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Data irregularity in cancer genomics studies has been widely observed in the form of outliers and heavy-tailed distributions in the complex traits. In the past decade, robust variable selection methods have emerged as powerful alternatives to the nonrobust ones to identify important genes associated with heterogeneous disease traits and build superior predictive models. In this study, to keep the remarkable features of the quantile LASSO and fully Bayesian regularized quantile regression while overcoming their disadvantage in the analysis of high-dimensional genomics data, we propose the spike-and-slab quantile LASSO through a fully Bayesian spike-and-slab formulation under the robust likelihood by adopting the asymmetric Laplace distribution (ALD). The proposed robust method has inherited the prominent properties of selective shrinkage and self-adaptivity to the sparsity pattern from the spike-and-slab LASSO (Roc̆ková and George, J Am Stat Associat, 2018, 113(521): 431-444). Furthermore, the spike-and-slab quantile LASSO has a computational advantage to locate the posterior modes via soft-thresholding rule guided Expectation-Maximization (EM) steps in the coordinate descent framework, a phenomenon rarely observed for robust regularization with nondifferentiable loss functions. We have conducted comprehensive simulation studies with a variety of heavy-tailed errors in both homogeneous and heterogeneous model settings to demonstrate the superiority of the spike-and-slab quantile LASSO over its competing methods. The advantage of the proposed method has been further demonstrated in case studies of the lung adenocarcinomas (LUAD) and skin cutaneous melanoma (SKCM) data from The Cancer Genome Atlas (TCGA)., (© 2024 John Wiley & Sons Ltd.)

Background: Melanoma is a highly aggressive tumor, predominantly found in the skin, recognized as skin cutaneous melanoma (SKCM). Lymph node metastasis is commonly used as the route of metastasis in SKCM, necessitating the discovery of prognostic genes associated with this process for improved prognosis., Methods: The prognostic significance of lymph node metastasis in SKCM was assessed through Kaplan-Meier analysis in SEER and TCGA-SKCM datasets. Prognostic genes were identified and a prognostic risk model was constructed Enrichment analysis and immune cell infiltration analysis were also carried out.Moreover, a validation in vitro and in vivo were conducted by CCK8,flow cytometry, transwell and animal study., Results: The Kaplan-Meier survival curve revealed that patients with lymph node metastasis had a worse prognosis compared to those without. FCGR3B and PRF1 were screened by TCGA analysis.Additionally, significant differences in nine immune cell types were observed between the two risk groups. Notably, a strong positive association with CD8 T cells and a negative relationship with M2 macrophages were exhibited by PRF1. The validation of our nomogram were conducted in vitro and in vivo, and the results showed the correlations between CD8 + T cell and PRF1., Conclusion: In summary, two prognostic genes (FCGR3B and PRF1) were identified, and a prognostic risk model was developed for SKCM. These findings provide a novel approach for the diagnosis and treatment of SKCM., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Many investigation have sought to identify therapeutic targets and treatment strategies for skin cutaneous melanoma (SKCM). Numb, an endocytic adaptor protein, is known to act as a tumor suppressor in various human cancers. However, the roles of Numb and its homolog NumbL in immune microenvironment, and their effect on melanoma remain largely unexplored., Methods: We analyzed the expression levels of Numb and NumbL, as well as immune signatures of SKCM patients by UCSCXenaShiny v1 database. We also constructed animal model using Numb and NumbL conditional knockout (cKO) mice. Distribution analysis of immune cells in tumors was performed by flow cytometry and pathology staining., Results: Numb and NumbL were found to be consistently expressed at low levels in SKCM patients. In addition, alterations in tumor immune microenvironment were identified. The CD8 + T, CD19 + B, and NK1.1 + CD49 + cells were decreased in tumors of Numb and NumbL cKO mice, confirming previous bioinformatics analysis of immune signatures. Additionally, we observed CD68 + macrophages to be increased as judged by tumor pathology staining., Conclusion: Numb and NumbL were found to inhibit melanoma cell growth by modulating immune cell activity. These results suggested that Numb and NumbL may be potential therapeutic targets for SKCM patient immunotherapy., Competing Interests: Declarations Ethics approval and consent to participate Animal involved in this study were in accordance with the Animal Care Committee, and approved by the Institutional Animal Care of Xi’an Jiaotong University (No. 2022-0069). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cutaneous melanoma incidence varies consistently across body sites between men and women, but the underlying causes of these differences remain unclear. To date, no prospective studies have examined risk factors for melanoma separately for men and women according to body site., Objectives: We aimed to examine the association between identified constitutional, genetic and environmental risk factors for invasive melanoma of different body sites among men and women., Methods: We compared the association between constitutional, genetic and environmental risk factors for invasive melanoma on different body sites separately for men and women in a population-based prospective cohort study of 17 774 men and 21 070 women aged between 40 and 69 years who were residents of Queensland, Australia at baseline in 2011. Participants were followed until December 2021. We examined risk factors including hair colour, tanning ability, naevus density and proxies for high cumulative sun exposure, all self-reported at baseline. We also examined polygenic risk score (PRS) derived from summary statistics from a melanoma genome-wide association study meta-analysis., Results: During a median 10.4 years of follow-up, 455 men and 331 women developed an incident invasive melanoma; the mean age at diagnosis was lower in women than in men (62.6 vs. 65.0 years). The most common body site was the trunk in men (45.1%), and the upper (36.8%) and lower limbs (27.4%) in women. High naevus density and proxy measures of high cumulative sun exposure were similarly associated with melanoma at all sites in men and women. In both sexes, high genetic risk was associated with melanoma on all body sites except the head and neck. We observed differences between men and women in the association between PRS and melanoma of the trunk [highest vs. lowest tertile of PRS: hazard ratio (HR) 2.78, 95% confidence interval (CI) 1.64-4.69 for men; HR 1.55, 95% CI 0.63-3.80 for women] and nonsignificant but large differences for the lower limbs (HR 5.25, 95% CI 1.80-15.27 for men; HR 1.75, 95% CI 0.88-3.47 for women)., Conclusions: While there are a number of potential explanations for these findings, this raises the possibility that genetic factors other than those related to pigmentation and naevus phenotypes may play a role in the predilection for melanoma to arise on different sites in men and women., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Melanoma arising in association with a blue nevus (BN) is rare but has molecular similarities to uveal melanoma (UM), including GNAQ/11 mutations. Tebentafusp was recently approved for UM based on improved overall survival in a phase 3 study. We hypothesized that tebentafusp may be active in BN-associated melanoma. Here, we present a case of metastatic BN-associated melanoma with rapid response and ~1 year of disease control on tebentafusp. We also explore molecular and histological features of secondary resistance. Our case highlights that PD-1-resistant melanomas should be screened for GNAQ/11 mutations, as tebentafusp may be a treatment option in this extremely rare disease., Competing Interests: Competing interests: ANS reports grants and personal fees from Bristol-Myers Squibb, Immunocore, Novartis, and Castle Biosciences, and institutional grants from Bristol-Myers Squibb, Immunocore, Novartis, Targovax, Pfizer, Mural Oncology, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linnaeus Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics, Obsidian Therapeutics. PF reports equity in GE Healthcare, Iovance, Gilead. JDW is a consultant for Apricity, Ascentage Pharma, Bicara Therapeutics, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Takeda, Tizona, Trishula Therapeutics, Immunocore (on their Data Safety Board), Scancell. JDW received grant/research support from Bristol Myers Squibb, Enterome. JDW has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, Xenimmune. JDW is an inventor on the following patents: Xenogeneic DNA Vaccines, Newcastle Disease viruses for Cancer Therapy, Myeloid-derived suppressor cell (MDSC) assay, Prediction of Responsiveness to Treatment with Immunomodulatory Therapeutics and Method of Monitoring Abscopal Effects During Such Treatment, Anti-PD1 Antibody, Anti-CTLA4 antibodies, Anti-GITR antibodies and methods of use thereof. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ultraviolet (UV) B-induced damage in human epidermal keratinocytes (HEKs) initiates photocarcinogenesis. However, how diabetes influences photocarcinogenesis is not well understood. To investigate the impact of high-glucose environments on responses to UVB, we cultured HEKs in normal-glucose (NG) or high-glucose (HG) conditions (G6 and G26), followed by UVB irradiation at 25 mJ/cm 2 (G6UVB and G26UVB). We performed next-generation sequencing and analyzed HEKs' expression profiles bioinformatically to identify candidate genes and cellular responses involved. We found UVB induced consistent responses in both NG- and HG-cultivated HEKs, but it also triggered certain distinct processes and pathways specifically in the HG groups. The 459 differentially expressed (DE) genes in the HG groups revealed their roles in chromatin remodeling, nucleosome assembly, and interferon signaling activation. Moreover, the 29 DE genes identified in G26UVB/G6UVB comparison, including the potent tumor suppressor gene TFPI2, were considered key genes contributing to HEKs' altered response to UVB in HG environments. UVB irradiation induced significantly higher TFPI2 expression in HG-cultivated HEKs than their NG-cultivated counterpart. Finally, HG-cultivation significantly increased oxidative stress, cyclobutane pyrimidine dimer formation, and apoptosis, while reducing HEKs' viability after UVB irradiation. These changes under HG conditions probably mediate cell fate toward death and tumor regression. Overall, our findings provide evidence and associated molecular basis on how HG conditions reduce keratinocytes' photocarcinogenic potential following UVB exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas., (© 2024 UICC.)

