{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"study_type":["Cancer Genomics"],"full_dataset_link":["https://ega-archive.org/studies/EGAS00001006644"],"host":["EGA"],"description":["EGA study EGAS00001006644"],"dataset_title":["WES_WGS_RNAseq","Single Cell Genome Sequence for DLP+ library A96141A"],"category":["restricted"],"repository":["EGA"],"additional_accession":[]},"is_claimable":false,"name":"Multi-organ landscape of terminal, therapy-resistant, cutaneous melanoma","description":"Patients succumb to cutaneous melanoma (CM) after metastasis and failure of present-day MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) therapies. Here we analyzed the genomic and transcriptomic landscape of multi-organ tumor and tumor-adjacent tissues from eleven rapid autopsies of individuals with CM who were treated with either or both MAPKi and/or ICB and succumbed to acquired therapy resistance. We discovered that, compared to melanoma from the preceding era, terminal, therapy-resistant melanoma harbor shifted mutational spectra and increased mutational burdens and frequencies in genes enriched for immune-evasive and resistance-driver processes. MAPKi specifically selects for signatures of defective homologous-recombination, mismatch, and base-excision repair mechanisms. Large, non-clustered deletions, inversions, and especially inter-chromosomal translocations dominate rearrangements, with breakpoints suggesting non-homologous end-joining. Organ-specific, tumor cel-enriched transcriptomes and ligand-receptor cross-talks (between tumors and tumor-adjacent macroenvironments) indicate differential interferon, neural, metabolic (oxidative-phosphorylation), and complement pathways. Terminal, therapy-resistant melanoma display an immune-desert, CD8+-macrophage-biased archetype enriched for T-cell exhaustion and type-2 immunity. Specifically, brain metastases enrich for pro-tumorigenic macrophages, mast cells, and eosinophils. This multi-organ perspective of lethal, therapy-resistant CM lays a foundation to improve therapeutic strategies.","dates":{"updated":"2023-04-19 16:10:05"},"accession":"EGAS00001006644","cross_references":{"TAXONOMY":["9606"],"EGA":["EGAD00001009499","EGAD00001009513","EGAC00000000011","EGAC00001002884"]}}