Characterization of prognosis and immune infiltration by a novel glutamine metabolism-related model in cutaneous melanoma

Glutamine metabolism(GM)plays an important role in tumor growth and proliferation.Skin cutaneous melanoma(SKCM)is a glutamine-dependent cancer.However,the molecular characteristics and action mechanism of GM on SKCM remain unclear.Therefore,we aimed to explore the effects of GM-related genes on survival,clinicopathological characteristics,and the tumor microenvironment in SKCM.In this study,682 SKCM samples were obtained from the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Consensus clustering was used to classify SKCM samples into distinct subtypes based on 41 GM-related genes.Differences in survival,immune infiltration,clinical characteristics,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways as well as differentially expressed genes(DEGs)between subgroups were evaluated.A prognostic model was constructed according to prognostic DEGs.Differential analyses in survival,immune infiltration,tumor microenvironment(TME),tumor mutation burden(TMB),stemness,and drug sensitivity between risk groups were conducted.We identified two distinct GM-related subtypes on SKCM and found that GM-related gene alterations were associated with survival probability,clinical features,biological function,and immune infiltration.Then a risk model based on six DEGs(IL18,SEMA6A,PAEP,TNFRSF17,AIM2,and CXCL10)was constructed and validated for predicting overall survival in SKCM patients.The results showed that the risk score was negatively correlated with CD8+T cells,activated CD4+memory T cells,M1 macrophages,andγδT cells.The group with a low-risk score was accompanied by a better survival rate with higher TME scores and lower stemness index.Moreover,the group with high-and low-risk score had a significant difference with the sensitivity of 75 drugs(p<0.001).Overall,distinct subtypes in SKCM patients based on GM-related genes were identified and the risk model was constructed,which might contribute to prognosis prediction,guide clinical therapy,and develop novel therapeutic strategies.

Diagnostic biopsy of cutaneous melanoma, sentinel lymph node biopsy and indications for lymphadenectomy

The incidence of cutaneous melanoma appears to be increasing worldwide and this is attributed to solar radiation exposure.Early diagnosis is a challenging task.Any clinically suspected lesion must be assessed by complete diagnostic excision biopsy(margins 1-2 mm);however,there are other biopsy techniques that are less commonly used.Melanomas are characterized by Breslow thickness as thin(<1 mm),intermediate(1-4 mm)and thick(>4 mm).This thickness determines their biological behavior,therapy,prognosis and survival.If the biopsy is positive,a wide local excision(margins 1-2 cm)is finally performed.However,metastasis to regional lymph nodes is the most accurate prognostic determinant.Therefore,sentinel lymph node biopsy(SLNB)for diagnosed melanoma plays a pivotal role in the management strategy.Complete lymph node clearance has undoubted advantages and is recommended in all cases of positive SLN biopsy.A PET-CT(positron emission tomography-computed tomography)scan is necessary for staging and follow-up after treatment.Novel targeted therapies and immunotherapies have shown improved outcomes in advanced cases.

Bsm I(rs1544410) and Fok I(rs2228570) vitamin D receptor polymorphisms, smoking, and body mass index as risk factors of cutaneous malignant melanoma in northeast Italy

Objective:To investigate whether vitamin D receptor gene(VDR)Bsm I-rs1544410 and Fok I-rs2228570 polymorphisms,smoking duration,and body mass index(BMI)are risk factors for cutaneous melanoma,especially metastatic melanoma.Methods:We studied 120 cutaneous melanoma cases[68 stage I and II non-metastatic melanoma(NMet M)patients,plus 52Stage III and IV metastatic melanoma(Met M)patients],and 120 matching healthy controls from northeast Italy.VDR polymorphisms were measured by restriction fragment length polymorphism analysis.Absence or presence of Bsm I and Fok I restriction sites was denoted by"B"and"F"or by"b"and"f,"respectively.Results:VDR-Bsm I bb genotype was more frequent among Met M(32.7%)than among NMet M cases(13.2%),with odds ratio(OR)=3.18.Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk:≥20 years of smoking(OR=2.43);≥20 years of smoking combined with bb(OR=4.78),Bb+bb(OR=2.30),Ff(OR=3.04),and Ff+ff(OR=3.08);obesity(BMI>30Conclusions:Risk factors for cutaneous Met M include two VDR polymorphisms combined with smoking duration and obesity.Results suggest gene-environment implications in melanoma susceptibility and severity.Future studies in larger cohorts and in subjects with different genetic background are warranted to extend our findings.