Background: While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma., Methods: We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas., Results: A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20 + (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4 + and CD8 + T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p<0.001), and samples without LA/TLS were enriched with pigmentation/neural network gene signatures. The presence of LA was significantly associated with tumor-free regional lymph node status (p=0.002). In multivariable analysis, after adjusting for age, sex, sample type, and stage, the presence of LA was associated with improved patient overall survival (OS) (HR=0.52, 95% CI 0.31 to 0.87, p=0.01)., Conclusion: Melanoma frequently contains LA, which tends to form in diverse locations in the tumor microenvironment in association with improved overall survival and tumor-free regional lymph node status in patients with primary disease., Competing Interests: Competing interests: JMK: consultation with Amgen (with Davar and Najjar), Ankyra Therapeutics, Applied Clinical Intelligence, Axio Research, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, CytomX Therapeutics, DermTech, Fenix Group International, Harbour BioMed, Immunocore, iOnctura, Iovance Biotherapeutics, IQVIA, Istari Oncology, Jazz Pharmaceuticals, Lytix Biopharma AS, Magnolia Innovation, Merck, Natera, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical, PathAI, Pfizer, Piper Sandler & Co., PyrOjas Corporation, Regeneron Pharmaceuticals, Replimune, Scopus BioPharma, SR One Capital Management, Takeda, Valar Labs. JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mesenchymal epithelial transition factor (MET) variant is an independent prognostic factor for worse prognosis in patients with lung cancer or gastroesophageal adenocarcinoma. MET gene variants can be regarded as a subtype of melanoma but there is a lack of studies regarding the frequency of MET genetic alterations and the efficacy of immunotherapy in melanoma patients. The purpose of this study is to explore potential therapeutic strategies for melanoma subtypes with MET alterations., Methods: A total of 1751 malignant melanomas were analyzed to illustrate the landscape of MET mutations. We collected 55 melanoma cases from multicenter for a retrospective cohort from 2010 to 2023. We analyzed the impact of MET amplification on the efficacy of immunotherapy in the retrospective cohort after propensity score matching (PSM) and a pancancer cohort. CIBERSORT was used to evaluate the immune infiltration., Results: There were no instances of MET 14 exon skipping, and only instances of MET amplification were found in the 1751 melanomas and our retrospective cohort. Cox proportional hazards model analysis showed that MET amplification (P = 0.006) was significantly associated with poorer overall survival (OS) in patients who received immunotherapy as the first-line treatment. Compared with patients with MET amplification, patients in the negative control (NC) group had a significantly better OS (P = 0.022) after PSM. Analysis of 1661 pancancer cases with the MSK-IMPACT assay showed that patients receiving immunotherapy in the MET amplification group had a trend toward worse OS than those without MET amplification (P = 0.025)., Conclusions: This database analysis showed that the main type of MET mutation is amplification in malignant melanoma. MET-amplified solid tumors might be considered for targeted therapy, as MET amplification can be regarded as a risk factor affecting the prognosis of patients with tumors treated with immunotherapy., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Ethical Committee of Fujian Cancer Hospital (K2023-097–01) in accordance with the Declaration of Helsinki. The patients in this manuscript have given written informed consent to publication of their case details. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers., (© 2024. The Author(s).)

