragmatic framework for identifying patients who may benefit from genetic counseling and tailored surveillance strategies.