Survival benefit of sentinel lymph node biopsy in Asian melanoma patients

Sentinel lymph node biopsy (SLNB) provides important prognostic information for early-stage melanomas. However, statistics regarding the survival comparison between SLNB and nodal observation in Asia, where acral lentiginous melanoma (ALM) predominates, are limited. This study aimed to identify if SLNB offered survival benefits over nodal observation in early-stage melanomas in Taiwan. The retrospective study included 227 patients who met the SLNB criteria according to the National Comprehensive Cancer Network guidelines and were treated at National Taiwan University Hospital from June 1997 to June 2021. Survival analysis was performed using Kaplan–Meier curves and Cox proportional hazards regression models. Of the study population, ALM accounted for 73.1%; 161 patients (70.9%) underwent SLNB and 66 patients (29.1%) were under nodal observation. Multivariate analysis showed significantly improved melanoma-specific survival (hazard ratio [HR], 0.6; p = .02) in the SLNB group. Among those who underwent completion lymph node dissection (CLND), the non-sentinel node positivity rate was 44.4%. Immediate CLND resulted in significantly longer melanoma-specific survival and distant-metastasis-free survival (DMFS) compared to nodal observation. (HR, 0.2; p = .01 for melanoma-specific survival. HR, 0.3; p = .046 for DMFS). In conclusion, SLNB may provide survival benefits of cutaneous melanoma over nodal observation in the Taiwanese population.     

Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma

The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark’s multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking ‘field melanocytes’, which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.     

Genetic and molecular characterization of uveal melanoma cell lines

The recent identification of frequent activating mutations in GNAQ or GNA11 in uveal melanoma provides an opportunity to better understand the pathogenesis of this melanoma subtype and to develop rational therapeutics to target the cellular effects mediated by these mutations. Cell lines from uveal melanoma tumors are an essential tool for these types of analyses. We report the mutation status of relevant melanoma genes, expression levels of proteins of interest, and DNA fingerprinting of a panel of uveal melanoma cell lines used in the research community.     

Emerging molecular targets in melanoma invasion and metastasis

Metastatic cutaneous melanoma accounts for the majority of skin cancer deaths due to its aggressiveness and high resistance to current therapies. To efficiently metastasize, invasive melanoma cells need to change their cytoskeletal organization and alter contacts with the extracellular matrix and the surrounding stromal cells. Melanoma cells can use different migratory strategies depending on varying environments to exit the primary tumour mass and invade surrounding and later distant tissues. In this review, we have focused on tumour cell plasticity or the interconvertibility that melanoma cells have as one of the factors that contribute to melanoma metastasis. This has been an area of very intense research in the last 5 yr yielding a vast number of findings. We have therefore reviewed all the possible clinical opportunities that this new knowledge offers to both stratify and treat cutaneous malignant melanoma patients.     

Radiation-inducible human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy: a novel treatment for radioresistant uveal melanoma

Uveal melanoma (UM) is one of the most therapy-resistant cancers. Radiotherapy is the preferred treatment for most cases of UM. However, some UM cells, such as the SP6.5 or OM431 cell lines, are relatively radioresistant. In this study, we attempted to improve the current UM therapy using an adenovirus radio-inducible gene therapy system. The antitumor adenovirus was constructed by inclusion of the radiation-inducible early growth response gene 1 (EGR1) promoter and the anticancer tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. We demonstrated that the UM SP6.5 and OM431 cell lines were susceptible to the TRAIL-induced antitumor effect. TRAIL expression was enhanced in the adenovirus containing EGR1/TRAIL (Ad-ET) treatment group by radiotherapy, whereas Ad-ET significantly increased cell death and apoptosis caused by radiotherapy. In mice bearing xenograft tumors, apoptotic cells were detected in pathological tumor sections. Adenovirus Ad-ET combined with radiation therapy significantly inhibited tumor growth compared with the other treatment groups (P < 0.01). Our findings indicate that radioresponsive gene therapy has the potential to be a more effective and specific therapy for UM because the therapeutic gene can be spatially or temporally controlled by exogenous radiation.     

