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Melanoma pathogenesis, conventionally perceived as a linear accumulation of molecular changes, discloses substantial heterogeneity driven by non-linear biological processes, including the direct transformation of melanocyte stem cells. This heterogeneity manifests in diverse biological phenotypes and developmental states, influencing variable responses to treatments. Unveiling the aberrant mechanisms steering melanoma initiation, progression, and metastasis is imperative. Beyond mutations in oncogenic and tumor suppressor genes, the involvement of distinct molecular pathways assumes a pivotal role in melanoma pathogenesis. Ultraviolet (UV) radiations, a principal factor in melanoma etiology, categorizes melanomas based on cumulative sun damage (CSD). The genomic landscape of lesions correlates with UV exposure, impacting mutational load and spectrum of mutations. The World Health Organization's 2018 classification underscores the interplay between sun exposure and genomic characteristics, distinguishing melanomas associated with CSD from those unrelated to CSD. The classification elucidates molecular features such as tumor mutational burden and copy number alterations associated with different melanoma subtypes. The significance of the mutated BRAF gene and its pathway, notably BRAFV600 variants, in melanoma is paramount. BRAF mutations, prevalent across diverse cancer types, present therapeutic avenues, with clinical trials validating the efficacy of targeted therapies and immunotherapy. Additional driver mutations in oncogenes further characterize specific melanoma pathways, impacting tumor behavior. While histopathological examination remains pivotal, challenges persist in molecularly classifying melanocytic tumors. In this review, we went through all molecular characterization that aid in discriminating common and ambiguous lesions. Integration of highly sensitive molecular diagnostic tests into the diagnostic workflow becomes indispensable, particularly in instances where histology alone fails to achieve a conclusive diagnosis. A diagnostic algorithm based on different molecular features inferred by the various studies is here proposed., Competing Interests: Declaration of Competing Interest Authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Improvement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However, epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents., Methods: Melanoma cell lines, characterized for mutational and differentiation profile, were treated with inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), BET proteins (JQ1 and OTX-015), and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets., Results: Epigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine, irrespective of the mutational and differentiation profiles of the melanoma cell lines, to a lesser extent by givinostat, but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies, but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature, containing activated molecules of the TLR, NF-kB, and IFN innate immunity pathways, was induced in drug-treated melanoma, mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset., Conclusions: The DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested, supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches., (© 2022. The Author(s).)

Introduction: Multiple primary melanomas (MPM) occur up to 8% of patients with cutaneous malignant melanoma (CMM). They are often sporadic harbouring several somatic mutations, but also familial cases harbouring a CDKN2A germline mutation have been describe in Caucasian populations. The aim of this study was to investigate the incidence, the distribution patterns and the impact of known and unknown germline and somatic mutations in patients with MPM from Italy., Materials and Methods: One-hundred and two MPM patients were enrolled for germline mutation analysis, and five patients with at least four MPMs were identified for somatic mutation analysis. The demographic, pathologic and clinical features were retrieved from medical records. Molecular analysis for both germline and somatic mutations was performed in genomic DNA from peripheral blood and tissue samples, respectively, through a next generation sequencing approach, using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup for somatic analysis and a commercial cancer hotspot panel for somatic analysis., Results: CDKN2A mutations were detected in 6/16 (37.5%) and 3/86 (3.5%) MPM cases with and without family history for melanoma, respectively. Furthermore, multiple MC1R and, to a lesser extent, ATM variants have been identified. BAP1 variants were found only in MPM patients from southern Italy. The most frequent somatic variants were the pathogenic BRAF V600E and TP53, followed by KIT, PIK3CA, KDR, and NRAS. Single APC, ERBB4, MET, JAK3 and other variants with unknown function were also detected., Conclusions: CDNK2A mutation is the most relevant susceptibility mutation in Italian patients with MPM, especially those with a family history for CMM. The prevalence of this mutation and other sequence variants identified in this study varies among specific sub-populations. Furthermore, some heterogeneity in driver somatic mutations between sporadic MPMs has been observed, as well as in a number of associated sequence variants the clinical impact of which needs to be further elucidated.

