Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma
Abstract Background We developed an integrated multi-omics analysis in metastatic melanoma (MM) cohorts to associate DNA methylation profiles with tumor progression, survival, response to adjuvant immunotherapy, structure of the tumor immune microenvironment and transcriptional programs of immunity...
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2025-07-01
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| Online Access: | https://doi.org/10.1186/s13046-025-03474-9 |
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| author | Andrea Anichini Francesca P. Caruso Vincenzo Lagano Teresa M. R. Noviello Rossella Tufano Gabriella Nicolini Alessandra Molla Ilaria Bersani Francesco Sgambelluri Alessia Covre Maria F. Lofiego Sandra Coral Anna Maria Di Giacomo Elena Simonetti Barbara Valeri Mara Cossa Filippo Ugolini Sara Simi Daniela Massi Massimo Milione Andrea Maurichi Roberto Patuzzo Mario Santinami Michele Maio Michele Ceccarelli Roberta Mortarini On behalf of the EPigenetic Immune-oncology Consortium Airc (EPICA) investigators |
| author_facet | Andrea Anichini Francesca P. Caruso Vincenzo Lagano Teresa M. R. Noviello Rossella Tufano Gabriella Nicolini Alessandra Molla Ilaria Bersani Francesco Sgambelluri Alessia Covre Maria F. Lofiego Sandra Coral Anna Maria Di Giacomo Elena Simonetti Barbara Valeri Mara Cossa Filippo Ugolini Sara Simi Daniela Massi Massimo Milione Andrea Maurichi Roberto Patuzzo Mario Santinami Michele Maio Michele Ceccarelli Roberta Mortarini On behalf of the EPigenetic Immune-oncology Consortium Airc (EPICA) investigators |
| author_sort | Andrea Anichini |
| collection | DOAJ |
| description | Abstract Background We developed an integrated multi-omics analysis in metastatic melanoma (MM) cohorts to associate DNA methylation profiles with tumor progression, survival, response to adjuvant immunotherapy, structure of the tumor immune microenvironment and transcriptional programs of immunity and melanoma differentiation. Methods Lesions (n = 191) from a fully annotated, retrospective cohort of 165 AJCC 8th Stage III and IV melanoma patients (EPICA cohort) were characterized by reduced representation bisulfite sequencing, RNA sequencing, whole exome sequencing, quantitative immunohistochemistry and multiplex immunofluorescence analysis. The TCGA melanoma datasets were used for validation. Pre-therapy lesions (n = 28) from a cohort of MM patients treated with adjuvant immune checkpoint blockade were characterized for the DNA methylation profile. Impact of a DNMT inhibitor on DNA methylation and transcriptomic profiles of melanoma cell lines was investigated by EPIC arrays and Clariom S arrays. Results Four tumor subsets (i.e. DEMethylated, LOW, INTermediate and CIMP) with progressively increasing levels of DNA methylation were identified in EPICA, TCGA MM and TCGA primary melanoma cohorts. EPICA patients with LOW methylation tumors exhibited a significantly longer survival and a lower progression rate to more advanced AJCC stages, compared to patients with CIMP tumors. In an adjuvant immune checkpoint blockade cohort, patients with DEM/LOW pre-therapy lesions showed significantly longer relapse-free survival compared to those with INT/CIMP lesions. RNA-seq data analysis revealed that LOW and CIMP EPICA tumors showed opposite activation of master molecules influencing prognostic target genes, and differential expression of immunotherapy response and melanoma differentiation signatures. Compared to CIMP tumors, LOW lesions showed enrichment for CD8+ TCF-1+ PD-1+ TIM-3− pre-exhausted and CD8+ TCF-1− PD-1+ TIM-3+ exhausted T cells, more frequent retention of HLA Class I antigens and a de-differentiated melanoma phenotype. The differentiation and immune-related transcriptional features associated with LOW vs CIMP lesions were tumor-intrinsic programs retained in-vitro by melanoma cell lines. Consistently, treatment of differentiated melanoma cell lines with a DNMT inhibitor induced global DNA de-methylation, promoted de-differentiation and upregulated viral mimicry and IFNG predictive signatures of immunotherapy response. Conclusions These results reveal the biological, prognostic and therapeutic relevance of DNA methylation classes in MM and support methylome targeting strategies for precision immunotherapy. |
| format | Article |
| id | doaj-art-c9f478ce15c54feca9d8fd351e470100 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-c9f478ce15c54feca9d8fd351e4701002025-08-20T03:46:15ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-07-0144112010.1186/s13046-025-03474-9Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanomaAndrea Anichini0Francesca P. Caruso1Vincenzo Lagano2Teresa M. R. Noviello3Rossella Tufano4Gabriella Nicolini5Alessandra Molla6Ilaria Bersani7Francesco Sgambelluri8Alessia Covre9Maria F. Lofiego10Sandra Coral11Anna Maria Di Giacomo12Elena Simonetti13Barbara Valeri14Mara Cossa15Filippo Ugolini16Sara Simi17Daniela Massi18Massimo Milione19Andrea Maurichi20Roberto Patuzzo21Mario Santinami22Michele Maio23Michele Ceccarelli24Roberta Mortarini25On behalf of the EPigenetic Immune-oncology Consortium Airc (EPICA) investigatorsDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriBiogem Institute of Molecular Biology and GeneticsDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriSylvester Comprehensive Cancer Center, and Department of Public Health Sciences, Miller School of Medicine, University of MiamiBiogem Institute of Molecular Biology and GeneticsDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriUniversity of Siena, Italy, and