Kinase gene fusions in defined subsets of melanoma

Genomic rearrangements resulting in activating kinase fusions have been increasingly described in a number of cancers including malignant melanoma, but their frequency in specific melanoma subtypes has not been reported. We used break‐apart fluorescence in situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1. Of these, three were confirmed by Immunohistochemistry (IHC) or sequencing and one was found to be an ARMC10‐BRAF fusion that has not been previously reported in melanoma. These fusions occurred in different subtypes of melanoma but all in tumors lacking known driver mutations. Our data suggest gene fusions are more common than previously thought and should be further explored particularly in melanomas lacking known driver mutations.     

Acral lentiginous melanoma: Basic facts,biological characteristics and research perspectives of an understudied disease

Acral lentiginous melanoma is a histological subtype of cutaneous melanoma that occurs in the glabrous skin of the palms, soles and the nail unit. Although in some countries, particularly in Latin America, Africa and Asia, it represents the most frequently diagnosed subtype of the disease, it only represents a small proportion of melanoma cases in European‐descent populations, which is partially why it has not been studied to the same extent as other forms of melanoma. As a result, its unique genomic drivers remain comparatively poorly explored, as well as its causes, with current evidence supporting a UV‐independent path to tumorigenesis. In this review, we discuss current knowledge of the aetiology and diagnostic criteria of acral lentiginous melanoma, as well as its epidemiological and histopathological characteristics. We also describe what is known about the genomic landscape of this disease and review the available biological models to explore potential therapeutic targets.     

Mouse models of uveal melanoma: Strengths,weaknesses, and future directions

Uveal melanoma is the most common primary malignancy of the eye, and a number of discoveries in the last decade have led to a more thorough molecular characterization of this cancer. However, the prognosis remains dismal for patients with metastases, and there is an urgent need to identify treatments that are effective for this stage of disease. Animal models are important tools for preclinical studies of uveal melanoma. A variety of models exist, and they have specific advantages, disadvantages, and applications. In this review article, these differences are explored in detail, and ideas for new models that might overcome current challenges are proposed.     

Immune implication of an autophagy-related prognostic signature in uveal melanoma

Uveal Melanoma (UM) is a rare cancer deriving from melanocytes within the uvea. It has a high rate of metastasis, especially to the liver, and a poor prognosis thereafter. Autophagy, an intracellular programmed digestive process, has been associated with the development and progression of cancers, with controversial pro- and anti-tumour roles. Although previous studies have been conducted on autophagy-related genes (ARGs) in various cancer types, its role in UM requires a deeper understanding for improved diagnosis and development of novel therapeutics. In the present study, Zheng et al. used univariate Cox regression followed by least absolute shrinkage and selection operator (Lasso) regression to identify a robust 9-ARG signature prognostic of survival in a total of 230 patients with UM. The authors used the Cancer Genome Atlas (TCGA) UM cohort as a training cohort (n=80) to identify the signature and validated it in another four independent cohorts of 150 UM patients from the Gene Expression Omnibus (GEO) repository ({"type":"entrez-geo","attrs":{"text":"GSE22138","term_id":"22138"}}GSE22138, {"type":"entrez-geo","attrs":{"text":"GSE27831","term_id":"27831"}}GSE27831, {"type":"entrez-geo","attrs":{"text":"GSE44295","term_id":"44295"}}GSE44295 and {"type":"entrez-geo","attrs":{"text":"GSE84976","term_id":"84976"}}GSE84976). This 9-ARG signature was also significantly associated with the enrichment of cancer hallmarks, including angiogenesis, IL6-KJAK-STAT3 signalling, reactive oxygen species pathway and oxidative phosphorylation. More importantly, this signature is associated with immune-related functional pathways and immune cell infiltration. Thus, this 9-ARG signature predicts prognosis and provides deeper insights into the immune mechanisms in UM, with potential implications for future immunotherapy.     

