Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure
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PROVIDER: PRJNA837210 | ENA |
REPOSITORIES: ENA
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Project description:Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have never been characterized in clinical biospecimen. DNA methylome, genome and transcriptome analyses of cutaneous melanoma in two cohorts identified UV-related alterations in regulatory regions and immunological pathways and revealed novel cancer driver genes affecting patient survival. TAPBP, the top gene and a member of the immunoglobulin superfamily, encompassed several CpG methylation sites altered by UV and independently validated by bisulfite pyrosequencing, providing cost-effective opportunities for clinical application. The DNA methylome also highlighted non UV-related aberrations underlying pathological differences between cutaneous and acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions in multi-ethnic backgrounds reveal translationally impactful mechanisms in melanomagenesis.
2022-05-12 | GSE202750 | GEO
Project description:Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival. TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.
| S-EPMC9287446 | biostudies-literature
Project description:Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma
| PRJNA1017461 | ENA
Project description:Genetics and Pathobiology of Cutaneous Mosaic Disorders
| PRJNA1160916 | ENA
Project description:We performed microRNA sequencing of primary human FFPE Acral Melanoma (AM), Cutaneous Melanoma (CM), Acral Nevi (AN), and Cutaneous Nevi (CN). We found that previously identified ratios of microRNAs, particularly miR-21-5p and miR-211-5p, were able to accurately classify benign and malignant melanocytic neoplasia, both in non-acral cutaneous melanomas and nevi (CM vs CN), as well as matched acral melanoma and nevi (AM vs AN). Receiver operating characteristic area under the curve (AUC) of Ensemble models trained using these microRNA ratios demonstrated AUCs of 0.88-0.90 across these melanoma subtypes, suggesting the potential utility of these ratios as a biomarker of malignancy in melanocytic neoplasia.
2024-08-14 | GSE266413 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE28909: Genome wide analysis of acral melanoma (Illumina) GSE28910: Genome wide analysis of acral melanoma (Affymetrix) Refer to individual Series
2011-12-13 | E-GEOD-28913 | biostudies-arrayexpress
Project description:Background:Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results: 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. Conclusions: A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.
2023-10-20 | GSE243238 | GEO
Project description:Genotyping of a matched normal, primary and metastatic acral melanoma DNA from blood and one matched Primary and one metastatic acral melanoma was genotyped on Affmetrix SNP6
2011-12-13 | E-GEOD-28910 | biostudies-arrayexpress
Project description:Assessment of mutation on expression levels Transcriptomic profile of a matched primary and metastatic acral melanoma One Primary and one metastatic acral melanoma transcript expression were assayed (no matched normal)
2011-12-13 | E-GEOD-28909 | biostudies-arrayexpress