This study aims to rigorously explore the potential causal relationships among gut microbiota (GM), immune cells, and melanoma skin cancer among participants from Europe, where this disease exhibits significant prevalence and profound societal impact. Using the genome-wide association analysis database, a double-sample Mendelian randomization (MR) analysis was drawn upon to investigate GM, immune cells, and melanoma skin cancer. The inverse variance weighted approach was applied to estimate the causal connections among these variables. A two-step MR analysis was employed to quantitatively gauge the impact of immune cells mediated GM on melanoma skin cancer. To address potential sources of bias, such as pleiotropy and heterogeneity, multiple analytical techniques were integrated. The MR analysis pinpointed 6 GM taxa related to either an augmented or declined risk of late-stage melanoma skin cancer. In the same vein, 32 immune cell phenotypes were noticed as correlates with modified risk of melanoma skin cancer. Our study also implies that the probable association between GM and melanoma could be facilitated by 5 immune cell phenotypes. The findings of our study underline certain GM taxa and immune cells as potential influencers on the onset and development of melanoma skin cancer. Importantly, our results spotlight 5 immune cell phenotypes as potential agents mediating this association., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Mucosal melanoma (MucM) is a rare cancer with a poor prognosis and low response rate to immune checkpoint inhibition (ICI) compared with cutaneous melanoma (CM). To explore the immune microenvironment and potential drivers of MucM's relative resistance to ICI drugs, we characterized 101 MucM tumors (43 head and neck [H&N], 31 female urogenital, 13 male urogenital, 11 anorectal, and 3 other gastrointestinal) using bulk RNA-Seq and immunofluorescence. RNA-Seq data show that MucM has a significantly lower IFN-γ signature levels than CM. MucM tumors of the H&N region show a significantly greater abundance of CD8+ T cells, cytotoxic cells, and higher IFN-γ signature levels than MucM from lower body sites. In the subcohort of 35 patients with MucM treated with ICI, hierarchical clustering reveals clusters with a high and low degree of immune infiltration, with a differential ICI response rate. Immune-associated gene sets were enriched in responders. Signatures associated with cancer-associated fibroblasts, macrophages, and TGF-β signaling may be higher in immune-infiltrated, but ICI-unresponsive tumors, suggesting a role for these resistance mechanisms in MucM. Our data show organ region-specific differences in immune infiltration and IFN-γ signature levels in MucM, with H&N MucM displaying the most favorable immune profile. Our study might offer a starting point for developing more personalized treatment strategies for this disease.

The prognostic value of BRAF V600 mutation level on clinical outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and MEK inhibitors remains uncertain. The association was retrospectively analysed between BRAF V600 mutation level (defined as the ratio of the quantification of the BRAF V600 allele to the percentage of tumoral cells in the sample analysed) and progression-free and overall survival (PFS and OS, respectively) and 3-month response rate in a cohort of 58 patients with metastatic melanoma who harboured BRAF V600E/K mutations and received dual targeted-therapy BRAF/MEK inhibitors. The BRAF mutation level cut-off determined by the area under the receiver operating characteristic curve after internal validation by bootstrap methods was 0.44. Risk of poor PFS and OS was associated with BRAF V600 mutation level > 0.44 on multivariate analysis (p = 0.02 and p = 0.02, respectively) after adjusting for major confounding factors (age, sex, lactate dehydrogenase level, brain metastasis, and treatment line). No association was found between BRAF mutation level and 3-month response rate. Our study shows that high BRAF V600 mutation level in melanoma tissue was associated with poor prognosis in patients with metastatic melanoma treated with BRAF and MEK inhibitors.

Background: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival., Methods: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival., Results: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports., Conclusions: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2024 Massachusetts Medical Society.)

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary malignant melanoma. We conducted a tissue microarray analysis of immunohistochemical ENOX2 protein expression and The Cancer Genome Atlas (TCGA) ENOX2 RNA expression analysis, as well as viability assays and Western blots of melanoma cell lines treated with the ENOX2 inhibitor phenoxodiol (PXD) and BRAF inhibitor (BRAFi) vemurafenib. We discovered that high ENOX2 expression is associated with decreased overall (OS), disease-specific (DSS) and metastasis-free survival (MFS) in primary melanoma (PM) and a reduction in electronic tumor-infiltrating lymphocytes (eTILs). A gradual rise in ENOX2 expression was found with an increase in malignant potential from benign nevi (BNs) via PMs to melanoma metastases (MMs), as well as with an increasing tumor thickness and stage. These results highlight the important role of ENOX2 in cancer growth, progression and metastasis. The ENOX2 expression was not limited to malignant cell lines but could also be found in keratinocytes, fibroblasts and melanocytes. The viability of melanoma cell lines could be inhibited by PXD. A reduced induction of phospho-AKT under PXD could prevent the development of acquired BRAFi resistance. In conclusion, ENOX2 may serve as a potential prognostic marker and therapeutic target in malignant melanoma.

Malignant melanoma is a difficult-to-treat skin cancer with increasing incidence worldwide. Although type-I interferon (IFN) is no longer part of guidelines, several melanoma patients are treated with type-I interferon (IFN) at some point of the disease, potentially affecting its genetic progression. We run genome-wide copy number variation (CNV) analysis on previously type-I IFN-treated (n = 17) and control (n = 11) visceral metastases of melanoma patients. Results were completed with data from the TCGA and MM500 databases. We identified metastasis- and brain metastasis-specific gene signatures mostly affected by CN gains. Some cases were genetically resistant to IFN showing characteristic gene alterations (e.g. ABCA4 or ZEB2 gain and alterations of DNA repair genes). Analysis of a previously identified type-I IFN resistance gene set indicates that only a proportion of these genes was exclusive for the IFN-treated metastases reflecting a possible selective genomic pressure of endogenous IFNs during progression. Our data suggest that previous type-I IFN treatment and/or endogenous IFN production by immune response affect genomic progression of melanoma which may have clinical relevance, potentially influence immune checkpoint regulation in the tumor microenvironment., (© 2024. The Author(s).)

Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival., Materials and Methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets., Results: Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP ( P = .01) and LM ( P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM., Conclusion: Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