Genomic characterisation of acral melanoma cell lines

Acral melanoma is a rare melanoma subtype with distinct epidemiological, clinical and genetic features. To determine if acral melanoma cell lines are representative of this melanoma subtype, six lines were analysed by whole-exome sequencing and array comparative genomic hybridisation. We demonstrate that the cell lines display a mutation rate that is comparable to that of published primary and metastatic acral melanomas and observe a mutational signature suggestive of UV-induced mutagenesis in two of the cell lines. Mutations were identified in oncogenes and tumour suppressors previously linked to melanoma including BRAF, NRAS, KIT, PTEN and TP53, in cancer genes not previously linked to melanoma and in genes linked to DNA repair such as BRCA1 and BRCA2. Our findings provide strong circumstantial evidence to suggest that acral melanoma cell lines and acral tumours share genetic features in common and that these cells are therefore valuable tools to investigate the biology of this aggressive melanoma subtype. Data are available at: http://rock.icr.ac.uk/collaborations/Furney_et_al_2012/.     

Analysis of monosomy‐3 in immunomagnetically isolated circulating melanoma cells in uveal melanoma patients

Monosomy‐3 in primary uveal melanoma (UM) is associated with a high risk of metastasis and mortality. Although circulating melanoma cells (CMC) can be found in most UM patients, only approximately 50% of the patients develop metastases. We utilized a novel immuno‐FISH assay to detect chromosome‐3 in intact CMC isolated by dual immunomagnetic enrichment. Circulating melanoma cells were detected in 91% of the patients (n = 44) with primary non‐metastatic UM, of which 58% were positive for monosomy‐3. The monosomy‐3 status of CMC corresponded to the monosomy‐3 status of the primary tumor in 10 of the 11 patients where this could be tested. Monosomy‐3 in the CMC was associated with an advanced tumor stage (P = 0.046) and was detected in all four patients who developed metastasis within the follow‐up period of 4 yr. This non‐invasive technique may enable the identification of UM patients at risk for metastasis particularly when a primary tumor specimen is unavailable.     

A major responder to ipilimumab and nivolumab in metastatic uveal melanoma with concomitant autoimmunity

The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single‐agent immunotherapy in phase III trials. Clinical trials of combination CTLA‐4 and PD‐1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74‐year‐old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab. He developed sequential autoimmune transaminitis, diabetes and uveitis, which necessitated discontinuation of maintenance nivolumab 3 months after commencement of treatment. The patient continues to demonstrate an ongoing partial response 10 months from the initial combination immunotherapy, with the evidence of depigmentation of the primary ocular tumour.     

Proteomics in uveal melanoma research: opportunities and challenges in biomarker discovery

Uveal melanoma (UM) is the most frequent primary intraocular tumor in adult humans. Despite the significant advances in diagnosis and treatment of UM in the last decades, the prognosis of UM sufferers is still poor. Metastatic liver disease is the leading cause of death in UM and can develop after a long disease-free interval, suggesting the presence of occult micrometastasis. Proteomics technology has opened new opportunities for elucidating the molecular mechanism of complex diseases, such as cancer. This article will review the recent developments in biomarker discovery for UM research by proteomics. In the last few years, the first UM proteomics-based analyses have been launched, yielding promising results. An update on recent developments on this field is presented.     

The mutational burden of acral melanoma revealed by whole‐genome sequencing and comparative analysis

Acral melanoma is a subtype of melanoma with distinct epidemiological, clinical and mutational profiles. To define the genomic alterations in acral melanoma, we conducted whole‐genome sequencing and SNP array analysis of five metastatic tumours and their matched normal genomes. We identified the somatic mutations, copy number alterations and structural variants in these tumours and combined our data with published studies to identify recurrently mutated genes likely to be the drivers of acral melanomagenesis. We compared and contrasted the genomic landscapes of acral, mucosal, uveal and common cutaneous melanoma to reveal the distinctive mutational characteristics of each subtype.     

