EGAGenomicsCancer Genomicshttps://ega-archive.org/studies/EGAS00001006644EGAEGA study EGAS00001006644WES_WGS_RNAseqSingle Cell Genome Sequence for DLP+ library A96141ArestrictedEGATherapy, cutaneous melanoma, Melanoma of the Skin, Malignant Melanoma of Skin, insensitive, melanoma of the skin, Malignant melanoma of skin (disorder), Melanoma of skin, malignant scalp melanoma, malignant melanoma of skin stage unspecified, MM - Malignant melanoma of skin, Malignant melanoma of other specified skin site, zone of skin melanoma (disease), element, unspecified (disorder), malignant lower limb melanoma, cancer of skin, Melanoma of Skin, site unspecified, unspecified, Melanoma, malignant melanoma of skin, melanoma, stage unspecified, malignant neck melanoma, NOS, malignant melanoma of skin of trunk except scrotum, Malignant melanoma of skin NOS (disorder), Stage Unspecified, Skin, malignant melanoma (of skin), Malignant Melanoma (of Skin), melanoma of skin, Malignant melanoma of skin, organ, treatment, Malignant melanoma of skin of other and unspecified parts of face, malignant lip melanoma, malignant ear melanoma, Malignant Cutaneous Melanoma, skin, resistant, malignant trunk melanoma, malignant melanoma of ear and/or external auricular canal, Malignant melanoma of other specified skin site (disorder), zone of skin melanoma, MALIG MELANOMA SKIN NEC, Treatments, cutaneous melanoma (disease), malignant melanoma of skin of lower limb, melanoma (disease) of zone of skin, [X]Malignant melanoma of skin, Malignant melanoma of other specified sites of skin, MALIG MELANOMA SKIN NOS, Therapeutic, cutaneous (skin) melanoma, anatomical unit, malignant cutaneous melanoma, malignant melanoma of skin of upper limb, malignant upper limb melanoma, body organ, disease management, MAL MELANOM FACE NEC/NOS., Therapies, Treatment, skin melanomaDmErk, extracellular signal-regulated kinase activity, pp44mapk, Materials, Metastasis, acetylglucosaminyltransferase-like protein, CELNOS, A4, neoplasm metastasis, Tumor, CG17228, phosphorylation, Prp4 protein kinase activity, 1135/09, dmTAF[[II]]230, 1135/07, unspecified, LeMPK3, macrophage, ATP-protein transphosphorylase activity, p44mpk, ATP:protein phosphotransferase (non-specific) activity, 0451/09, Dp38, SAPK2, myd, SEM, Sem, Genetic Recombination, organ, MAP-k, treatment, gamma sarcoglycan, 0244/09, AU041214, like-acetylglucosaminyltransferase, TFIID TAF250, pp42, cel, Tissue, DROPROSA, T Lymphocyte Exhaustion, Dsor2, Mbp-1, MALIG MELANOMA SKIN NEC, Tissue Basophils, suprasegmental levels of nervous system, sem, 671/2, HERA-B, BER, HERA-A, Tumors, ERK-A, p82 kinase activity, dTAF[[II]]230, Ligand, suprasegmental structures, dpERK, dpErk, anatomical protrusion, functional failure, typical plasmatocyte, betaIIPKC, TAF200, DmMAPK, Malignant Melanomas, PMK-2, dp-ERK, PMK-1, monocyte-derived macrophage, enthesitis related arthritis, not genetically inherited, PMK-3, Wee-kinase activity, Benign, malignant melanoma of skin, stage unspecified, ER, mKIAA0609, 1316/02, pMAPK, pMapK, BcDNA:HL08040, sarcoglycan, END, Monocyte-Derived Macrophages, fg, Malignant melanoma of skin of other and unspecified parts of face, DmERKA, rl/MAPK, 1167/13, non-specific serine/threonine protein kinase activity, Benign Neoplasms, l(2)41Ac, Malignant Neoplasms, MDC1D, CT34260, dpERk, enr, antagonists and inhibitors, Taf250, cutaneous (skin) melanoma, Material, serine-specific protein kinase activity, 35kD dystrophin-associated glycoprotein, Cells, SAPK, HIPK2, cytidine 3', l(1)16Fg, histiocyte, Wee 1-like kinase activity, other neoplasm, 0989/01, TAF230, pds, MAL MELANOM FACE NEC/NOS, atypia, glycogen synthase A kinase activity, Malignant melanoma of skin (disorder), Neoplasms, glycogen synthase kinase 3 activity, 12559, AA420328, 0763/13, LARGE1, phosphorylase b kinase kinase activity, unspecified (disorder), EK2-1, site unspecified, melanoma (disease), DmelCG17228, ERA, Era, atypical, juvenile spondylarthropathy, Prosp, MAM, gamma-SG, ribosomal protein