Dab2 is an endocytic adaptor protein involved in various physiological processes and signaling pathways. Dab2 is deregulated in various cancers; however, its role in skin squamous cell carcinoma ( SCC) has not been elucidated yet. In the present study, we used the DMBA/TPA induced murine skin carcinogenesis model to examine the role of Dab2 in skin tumour progression. We generated tamoxifen inducible Dab2 conditional knockout system for our study. Loss of Dab2 led to delayed papilloma initiation and reduced papilloma burden. Delayed papilloma initiation was due to reduce proliferative potential of the papillomas due to Dab2 loss. Furthermore, while the WT papillomas progressed to SCC, the papillomas formed in Dab2 cKO mice failed to undergo malignant conversion to SCC. Dab2 cKO tumours showed reduced expression of K8, a marker for aggressive tumour. Moreover, Dab2 ckO tumours failed to undergo EMT as shown by reduced expression of Vimentin and Twist1. Dab2 cKO tumours also showed reduced expression of Sox2, a stem cell marker. Furthermore, qPCR analysis showed upregulation of Dab2 expression in the human skin cancer cell lines as compared to normal human skin keratinocytes. In patients, TCGA data analysis of skin cancer melanoma (SKCM) showed a trend where high levels of Dab2 correlated with poor overall survival. The present study shows that Dab2 promotes tumour progression in skin SCC., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Melanoma is the most dangerous form of skin cancer. Hence, a better understanding of molecular mechanisms in melanoma pathogenesis is urgently needed, which provides a new insight into the therapy of melanoma. DTL gene is screened out in melanoma pathogenesis by integrated bioinformatics analysis, and its expression is validated in the tissue and cell samples of melanoma. Forced DTL expression facilitates the proliferation, invasion, migration and EMT of melanoma cells, while DTL knockdown suppresses the biological behavior of melanoma cells. In addition, DTL promotes the malignancy of melanoma in vivo. Mechanistically, BUB1 is the crucial downstream target of DTL. Reduced DTL expression suppresses BUB1 expression, while enhanced DTL expression induces BUB1 upregulation. Rescue experiments showed that growing and migrating of melanoma cells induced by DTL are partially impaired by BUB1 inhibition. In addition, the expression of phosphorylated ERK (p-ERK) and the downstream transcription factor E2F1 are reduced when DTL expression is blocked. Meanwhile, BUB1 levels are decreased when the expression of p-ERK or E2F1 is repressed. Notably, the growth and migration of melanoma cells by inhibition of ERK and knockdown of E2F1 was rescued by overexpressing BUB1. DTL gene may be a prognosis marker and represent a unique potential target for melanoma patients. DTL supports the biologically malignant activity of melanoma cells via the ERK/E2F1/BUB1 axis., (© 2024. The Author(s).)

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine neoplasm of the skin. Immunosuppression, ultraviolet radiation and the integration of Merkel cell polyomavirus (MCPyV) have all been shown to be involved in the pathogenesis of this malignancy. We performed whole genome sequencing on two MCPyV-negative cases of MCC that demonstrated very different clinical presentations and outcomes, and mutational profiles. The first case exhibited a highly aggressive clinical course, absence of UV-signature mutations and a low tumor mutational burden. A rearrangement in the tumor suppressor gene SUFU was identified, a likely driver and potential target of the Hedgehog signaling pathway. Meanwhile, the second case exhibited a less aggressive behavior, harbored UV-signature mutations, and a high mutational burden including mutations in TP53 and RB1., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Max F. Levine and Aditya Deshpande are employees at Isabl, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Equine sarcoids are common non-metastasising skin tumours in horses, associated with bovine papillomavirus (BPV) infection. Six subtypes are recognised (occult, verrucose, nodular, fibroblastic, mixed and malevolent lesions), with variable clinical behaviour. The pathophysiology underlying varying tumour phenotype is poorly understood, and previous data on associations with viral load have been conflicting. To better understand this clinical variation, we investigated associations between tumour subtype and viral load, viral early protein gene expression, and expression of 10 host genes by quantitative polymerase chain reaction in 27 sarcoids and 5 normal skin samples. Viral DNA copy number did not differ between subtypes but was significantly higher in animals with fewer tumours. Expression of BPV E2 and E6 was higher in occult lesions compared to fibroblastic or nodular lesions, while E5 expression was higher in previously-treated lesions. Of the host genes, only IL6 and IL1B differed between subtypes, with higher expression in fibroblastic lesions, while IL10 and CCL5 were elevated compared to skin in all lesion types, and elevations in TNF and TGFB1 were significant for occult lesions only. Expression of TLR9, ATR, VEGFA and PTGS2 in sarcoids was not significantly different from normal skin, suggesting differences between BPV and human papillomavirus tumorigenesis. Results for BPV viral load and gene expression differed from previous reports and are insufficient to explain the spectrum of tumour phenotypes. Activation of both pro-inflammatory and anti-inflammatory immune pathways in sarcoids could influence tumour growth and effective immune responses, and the contribution of specific infiltrating immune cells requires further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare peripheral T-cell lymphoma characterized by cutaneous lesions and immunologic manifestations. The five-year survival rate of SPTCL has been reported to be over 80%, indicating a favorable prognosis. Recent studies have uncovered recurrent germline variants in HAVCR2, encoding an immunomodulator. In this study, we integrated whole-exome sequencing data from 60 samples collected from 36 SPTCL patients, encompassing six patients of our cohort and 30 patients of publicly available data. We identified 138 somatic mutations in skin tumors of 24 patients and HAVCR2 germline mutations in 23 of 29 patients. HAVCR2 p.Tyr82Cys mutations were identified in four of six Japanese patients. During the clinical courses of four patients, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone were administered to all patients, but it resulted in incomplete responses in all four patients. However, disease conditions of all patients remained stable with additional treatment, including autologous peripheral blood stem cell transplantation. Over a 7.5-year median follow-up, one patient developed autoimmune-related diseases, while one developed other hematological malignancy, resulting in death. To our knowledge, this is the first report of recurrent HAVCR2 germline mutations in Japanese patients, suggesting the necessity for long-term follow-up., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Abstract: Lymphomatoid papulosis (LyP) belongs to the CD30 + skin lymphoproliferative disorders; it is defined as a chronic, recurrent, self-healing eruption of papules and small nodules with the histopathologic features of a cutaneous T-cell lymphoma. It is classified according to histopathology into subtypes A to F and with chromosomal rearrangement 6p25.3. Type D is characterized by epidermotropism of atypical CD8 + and CD30 + lymphocytes, small to medium size, forming papules and nodules with erosion and necrosis, which represents a formidable challenge in the differential diagnosis with aggressive cutaneous cytotoxic lymphomas. We present the clinical case of a 22-year-old man with subacute dermatosis, who underwent a skin biopsy with a report of LyP. Immunohistochemistry showed negative CD4, CD5, granzyme-B markers and positive CD3, CD30, CD8, CD56, and (T-cell intracellular antigen 1) TIA-1 markers, concluding the diagnosis of type D LyP. The course of the disease is recurrent; however, the prognosis is good with a 10-year survival of 100%. We present the case of a mestizo-ancestry patient who developed a type-D LyP, and, to the best of our knowledge, there are no publications of type D LyP from Latin-American authors or about mestizo-ancestry (or hispanic) patients; therefore, we consider of relevance to inform about these findings., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The section on mesenchymal tumors in the 5th edition of WHO classification of skin tumors has undergone several changes, the most important of which is the inclusion of newly identified tumor entities, which will be the main focus of this review article. These specifically include three novel cutaneous mesenchymal tumors with melanocytic differentiation, and rearrangements of the CRTC1::TRIM11, ACTIN::MITF, and MITF::CREM genes as well as EWSR1::SMAD3-rearranged fibroblastic tumors, superficial CD34-positive fibroblastic tumors, and NTRK-rearranged spindle cell neoplasms. Some of the other most important changes will be briefly mentioned as well., Competing Interests: Declarations The study was conducted following the rules set by the Faculty Hospital in Pilsen Ethics Committee. Informed consent was not required for the study Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Melanomas arise from transformed melanocytes, positioned at the dermal-epidermal junction in the basal layer of the epidermis. Melanocytes are completely surrounded by keratinocyte neighbors, with which they communicate through direct contact and paracrine signaling to maintain normal growth control and homeostasis. UV radiation from sunlight reshapes this communication network to drive a protective tanning response. However, repeated rounds of sun exposure result in accumulation of mutations in melanocytes that have been considered as primary drivers of melanoma initiation and progression. It is now clear that mutations in melanocytes are not sufficient to drive tumor formation-the tumor environment plays a critical role. This review focuses on changes in melanocyte-keratinocyte communication that contribute to melanoma initiation and progression, with a particular focus on recent mechanistic insights that lay a foundation for developing new ways to intercept melanoma development., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)

