Dataset Information

A Comprehensive Analysis of Cutaneous Melanoma Patients in Greece Based on Multi-Omic Data.

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

SUBMITTER: Kontogianni G

PROVIDER: S-EPMC9913631 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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A Comprehensive Analysis of Cutaneous Melanoma Patients in Greece Based on Multi-Omic Data.

Kontogianni Georgia G Voutetakis Konstantinos K Piroti Georgia G Kypreou Katerina K Stefanaki Irene I Vlachavas Efstathios Iason EI Pilalis Eleftherios E Stratigos Alexander A Chatziioannou Aristotelis A Papadodima Olga O

Cancers 20230128 3

Cutaneous melanoma (CM) is the most aggressive type of skin cancer, and it is characterised by high mutational load and heterogeneity. In this study, we aimed to analyse the genomic and transcriptomic profile of primary melanomas from forty-six Formalin-Fixed, Paraffin-Embedded (FFPE) tissues from Greek patients. Molecular analysis for both germline and somatic variations was performed in genomic DNA from peripheral blood and melanoma samples, respectively, exploiting whole exome and targeted se ...[more]

PMID: 36765773

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Project description:The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.

Project description:BackgroundCutaneous Melanoma (CM) is a malignant disease with increasing incidence and high mortality. Ferroptosis is a new kind of cell death and related to tumor blood and lymphatic metastasis. This study aims at using bioinformatics technology to construct a prognostic signature and identify ferroptosis-related biomarkers to improve the prognosis and treatment of cutaneous melanoma.MethodsWe used bioinformatics tools to analyze RNA sequencing expression data with clinical information from multiple databases, utilized varieties of statistical methods to construct a ferroptosis-related prognostic signature of cutaneous melanoma and screened out specific genes with independent prognostic ability.ResultsWe obtained 22 ferroptosis-related (P < 0.05) prognostic DEGs in the uniCox regression analysis, among which 10 high-expressed genes (ATG5, CHAC1, FANCD2, FBXL5, HMOX2, HSPB1, NQO1, PEBP1, PRNP, SLC3A2) were screened out by LASSO regression analysis to establish a predictive model. Meanwhile, the ferroptosis-related signature and the nomogram we drew performed an excellent performance based on Kaplan-Meier (K-M), Receiver operating characteristic (ROC) and calibration curves. Univariate and multivariable cox analyses displayed that our model was greater than other prognostic features. GO and KEGG analyses revealed that 10-biomarker signature was mainly related to epidermis differentiation and immunity. ssGSEA analysis indicated that the immune status between the two risk groups was highly different. Besides, we found that two genes (CP, ZEB1) had independent prognostic ability and can be applied for drug research. Both genes were highly related to immunity. GSEA illustrated that ZEB1 may be involved in cellular functions such as proliferation, apoptosis, and migration, while CP was closely connected to immune cell related functions.ConclusionThe present study suggested a 10-biomarker signature can be clinically used to predict the prognosis of cutaneous melanoma, which was better than conventional factors. CP and ZEB1 were independent prognostic genes and can be applied to guide treatment. In addition, ZEB1 mutation was highly related to overall survival in cutaneous melanoma, while CP may be associated with tumor progression. Our study comprehensively analyzed the relationship between iron metabolism, ferroptosis-related genes, and the prognosis of cutaneous melanoma, provided new insight for molecular mechanisms and treatment of ferroptosis and cutaneous melanoma.

Project description:Cutaneous melanoma (CM) is an aggressive skin cancer with high metastatic potential and poor prognosis. Splicing factors, which regulate pre-mRNA alternative splicing (AS) events, have been suggested as potential therapeutic targets in CM. The objective of this study was to identify candidate splicing factors involved in CM through a systems biology approach and to elucidate their roles in CM progression. 390 AS events associated with patient survival were identified using bivariate Cox regression and receiver operating characteristic (ROC) analyses. 121 splicing factors significantly associated with patient prognosis were screened by univariate Cox regression analysis. A bipartite association network between AS events and splicing factors was constructed using Spearman correlation analysis. Based on the network topology, five candidate splice factors were identified. Among them, U2SURP, a poorly characterized serine/arginine-rich protein family member, was selected for further analysis in CM. Results indicated that U2SURP gene expression was significantly negatively correlated with the Immune Infiltration Score, the infiltration levels of dendritic cells, gamma-delta T cells, natural killer (NK) cells, and cytotoxic cells, as well as the expression of the immune checkpoint gene PD-1, suggesting that U2SURP may serve as a potential target for CM immunotherapy. Experimental validation showed that U2SURP mRNA and protein were overexpressed in CM cells, and silencing of U2SURP using siRNA significantly reduced CM cell survival, proliferation and migration. Furthermore, single-cell functional analysis showed that U2SURP gene expression was positively correlated with CM cell proliferation and differentiation. This study systematically identified candidate splicing factors involved in CM and provided new insights into the role of U2SURP in CM progression. These findings contribute to a deeper understanding of the pathogenesis of CM and establish new approaches for identifying splicing-related cancer therapeutic targets.

Dataset Information

A Comprehensive Analysis of Cutaneous Melanoma Patients in Greece Based on Multi-Omic Data.

Publications

A Comprehensive Analysis of Cutaneous Melanoma Patients in Greece Based on Multi-Omic Data.

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