Cutaneous melanoma is one of the most frequent malignancies of the skin in Caucasian populations. Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. The estimated incidence of multiple primary melanoma (MPM) ranges from 1.2% to 8.2% of cases, with a high preponderance of melanomas occurring metachronously. The aim of this study was to describe dermoscopic, microscopic, clinical, and molecular correlations between first and subsequent melanomas in patients with metachronous MPMs. Twenty-four paired melanomas from 12 MPM patients were evaluated for architectural characteristics based on dermoscopy and confocal microscopy, as well as for mutations in BRAF and NRAS genes by Sanger-based sequencing analysis. Specific scores used for classifying features of dermoscopy (global pattern; 7-point check list; ABCD Stolz score) and confocal microscopy (Segura and Pellacani) were compared with genetic and histological data. Consistency in dermoscopic patterns between the primary and subsequent cutaneous melanomas were observed in about two thirds of cases, whereas concordant features based on confocal microscopy were found in only about two fifths of cases. The majority of patients (7/12; 58%) presented consistent BRAF/NRAS mutation patterns between first and subsequent primary melanomas. A significant association between BRAF mutations and Pellacani score was evident. Similarities between the index melanoma and subsequent cutaneous melanomas were observed with regards to dermoscopic features and, to a much less extent, confocal microscopy findings. Our data further indicate that the Pellacani score may be used to predict BRAF mutations.

Cutaneous malignant melanoma, whose incidence is increasing steadily worldwide, is the result of complex interactions between individual genetic factors and environmental risk factors. Ultraviolet radiation represents the most important environmental risk factor for the development of skin cancers, including melanoma. Sun exposure and early sunburn during childhood are the principal causes of cutaneous melanoma insurgence in adults, with double the risk relative to a nonexposed population. Consequently, ultraviolet protection has long been recognized as an important measure to prevent such a malignancy. Biological and epidemiological data suggest that vitamin D status could affect the risk of cancer and play a role in cancer prevention by exerting antiproliferative effects. Solar radiations are critical for vitamin D synthesis in humans; however, uncontrolled and intensive sun exposure is dangerous to skin health and may contribute toward the development of cutaneous malignant melanoma. An optimum balance between sun protection and exposure is thus advocated. Additional research is required to confirm the preventive role of vitamin D in melanoma incidence or a positive influence on patient outcome.

The aim of this report was to study the descriptive and genetic epidemiology of malignant melanoma in North Sardinia, Italy, in the period 1992-2011. Epidemiological data were obtained from the local tumor registry, which is part of the Italian Association for Tumor Registries. Among patients included in the North Sardinia tumor registry, 316 patients first evaluated for familial recurrence of melanoma were submitted to mutation analysis in CDKN2A and CDK4 genes. The overall number of cases registered was 532. The male-to-female ratio was 1 : 1 and the mean age was 56 years for men and 55 years for women. The standardized incidence rates were 4.9/100 000 and 4.4/100 000 and the standardized mortality rates were 1.7/100 000 and 1.3/100 000 for men and women, respectively. The relative 5-year survival was 77% for men and 79% for women. In our series, 24/316 (7.6%) patients had a familial occurrence of melanoma (presence of at least one additional family member affected). Among these, one variant (Gly23Asp), reported previously as a low-frequency disease-causing mutation, was detected by mutational screening in the p16 gene only. With the exception of polymorphisms, none of either the sporadic melanoma patients or healthy controls presented a germline mutation in candidate genes. An increase in incidence and a decrease in mortality rates of malignant melanoma were registered in North Sardinia, from 1992 to 2011, whereas survival was similar to that reported in recent international reports. The high-penetrance melanoma susceptibility genes (CDKN2A and CDK4) are not involved in predisposition to melanoma in North Sardinia.

Background: Patients who develop cutaneous melanoma are at increased risk of developing a second primary melanoma. There are many aetiological reasons by which the risk of a second melanoma increases. Among others, genetic factors may contribute to modulating this risk. The risk of identifying a CDKN2A germline mutation increases with the number of primary melanomas and with the presence of familial history of melanoma. Patients with melanoma are especially encouraged to have regular follow-up visits with their dermatologist to perform clinical and dermatoscopic examination. In particular, dermoscopy could be very useful in multiple primary melanoma (MPM) patients., Objectives: To analyse the clinical and dermatoscopic features of multiple melanomas, focusing on those features that are more frequently found in the same patient to recognize them earlier and understand whether they appear with the similar peculiar dermatoscopic features, especially in CDKN2A carriers., Methods: Medical records of MPM patients were selected from a database including 1065 patients with histopathologically proven melanoma diagnosis, all treated at the dermatology clinic of the University of Florence from 2000 to 2013. Pictures of melanoma were independently and blindly administered to three dermatologist experts in dermoscopy to evaluate the presence or absence of ABCD criteria for each clinical image, and the main pattern for the dermoscopic images. The results were then analyzed and crossed to rate the clinical and dermoscopic features of MPM., Results: Seventy five (7.0%) of 1065 patients included in our database were found to carry an MPM disease. Among them, we selected 12 (16%) patients with three or more MPMs. The presence of the CDKN2A melanoma susceptibility gene was observed in 4/12 (33.33%) patients; two patients presented the C500G and c.5 + 1delG polymorphisms in the CDKN2A gene. In CDKN2A carriers, each patient showed a similar and specific dermatoscopic pattern in their lesions., Conclusions: Even being aware of the limitations of this study, according to hereditary characters and their modes of transmissions, we could speculate that for each patient with a CDKN2A germline mutation, it is possible to find the same kind of dermoscopical pattern among their melanocytic tumours., (© 2014 European Academy of Dermatology and Venereology.)