Hepatocyte growth factor (HGF) plays a critical role in promoting tumor migration, invasion, and metastasis, partly by upregulating integrins. The molecular mechanisms behind how HGF facilitates integrin-mediated tumorigenesis are not fully understood. In this study, we demonstrate that the ubiquitin-specific peptidase 22 (USP22) is essential for HGF-induced melanoma metastasis. HGF treatment dramatically increased the expression of both USP22 and multiple integrin family members in particular ITGAV, ITGB3, and ITGA1. An unbiased analysis of the TCGA database reveals integrins as common downstream targets of both USP22 and HGF across multiple human cancer types. Notably, CRISPR-mediated deletion of USP22 completely eliminates HGF-induced integrin expression in melanoma cells. At the molecular level, USP22 acts as a bona fide deubiquitinase for Sp1, a transcription factor for the ITGAV, ITGB3, and ITGA1 genes. USP22 interacts with and inhibits Sp1 ubiquitination, protecting against Sp1 proteasomal degradation. Supporting this, immunohistology analysis detects a positive correlation among USP22, Sp1, and integrin αv in human melanoma tissues. This study identifies the death from the signature gene USP22 as a critical positive regulator for HGF-induced integrin expression by deubiquitinating the Sp1 transcription factor during melanoma metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Tumors morphologically classified as pigmented epithelioid melanocytomas (PEMs) are genomically diverse, with the 2 most common genomic subtypes being PRKC fusions or PRKAR1A inactivating mutations. PRKC fusions activate the Gα q/11 pathway similar to blue nevi. Conversely, inactivating mutations in PRKAR1A activate the Gα s pathway. We hypothesize that PRKC fusions have greater genomic overlap with blue nevi compared with PRKAR1A-inactivated PEMs. We characterized the clinical and morphologic features of 21 PRKC and PRKACB fusion melanocytic tumors and compared this to PRKAR1A mutated PEMs. To test our hypothesis regarding greater genomic overlap between PRKC fusions and blue nevi relative to PRKAR1A mutated PEMs, we performed a principal component analysis (PCA) using mRNA expression data. Lastly, we performed a meta-analysis focusing on the outcome data of PRKC fusions. PRKC fusions occur at a younger median age than PRKAR1A mutated PEMs (16 vs. 27). Histologically, PRKC fusions have solid aggregates of epithelioid melanocytes not typical of PRKAR1A mutated PEMs. The PCA plot showed no overlap between the PRKC fusion group and the PRKAR1A-mutated PEMs. There was a significant overlap between PRKC fusions and blue nevi. A meta-analysis of PRKC fusion cases in the literature suggests melanoma is uncommon, but the loss of BAP-1 nuclear expression may be associated with an adverse prognosis as in tumors from the blue nevus family. PRKC fusion melanocytic tumors have greater genomic overlap with blue nevi compared with PRKAR1A mutated PEMs. We recommend categorizing benign PRKC fusion melanocytic tumors as blue fusion nevi/tumors., Competing Interests: Conflicts of Interest and Source of Funding: Dr P.G. has received royalties for textbooks from Elsevier. For the remaining authors, none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

Cutaneous melanoma is the most lethal of all skin tumors. Recently, cuproptosis, a novel form of cell death linked to oxidative phosphorylation, has emerged as an important factor. However, the precise role of cuproptosis in melanoma remains unclear. Our research explored the potential links between cuproptosis-related genes, prognosis, immune microenvironments, and melanoma treatments. Significantly, cuproptosis regulators showed remarkable differences between melanoma and normal tissues, establishing their relevance to melanoma. The newly developed cuproptosis-related gene signature (CGS) demonstrated a robust ability to predict overall survival (OS) in melanoma. We constructed a novel nomogram that combined clinical features with CGS to improve predictive accuracy. In addition, the study revealed correlations between CGS and immune cell populations, including CD8 + T cells, Tfh cells, B cells, and myeloid-derived suppressor cells. Within the CGS, Peptidylprolyl isomerase C (PPIC) emerged as the most strongly associated with poor prognosis and drug resistance in melanoma. PPIC was identified as a promoter of melanoma progression, enhancing cell invasiveness while concurrently suppressing CD8 + T cell activation. This comprehensive study not only elucidated the intricate connections between CGS, melanoma prognosis, immune microenvironment, and drug resistance but also provided compelling evidence supporting PPIC as a promising biomarker for predicting OS in melanoma treatment., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gene expression profiling technologies have revolutionized cell biology, enabling researchers to identify gene signatures linked to various biological attributes of melanomas, such as pigmentation status, differentiation state, proliferative versus invasive capacity, and disease progression. Although the discovery of gene signatures has significantly enhanced our understanding of melanocytic phenotypes, reconciling the numerous signatures reported across independent studies and different profiling platforms remains a challenge. Current methods for classifying melanocytic gene signatures depend on exact gene overlap and comparison with unstandardized baseline transcriptomes. In this study, we aimed to categorize published gene signatures into clusters based on their similar patterns of expression across clinical cutaneous melanoma specimens. We analyzed nearly 800 melanoma samples from six gene expression repositories and developed a classification framework for gene signatures that is resilient against biases in gene identification across profiling platforms and inconsistencies in baseline standards. Using 39 frequently cited published gene signatures, our analysis revealed seven principal classes of gene signatures that correlate with previously identified phenotypes: Differentiated, Mitotic/MYC, AXL, Amelanotic, Neuro, Hypometabolic, and Invasive. Each class is consistent with the phenotypes that the constituent gene signatures represent, and our classification method does not rely on overlapping genes between signatures. To facilitate broader application, we created WIMMS (what is my melanocytic signature, available at https://wimms.tanlab.org/), a user-friendly web application. WIMMS allows users to categorize any gene signature, determining its relationship to predominantly cited signatures and its representation within the seven principal classes., (© 2024 The Author(s). Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