Center for Immuno-Oncology, Department of Oncology, University Hospital of SienaUniversity of Siena, Italy, and Center for Immuno-Oncology, Department of Oncology, University Hospital of SienaUniversity of Siena, Italy, and Center for Immuno-Oncology, Department of Oncology, University Hospital of SienaUniversity of Siena, Italy, and Center for Immuno-Oncology, Department of Oncology, University Hospital of SienaUniversity of Siena, Italy, and Center for Immuno-Oncology, Department of Oncology, University Hospital of SienaDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale Dei TumoriSection of Anatomic Pathology, Department of Health Sciences, University of FlorenceSection of Anatomic Pathology, Department of Health Sciences, University of FlorenceSection of Anatomic Pathology, Department of Health Sciences, University of FlorenceDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Surgical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Surgical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriDepartment of Surgical Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriUniversity of Siena, Italy, and Center for Immuno-Oncology, Department of Oncology, University Hospital of SienaSylvester Comprehensive Cancer Center, and Department of Public Health Sciences, Miller School of Medicine, University of MiamiDepartment of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei TumoriAbstract Background We developed an integrated multi-omics analysis in metastatic melanoma (MM) cohorts to associate DNA methylation profiles with tumor progression, survival, response to adjuvant immunotherapy, structure of the tumor immune microenvironment and transcriptional programs of immunity and melanoma differentiation. Methods Lesions (n = 191) from a fully annotated, retrospective cohort of 165 AJCC 8th Stage III and IV melanoma patients (EPICA cohort) were characterized by reduced representation bisulfite sequencing, RNA sequencing, whole exome sequencing, quantitative immunohistochemistry and multiplex immunofluorescence analysis. The TCGA melanoma datasets were used for validation. Pre-therapy lesions (n = 28) from a cohort of MM patients treated with adjuvant immune checkpoint blockade were characterized for the DNA methylation profile. Impact of a DNMT inhibitor on DNA methylation and transcriptomic profiles of melanoma cell lines was investigated by EPIC arrays and Clariom S arrays. Results Four tumor subsets (i.e. DEMethylated, LOW, INTermediate and CIMP) with progressively increasing levels of DNA methylation were identified in EPICA, TCGA MM and TCGA primary melanoma cohorts. EPICA patients with LOW methylation tumors exhibited a significantly longer survival and a lower progression rate to more advanced AJCC stages, compared to patients with CIMP tumors. In an adjuvant immune checkpoint blockade cohort, patients with DEM/LOW pre-therapy lesions showed significantly longer relapse-free survival compared to those with INT/CIMP lesions. RNA-seq data analysis revealed that LOW and CIMP EPICA tumors showed opposite activation of master molecules influencing prognostic target genes, and differential expression of immunotherapy response and melanoma differentiation signatures. Compared to CIMP tumors, LOW lesions showed enrichment for CD8+ TCF-1+ PD-1+ TIM-3− pre-exhausted and CD8+ TCF-1− PD-1+ TIM-3+ exhausted T cells, more frequent retention of HLA Class I antigens and a de-differentiated melanoma phenotype. The differentiation and immune-related transcriptional features associated with LOW vs CIMP lesions were tumor-intrinsic programs retained in-vitro by melanoma cell lines. Consistently, treatment of differentiated melanoma cell lines with a DNMT inhibitor induced global DNA de-methylation, promoted de-differentiation and upregulated viral mimicry and IFNG predictive signatures of immunotherapy response. Conclusions These results reveal the biological, prognostic and therapeutic relevance of DNA methylation classes in MM and support methylome targeting strategies for precision immunotherapy.https://doi.org/10.1186/s13046-025-03474-9MelanomaDNA methylationImmune contextureImmune checkpoint blockadeDNMT inhibitor |
| spellingShingle | Andrea Anichini Francesca P. Caruso Vincenzo Lagano Teresa M. R. Noviello Rossella Tufano Gabriella Nicolini Alessandra Molla Ilaria Bersani Francesco Sgambelluri Alessia Covre Maria F. Lofiego Sandra Coral Anna Maria Di Giacomo Elena Simonetti Barbara Valeri Mara Cossa Filippo Ugolini Sara Simi Daniela Massi Massimo Milione Andrea Maurichi Roberto Patuzzo Mario Santinami Michele Maio Michele Ceccarelli Roberta Mortarini On behalf of the EPigenetic Immune-oncology Consortium Airc (EPICA) investigators Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma Journal of Experimental & Clinical Cancer Research Melanoma DNA methylation Immune contexture Immune checkpoint blockade DNMT inhibitor |
| title | Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma |
| title_full | Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma |
| title_fullStr | Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma |
| title_full_unstemmed | Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma |
| title_short | Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma |
| title_sort | integrated multi omics profiling reveals the role of the dna methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma |
| topic | Melanoma DNA methylation Immune contexture Immune checkpoint blockade DNMT inhibitor |
| url | https://doi.org/10.1186/s13046-025-03474-9 |
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