Background: Racial and geographic factors seem to affect the incidence of cutaneous and mucosal melanoma., Objective: To investigate the occurrence of BRAF and cKIT impairments in patients with sinonasal melanoma in Southern Italy., Methods: Eleven sinonasal melanomas were screened for BRAF mutations and cKIT alterations by immunohistochemistry (CD117), fluorescence in situ hybridization and sequencing analyses., Results: A high prevalence (4/11; 36%) of BRAF mutations and lack of cKIT mutations were observed. Amplification of cKIT was found in 18% of cases; cKIT expression was detectable in 18% non-overlapping cases. No correlation between CD117 and cKIT alterations was observed. One (6%) cKIT and two (12%) BRAF mutations were detected in an additional series of 17 acral/mucosal melanomas from the same geographic areas., Conclusion: Mutations of cKIT are infrequent in sinonasal melanoma in Southern Italy., (Copyright © 2013 S. Karger AG, Basel.)

The characterization of the molecular mechanisms involved in development and progression of melanoma could be helpful to identify the molecular profiles underlying aggressiveness, clinical behavior, and response to therapy as well as to better classify the subsets of melanoma patients with different prognosis and/or clinical outcome. Actually, some aspects regarding the main molecular changes responsible for the onset as well as the progression of melanoma toward a more aggressive phenotype have been described. Genes and molecules which control either cell proliferation, apoptosis, or cell senescence have been implicated. Here we provided an overview of the main molecular changes underlying the pathogenesis of melanoma. All evidence clearly indicates the existence of a complex molecular machinery that provides checks and balances in normal melanocytes. Progression from normal melanocytes to malignant metastatic cells in melanoma patients is the result of a combination of down- or up-regulation of various effectors acting on different molecular pathways.

Amelanotic melanoma (AM) is a rare subtype of melanoma with little or no clinically visible pigment; it is more difficult to diagnose than pigmented melanoma (PM), and has a worse prognosis. In the attempt to find a genetic explanation for the distinction between AM and PM, we conducted a case-case study, matching AM and PM patients, and testing them for germline mutations in high- (p16INK4A, p14ARF, CDK4) and low-penetrance (MC1R) melanoma susceptibility genes. Similar CDKN2A mutations were found in both sets of melanomas. A p14ARF splice germline mutation was detected for the first time in an Italian family with AM. This rare mutation, which has been described only once previously, may be involved in predisposition to the amelanotic phenotype in combination with germline MC1R variants and coordinate somatic expression of pigmentation genes and their regulators.

Background: The chromosome 9p21 and its CDKN locus, with the p16 tumour suppressor gene (CDKN2A), are recognized as the genomic regions involved in the pathogenesis of melanoma., Objectives: To elucidate further the role of such regions during the different phases of melanocytic tumorigenesis., Methods: Tissue sections from naevi, primary and metastatic melanomas were investigated by fluorescence in situ hybridization for allelic loss at the 9p21 chromosome and by immunochemistry for p16CDKN2A expression., Results: Dysplastic naevi and primary or secondary melanomas were found to carry hemizygous deletions within the entire 9p21 region at similar frequencies (varying from 55% to 62%). Allelic deletion spanning the CDKN locus was observed at significantly increased rates moving from early (7%) to advanced (28%) primary melanomas and to secondary melanoma lesions (37%) (P=0.018). Also, inactivation of the p16 gene (CDKN2A) was absent in naevi and present at steadily increasing rates moving from primary melanomas (7% early lesions to 17% advanced lesions) to melanoma metastases (62%) (P=0.004)., Conclusions: Our findings indicate that, in a model of sequential accumulation of genetic alterations, 9p21 deletions may play a role in melanocytic transformation and tumour initiation whereas rearrangements at the CDKN locus, and p16 gene (CDKN2A) inactivation may contribute to tumour progression.