The evolution of primary melanoma to lymph node and distant metastasis is incompletely understood. We examined the genomic diversity in melanoma progression in matched primary melanomas and lymph node and distant metastases from 17 patients. FISH analysis revealed cancer cell fractions with monotonic copy number alterations, including PHIP gain and PTEN loss, in the metastatic cascade. By contrast, the cancer cell fraction with copy number alterations for BPTF and MITF was reduced in lymph node metastases but increased in distant metastases. Separately, the cancer cell fraction with NCOA3 copy number alteration was comparable between primary tumors and lymph node metastases yet increased in distant metastases. These results suggest enrichment of the phosphoinositide 3-kinase and MITF pathways in the transition through the metastatic cascade. By contrast, next-generation sequencing analysis did not identify a consistent pattern of changes in variant allele frequency while revealing several intriguing findings, including decreased variant allele frequency in distant metastases and distinct drivers in lymph node versus distant metastases. These results provide evidence that distant melanoma metastasis does not always emanate from lymph node metastasis. These results enhance our understanding of clonal patterns of melanoma metastasis, with possible implications for targeted therapy and metastasis competency., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study "Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study" (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11-64 and 0-56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: The authors declare no conflicts of interest.

Background: Birt-Hogg-Dubé (BHD) syndrome is a genetic condition caused by pathogenic variants in the FLCN gene resulting in benign skin lesions, spontaneous pneumothorax, and increased risk for a variety of renal tumors. Skin manifestations of BHD include trichodiscoma (TD) and fibrofolliculoma (FF), which may represent the same pathologic entity. These lesions can identify BHD patients, who upon positive genetic testing can be considered for life-long surveillance for renal neoplasms., Objective: To characterize patients diagnosed with TD and FF including rates and outcomes of genetics referral., Methods: Retrospective chart reviews of patients with confirmed or possible diagnosis of TD or FF at the University of Michigan from September 2002 through October 2020 to assess pathologic findings, personal and family history of BHD manifestations, referral for genetic evaluation, and genetic testing results., Results: 64 patients had a pathologic diagnosis of TD or FF, 16 of whom (25%) were referred to cancer genetics. Fourteen patients completed genetic evaluation, 9 of whom were diagnosed with BHD (64%), with 6 unique pathogenic variants in FLCN., Conclusion: Providers should consider referral for genetic evaluation for patients with biopsy-proven TD or FF, as early diagnosis of BHD provides the opportunity for early detection and treatment of other BHD-associated conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Adjuvant radiation therapy (ART) for cutaneous squamous cell carcinoma is recommended based on a number of wide-ranging clinicopathologic features, which encompass a broad array of patients. The 40-gene expression profile (GEP) test classifies cutaneous squamous cell carcinoma tumors into low (class 1), higher (class 2A), or highest (class 2B) risk of nodal and/or distant metastasis. This study's hypotheses are as follows: (1) local recurrence is associated with metastatic disease progression and (2) 40-GEP, by identifying high risk for metastasis, could predict a metastasis-specific benefit from ART., Methods and Materials: Samples were obtained from 920 patients (ART-untreated: 496 class 1, 335 class 2A, and 33 class 2B; ART-treated: 11 class 1, 35 class 2A, and 10 class 2B) who were matched on clinical risk factors and stratified by ART status to create 49 matched patient strata. To control for the variety of characteristics and treatment selection bias, randomly sampled pairs of matched ART and non-ART patients comprising 10,000 resampled cohorts were each analyzed for 5-year metastasis-free survival and predicted time to metastatic event., Results: Of 96 patients experiencing local recurrence, 56.3% experienced metastasis; of those experiencing both, 88.9% experienced local recurrence before (75.9%) or concurrently (13.0%) with metastasis. After matching for clinicopathologic risk, median 5-year disease progression rates for resampled cohorts demonstrated approximately 50% improvement for class 2B ART-treated compared with ART-untreated cohorts. ART-treated class 2B cohorts had a 5-fold delay in predicted time to metastatic event and deceleration of disease progression compared with ART-untreated cohorts (Kolmogorov-Smirnov test, P < .01); this was not observed for patients with class 1 or 2A cSCC (P > .05 for each). No risk factor or staging system combined with ART status identified groups that would benefit from ART as well as 40-GEP., Conclusions: Forty-GEP identifies patients at the highest risk of nodal/distant metastasis who may derive the greatest benefit from ART, as well as patients who may have clinical indications for ART but are at low risk of metastasis. Compared with current guidelines, 40-GEP could provide greater specificity concerning the benefit of ART in individual patients., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Peripheral blood transcriptomes from 383 patients with newly diagnosed melanoma were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor-infiltrating lymphocytes) and evidence of systemic inflammation (high-sensitivity CRP and fibrinogen levels). Higher fibrinogen levels were associated with thicker primary tumors. In single-gene analysis, high-sensitivity CRP levels were significantly associated with higher blood CD274 expression (coding for PD-L1), but each was independently prognostic, with high-sensitivity CRP associated with increased mortality and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signaling pathways in the blood of people with thicker tumors and notable upregulation of signal transducer and activator of transcription 1 gene STAT1 in people with brisk tumor-infiltrating lymphocytes. Transcriptomic data provided evidence for increased NF-kB signaling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274, suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer tumor-infiltrating lymphocytes at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma, suggesting that systemic inflammation contributes to that reduced immune function., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Activating BRAF gene alterations are central to melanocytic tumor pathogenesis. A small, emerging subset of melanocytic tumors driven by BRAF fusions has distinct therapeutic implications and has been described to have Spitzoid morphology patterns. However, such morphological patterns do not encompass all cases, and little is known about the functional molecular events., Materials and Methods: We conducted a retrospective search through our molecular archives to identify melanocytic tumors with BRAF fusions. We reviewed clinical, histopathological, and genomic features. We further explored transcriptomic and protein-level findings., Results: Histopathologic patterns varied, with many cases without a distinctive pattern. We identified novel and diverse BRAF gene fusion partners. Differential transcriptomic analysis between low-risk BRAF fusion tumors and reference BRAF V600E tumors showed no differentially expressed genes. However, quantitatively stronger MAPK pathway activation of BRAF fusion tumors over BRAF V600E tumors was demonstrated by statistically significant stronger staining of p-ERK immunohistochemistry. Gene-specific RNA analysis shows comparable BRAF transcript levels between the two groups., Discussion and Conclusion: The quantitatively stronger activation of the MAPK pathway of BRAF fusion tumors, instead of qualitatively different transcriptomes, may account for the morphology difference from conventional BRAF V600E tumors. BRAF fusions likely act through dysregulated protein function rather than RNA upregulation related to the characteristics of the fusion partners., (© 2024 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