An autophagy-related prognostic signature associated with immune microenvironment features of uveal melanoma

Autophagy is involved in cancer initiation and progression but its role in uveal melanoma (UM) was rarely investigated. Herein, we built an autophagy-related gene (ARG) risk model of UM patients by univariate Cox regression and least absolute shrinkage and selection operator (Lasso) regression model and filtrated out nine prognostic ARGs in The Cancer Genome Atlas (TCGA) cohort. Survival and Receiver Operating Characteristic (ROC) Curve analysis in the TCGA and other four independent UM cohorts ({"type":"entrez-geo","attrs":{"text":"GSE22138","term_id":"22138"}}GSE22138, {"type":"entrez-geo","attrs":{"text":"GSE27831","term_id":"27831"}}GSE27831, {"type":"entrez-geo","attrs":{"text":"GSE44295","term_id":"44295"}}GSE44295 and {"type":"entrez-geo","attrs":{"text":"GSE84976","term_id":"84976"}}GSE84976) proved that the ARG-signature possessed robust and steady prognosis predictive ability. We calculated risk scores for patients included in our study and patients with higher risk scores showed worse clinical outcomes. We found the expressions of the nine ARGs were significantly associated with clinical and molecular features (including risk score) and overall survival (OS) of UM patients. Furthermore, we utilized univariate and multivariate Cox regression analyses to determine the independent prognostic ability of the ARG-signature. Functional enrichment analysis showed the ARG-signature was correlated with several immune-related processes and pathways like T-cell activation and T-cell receptor signaling pathway. Gene set enrichment analysis (GSEA) found tumor hallmarks including angiogenesis, IL6-JAK-STAT3-signaling, reactive oxygen species pathway and oxidative phosphorylation were enriched in high-risk UM patients. Finally, infiltrations of several immune cells and immune-related scores were found significantly associated with the ARG-signature. In conclusion, the ARG-signature might be a strong predictor for evaluating the prognosis and immune infiltration of UM patients.     

An 11-gene-based prognostic signature for uveal melanoma metastasis based on gene expression and DNA methylation profile

Uveal melanoma (UM) is the most common intraocular tumor worldwide. We proposed to identify a vital gene signature that has prognostic value for UM metastasis. For this purpose, we obtained a published DNA methylation and gene expression data set associated with UM from the Gene Expression Omnibus. The genes whose aberrant expression significantly associated with UM patients’ metastasis-free survival (MFS) were identified by applying a univariate Cox proportional hazards model to the gene expression data set followed by a robust likelihood-based survival analysis to screen the optimal prognostic gene signatures (PGS). A formula for calculating the risk score that represents UM metastasis risk was constructed by including the PGSs’ expression values weighted by their regression coefficients, which were obtained by a multivariate Cox regression analysis. As a result, aberrant expression of 2884 genes were found to be significantly associated with UM patients’ MFS, which were referred to as MFSGs, and 11 out of those MFSGs, GJC1, TCEA1, MFSD3, FAF2, TLCD1, GPAA1, CYC1, ASAP1, JPH1, LDB3, and KDELR3, were identified as PGSs through which we could accurately separate UM samples with shorter MFS from those with longer MFS. By combining the DNA methylation data set and MFSGs, we further identified 265 MFSGs, which contained CpG sites that significantly hyper- or hypo-methylated in UM samples compared with control samples. Functional enrichment analysis and pathway crosstalk analysis of those genes indicated significant enrichment of cancer-related pathways. In conclusion, we identified an 11-gene-based prognostic signature and several gene biomarkers for UM metastasis, which should be helpful for selecting an appropriate treatment method for specific patients with UM.