A multi-omics study on cutaneous and uveal melanoma

AIM:To present the multi-omics landscape of cutaneous melanoma(CM)and uveal melanoma(UM)from The Cancer Genome Atlas(TCGA).METHODS:The differentially expressed genes(DEGs)between CM and UM were found and integrated into a gene ontology enrichment analysis.Besides,the differentially expressed miRNAs were also identified.We also compared the methylation level of CM with UM and identified the differentially methylated regions to integrate with the DEGs to display the relationship between the gene expression and DNA methylation.The differentially expressed transcription factors(TFs)were identified.RESULTS:Though CM had more mutational burden than UM,they shared several similarities such as the same rankings in diverse variant types.Except GNAQ and GNA11,the other top 18 mutated genes of the combined group were mostly detected in CM instead of UM.On the transcriptomic level,4610 DEGs were found and integrated into a gene ontology enrichment analysis.We also identified 485 differentially expressed miRNAs.The methylation analysis showed that UM had a significantly higher methylation level than CM.The integration of differentially methylated regions and DEGs demonstrated that most DEGs were downregulated in UM and the hypo-and hypermethylation presented no obvious difference within these DEGs.Finally,116 hypermethylated TFs and 114 hypomethylated TFs were identified as differentially expressed TFs in CM when compared with UM.CONCLUSION:This multi-omics study on comparing CM with UM confirms that they differ in all analyzed levels.Of notice,the results also offer new insights with implications for elucidating certain unclear problems such as the distinct role of epithelial mesenchymal transition in two melanomas,the different metastatic routes of CM and UM and the liver tropism of metastatic UM.

Up-regulation of Human Leukocyte Antigen G Expression in Primary Cutaneous Malignant Melanoma Associated with Host-vs-tumor Immune Response

Human leukocyte antigen G （HLA-G） is one of the molecules implicated in immunotolerance. To investigate the role of HLA-G in primary cutaneous malignant melanoma （CMM）, a series of 47 skin melanocytic lesions were immunohistochemically evaluated. The correlation between HLA-G expression and CMM clinicohistopahtological data and Bcl-2 expression was also analyzed. HLA-G expression was detected in a variety of cell types. No significant difference in HLA-G expression was observed between malignant and non-malignant melanocytic lesions. HLA-G expression was significantly correlated with the inflammatory infiltration and Bcl-2 expression, whereas no significant correlation with ulceration, tumor thickness, clinical stage, histopathological subtypes were observed. HLA-G expression may be the result of host immune reaction in tumor microenvironment rather than a malignant feature of CMM.

Recent advancements in the diagnosis and treatment of acral melanoma

Acral melanoma(AM)is the most common histologic subtype of melanoma in dark-skinned patients and is associated with a worse prognosis and a high mortality rate,largely due to the inconspicuous nature of early-stage lesions,which can lead to late diagnosis.Because of the overlapping clinical and histopathological features of AM with other forms of cutaneous melanomas,early detection of AM requires a multidisciplinary approach that integrates various diagnostic modalities,including clinical examination,dermoscopy,histopathology,molecular testing,radiological imaging,and blood tests.While surgery is the preferred method of treatment for AM,other therapeutic options may be employed based on the stage and underlying etiology of the disease.Immune checkpoint inhibitors,molecular targeted therapy,radiotherapy,chemotherapy,and oncolytic virotherapy represent promising advanced treatment options for AM.In this review,we provide an overview of the latest advancements in diagnostic and therapeutic methods for AM,highlighting the importance of early detection and the prompt,individualized management of this challenging disease.

The crucial roles of m^(6)A RNA modifications in cutaneous cancers:Implications in pathogenesis,metastasis,drug resistance,and targeted therapies

N6-methyladenosine(m^(6)A)is the most abundant internal modification on RNA.It is a dynamical and reversible process,which is regulated by m^(6)A methyltransferase and m^(6)A demethylase.The m^(6)A modified RNA can be specifically recognized by the m^(6)A reader,leading to RNA splicing,maturation,degradation or translation.The abnormality of m^(6)A RNA modification is closely related to a variety of biological processes,especially the occurrence and development of tumors.Recent studies have shown that m^(6)A RNA modification is involved in the pathogenesis of skin cancers.However,the precise molecular mechanisms of m^(6)A-mediated cutaneous tumorigenesis have not been fully elucidated.Therefore,this review will summarize the biological characteristics of m^(6)A modification,its regulatory role and mechanism in skin cancers,and the recent research progress of m^(6)A-related molecular drugs,aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.