IL-6 signaling plays a crucial role in the survival and metastasis of skin cancer. NEDD4L acts as a suppressor of IL-6 signaling by targeting GP130 degradation. However, the effects of the NEDD4L-regulated IL-6/GP130 signaling pathway on skin cancer remain unclear. In this study, protein expression levels of NEDD4L and GP130 were measured in tumor tissues from patients with cutaneous squamous cell carcinoma. Skin tumors were induced in wild-type and Nedd4l-knockout mice, and activation of the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway was detected. The results indicated a negative correlation between the protein expression levels of NEDD4L and GP130 in cutaneous squamous cell carcinoma tissues from patients. Nedd4l deficiency significantly promoted 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin tumorigenesis and benign-to-malignant conversion by activating the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway, which was abrogated by supplementation with the GP130 inhibitor SC144. Furthermore, our findings suggested that NEDD4L can interact with GP130 and promote its ubiquitination in skin tumors. In conclusion, our results indicate that NEDD4L could act as a tumor suppressor in skin cancer, and inhibition of GP130 could be a potential therapeutic method for treating this disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The terms "onychofibroblast" (nail-specific fibroblast) and onychodermis (nail-specific dermis) were first introduced in 2006 and 2012, respectively, based on distinctive histologic and immunohistochemical features from the dermis of the surrounding skin and have been demonstrated in multiple studies. Recently, based on molecular research, the definition of onychodermis containing onychofibroblasts has been expanded to encompass the area located between the nail matrix and bed epithelium and periosteum. Single-cell RNA sequencing and in situ hybridization demonstrated that onychofibroblasts within the onychodermis express the genes including RSPO4, MSX1, WIF-1, and BMP5, which are implicated in nail formation and/or in disorders with nail phenotype. A mutation in RSPO4, a component of the Wnt signaling pathway, causes anonychia congenita. Nail matrix onychodermis and nail bed onychodermis share many similar characteristics which differ from the surrounding normal dermis of the skin. Comparative spatial transcriptomic and single-cell analyses of human nail units and hair follicles suggest that onychodermis is the counterpart of follicular dermal papilla, which plays a key role in hair follicle growth and morphogenesis. Onychomatricoma, as a nail-specific tumor, has been demonstrated to be a mesenchymal tumor that originates from onychofibroblasts and is associated with the upregulation of Wnt signaling. Collectively, the onychodermis and onychofibroblasts play crucial roles in nail development and these specialized nail mesenchymal elements are key components in the pathogenesis of onychomatricoma. The concept of onychodermis containing onychofibroblasts is very important for nail biology and pathology., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant interference with p53 function. These results suggest that supernumerary centrosomes impair proliferation in vitro as well as in vivo, resulting in reduced lifespan and delayed spontaneous as well as carcinogen-induced tumor formation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Moussa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Amelanotic melanoma (AM) is a subtype of hypomelanotic or completely amelanotic melanoma. AM is a rare subtype of melanoma that exhibits a higher recurrence rate and aggressiveness as well as worse surveillance than typical melanoma. AM shows a dysregulation of melanin production, cell cycle control, and apoptosis pathways. Knowing these pathways has an application in medicine due to targeted therapies based on the inhibiting elements of the abovementioned pathways. Therefore, we summarized and discussed AM biochemical and molecular induction pathways and personalized medicine approaches, clinical management, and future directions due to the fact that AM is relatively rare. AM is commonly misdiagnosed. Hence, the role of biomarkers is becoming significant. Nonetheless, there is a shortage of biomarkers specific to AM. BRAF, NRAS, and c-KIT genes are the main targets of therapy. However, the role of BRAF and KIT in AM varied among studies. BRAF inhibitors combined with MAK inhibitors demonstrate better results. Immune checkpoint inhibitors targeting CTLA-4 combined with a programmed death receptor 1 (PD-1) show better outcomes than separately. Fecal microbiota transplantation may overcome resistance to immune checkpoint therapy of AM. Immune-modulatory vaccines against indoleamine 2,3-dioxygenase (IDO) and PD ligand (PD-L1) combined with nivolumab may be efficient in melanoma treatment.

Background: New diagnostic tools are needed to improve the diagnosis and risk stratification of cutaneous melanoma. Disease-specific microRNA signatures have been previously described via NanoString profiling of solid biopsy tissue and plasma. This study validated these signatures via next-generation sequencing technology and compared their performance against clinical metrics and other published melanoma signatures., Methods: RNA from 64 plasma and 60 FFPE biopsy samples from individuals with invasive melanoma or related benign/control phenotypes was extracted and enriched for microRNA. RNA sequencing was performed to compute MEL38/MEL12 signature scores. The results were evaluated with published NanoString and RNA sequencing datasets, comprising 548 solid tissue samples and 217 plasma samples, to predict disease status and patient outcome., Results: The MEL38 diagnostic signature classifies patients into discrete diagnostic groups via RNA sequencing in either solid tissue or plasma (P < 0.001). In solid tissue, the prognostic MEL12 signature stratifies patients into low-, intermediate- and high-risk groups, independent of clinical covariates. The hazard ratios for 10-year overall survival, based on observed survival intervals, were 2.2 (MEL12 high-risk vs low-risk, P < 0.001) and 1.8 (intermediate-risk vs low-risk, P < 0.001), outperforming other published prognostic models. MEL12 also exhibited prognostic significance in the plasma of 42 patients with invasive disease., Conclusions: The MEL38 and MEL12 signatures can be assessed in either solid tissue or plasma using RNA-seq and are strong predictors of disease state and patient outcome. Compared with other genomic methods, MEL12 was shown to be the strongest predictor of poor prognosis. MicroRNA expression profiling offers objective, accurate genomic information about a patient's likelihood of invasive melanoma and prognosis., (© 2024. The Author(s).)

Cottontail rabbit papillomavirus (CRPV), the first papillomavirus associated with tumor development, has been used as a powerful model to study papillomavirus pathogenesis for more than 90 years. However, lack of a comprehensive analysis of the CRPV transcriptome has impeded the understanding of CRPV biology and molecular pathogenesis. Here, we report the construction of a complete CRPV transcription map from Hershey CRPV-induced skin tumor tissues. By using RNA-seq in combination with long-reads PacBio Iso-seq, 5' and 3' RACE, primer-walking RT-PCR, Northern blot, and RNA in situ hybridization, we demonstrated that the CRPV genome transcribes its early and late RNA transcripts unidirectionally from at least five distinct major promoters (P) and polyadenylates its transcripts at two major polyadenylation (pA) sites. The viral early transcripts are primarily transcribed from three "early" promoters, P90, P156, and P907 and polyadenylated at nt 4368 by using an early polyadenylation signal (PAS) at nt 4351. Like other low-risk human papillomaviruses and animal papillomaviruses, CRPV E6 and E7 transcripts are transcribed from three separate early promoters. Transcripts from two "late" promoters, P7525, and P1225, utilize either an early PAS for E1^E4 or a late PAS at 7399 for L2 and L1 RNA polyadenylation at nt 7415 to express capsid L2 and L1 proteins respectively. By using the mapped four 5' splice sites and three 3' splice sites, CRPV RNA transcripts undergo extensive alternative splicing to produce more than 33 viral RNA isoforms for production of at least 12 viral proteins, some of which without codon optimization are expressible in rabbit RK13 and human HEK293T cells. The constructed full CRPV transcription map in this study for the first time will enhance our understanding of the structures and expressions of CRPV genes and their contribution to molecular pathogenesis and tumorigenesis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Skin cutaneous melanoma (SKCM) poses a significant public health challenge due to its aggressive nature and limited treatment options. To address this, the study introduces the Tumor Mutational Burden-Derived Immune lncRNA Prognostic Index (TILPI) as a potential prognostic tool for SKCM., Methods: TILPI was developed using a combination of gene set variation analysis, differential expression analysis, and COX regression analysis. Additionally, functional experiments were conducted to validate the findings, focusing on the effects of STARD4-AS1 knockdown on SKCM tumor cell behavior. These experiments encompassed assessments of tumor cell proliferation, gene and protein expression, migration, invasion, and in vivo tumor growth., Results: The results demonstrated that knockdown of STARD4-AS1 led to a significant reduction in tumor cell proliferation and impaired migration and invasion abilities. Moreover, it resulted in the downregulation of ADCY4, PRKACA, and SOX10 gene expression, as well as decreased protein expression of ADCY4, PRKACA, and SOX10. In vivo experiments further confirmed the efficacy of STARD4-AS1 knockdown in reducing tumor growth., Conclusions: This study elucidates the mechanistic role of STARD4-AS1 and its downstream targets in SKCM progression, highlighting the importance of the ADCY4/PRKACA/SOX10 pathway. The integration of computational analysis with experimental validation enhances the understanding of TILPI and its clinical implications. Overall, the findings underscore the potential of novel computational frameworks like TILPI in predicting and managing SKCM, particularly through targeting the ADCY4/PRKACA/SOX10 pathway., (© 2024. The Author(s).)

Background: Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2 -related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1 -related or LZTR1 -related SWN., Methods: We assessed the variant detection rates for the three major SWN genes ( NF2 , LZTR1 and SMARCB1 ) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2 -related SWN at the time of genetic testing., Results: We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS)., Conclusions: There were similar proportions of LZTR1 , SMARCB1 or mosaic NF2 . However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification., Competing Interests: Competing interests: GE has received consultancy fees from AstraZeneca, Springworks and Everything Genetic., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1 eKO mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA)., Methods: The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs., Results: RNA sequencing (RNA-Seq) analysis of control and Mcpip1 eKO DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription., Conclusions: Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1 eKO papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis., (© 2024. The Author(s).)

Malignant melanoma is an aggressive cancer, with a high risk of metastasis and mortality rates, characterized by cancer cell heterogeneity and complex tumor microenvironment (TME). Single cell biology is an ideal and powerful tool to address these features at a molecular level. However, this approach requires enzymatic cell dissociation that can influence cellular coverage. By contrast, single nucleus RNA sequencing (snRNA-seq) has substantial advantages including compatibility with frozen samples and the elimination of a dissociation-induced, transcriptional stress response. To better profile and understand the functional diversity of different cellular components in melanoma progression, we performed snRNA-seq of 16,839 nuclei obtained from tumor samples along the growth of murine syngeneic melanoma model carrying a BRAFV600E mutation and collected 9 days or 23 days after subcutaneous cell injection. We defined 11 different subtypes of functional cell clusters among malignant cells and 5 different subsets of myeloid cells that display distinct global transcriptional program and different enrichment in early or advanced stage of tumor growth, confirming that this approach was useful to accurately identify intratumor heterogeneity and dynamics during tumor evolution. The current study offers a deep insight into the biology of melanoma highlighting TME reprogramming through tumor initiation and progression, underlying further discovery of new TME biomarkers which may be potentially druggable.

Background: Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood., Objectives: In order to better understand the molecular pathogenesis of cutaneous acral CD8+ TLPD and to identify further discriminatory markers to differentiate this lymphoma subtype from other CD8+ cutaneous lymphomas, we analysed five cases of cutaneous acral CD8+ TLPD for putative molecular alterations., Methods: Somatic alterations were assessed using whole-exome and targeted sequencing of paraffin-embedded tissue. Results were evaluated using immunohistochemical staining of respective relevant proteins. CD8+ cutaneous T-cell lymphomas (n = 12) served as control for KIR3DL1 staining., Results: Copy number variation analysis revealed a homozygous deletion of the KIR3DL1 gene in two of the analysed cases. This resulted in loss of KIR3DL1 protein expression, which was observed in all cases of cutaneous acral CD8+ TLPD. In contrast, KIR3DL1 expression was more variable in other CD8+ cutaneous T-cell lymphomas with 50% of analysed cases (n = 12) found to be positive. In addition, one further case of acral CD8+ TLPD harboured a loss-of-function mutation in the PIK3R1 gene, presumably activating the phosphoinositide 3-kinase-AKT pathway., Conclusions: Alterations of the KIR3DL1 gene may be of pathogenetic relevance for acral CD8+ TLPD. Loss of KIR3DL1 protein expression may support the diagnosis of this indolent lymphoma entity; however, this is not a subtype-specific discriminative feature., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)