S6 kinase II activity, MAL, agranular plasmatocyte, Malignant Melanoma (of Skin), Erk, ERK, PRKM1, PRKM2, protein-serine kinase activity, F15E12_6, dTAF[[II]]250, skin, cell, malignant trunk melanoma, MDDGB6, ligand, Naevocarcinoma, Exhaustions, STK32, ERa, Bone Marrow-Derived Macrophage, erk, l(3)rH013, melanoma (disease) of zone of skin, Neoplasias, Bone Marrow-Derived, dTAF250, Malignant melanoma of other specified sites of skin, ESR, Prodos, clustered, protein-cysteine kinase activity, anatomical unit, Hpr kinase activity, body organ, rll, skin melanoma, STK26, p38-2, preceding, tumor metastasis, myelin basic protein kinase activity, Cancer, 0671/02, inhibitors, l(3)j12C8, Malignant Melanoma of Skin, Malignant Neoplasm, 35 kDa dystrophin-associated glycoprotein, Metastases, Melanoma of skin, stress-activated kinase activity, Phosphorylations, Leu2, MAP-2 kinase activity, defective, BG:DS00004.13, protein serine kinase activity, encephalon, Cell, SGCG, protein phosphokinase activity, dTAF230, Melanoma of Skin, Metastase, l(3)rL433, Monocyte-Derived, PKA, l(3)rI160, PKC, 0441/16, stress-activated protein kinase activity, Malignant Melanoma, mapk2, mapk1, Neoplasm, TAF[[II]]250/230, Basophils, Skin, protein kinase p58 activity, ATCMPG1, MET, ATCMPG2, Macrophage, serine/threonine protein kinase activity, Taf[[II]]250, CG12559, Malignant Cutaneous Melanoma, DMDA1, Macrophages, increased number, dpERK1, ESTRR, Cancers, dsk1, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, l(3)rK204, like-glycosyltransferase, dpMAPK, malignant cutaneous melanoma, Bone Marrow-Derived Macrophages, granulocyte, protein serine-threonine kinase activity, SAP kinase activity, Neoplasia, glycogen synthase kinase activity, Melanoma of the Skin, l(3)rK137, MGC130048, recombination, protein kinase A activity, insensitive, Mpk2, malignant scalp melanoma, Mbp1, p42mapk, Neoplasm Metastases, Estra, T-Lymphocyte, ER[a], cancer metastasis, element, SR2-1, cancer of skin, H-ERA, Recombinations, melanoma, T Cell Exhaustion, kinase-related transforming protein, Monocyte-Derived Macrophage, malignant melanoma of skin of trunk except scrotum, mitogen-activated protein kinase activity, synganglion, mpk1, increased, Immune Processes, Immune Responses, Erk/Map kinase, MUB3_18, DERK-A, Malignant melanoma of other specified skin site (disorder), E(sina)7, MUB3.18, l(3)j6E2, Rl, Genetic Recombinations, Raf kinase activity, genetic, [X]Malignant melanoma of skin, MP kinase activity, serine kinase activity, 0320/10, DERK, Immune, DMPROSPER, atypical protein kinase C activity, malignant melanoma of skin of upper limb, disease management, MBP kinase II activity, Therapies, mitogen-activated S6 kinase activity, gamma-sarcoglycan, protein-aspartyl kinase activity, dERK, Malignancies, Exhaustion, Nr3a1, cutaneous melanoma, Therapy, MAP kinase 2 activity, melanoma of the skin, aberrant, Process, l(3)rO534, Mapk, gyltl1b-b, PRO, Pro, SG-gamma, Erk1, ERK1, ERK2, mapk1a, Bssl, TAFII-250, TAF250/230, MM - Malignant melanoma of skin, Malignant melanoma of other specified skin site, CYS, malignant lower limb melanoma, M phase-specific cdc2 kinase activity, TAFII250, PROS-1, Melanoma, PROS-2, T-Cell, mapk1b, MapK, malignant neck melanoma, MAPK, MDDGA6, pro, Genetic Materials, NOS, failure, T-Lymphocyte Exhaustion, KIAA0609, serine protein kinase activity, and GLY protein 2, erk2, mapk, Genetic Material, acetylglucosaminyltransferase-like 1A, Recombination, ERKa, phosphorylase B kinase kinase activity, malignant lip melanoma, and GLY protein 1, gyltl1b, malignant ear melanoma, BcDNA:RE08694, protein glutamyl kinase activity, resistant, Voila, l(2R)EMS45-39, p32, Encephalon, 0664/07, mdc1d, DmelCG12559, p38, Tissue Basophil, CG17603, gamma (35kDa dystrophin-associated glycoprotein), LARGE_HUMAN, TAF[[II]], Treatments, DpErk, DpERK, ErkA, ERKA, hydroxyalkyl-protein kinase activity, WEE1Hu, MALIG MELANOMA SKIN NOS, DMDA, Patient, spine, SR3-5, epsilon PKC, Eosinophil, juvenile enthesitis-related arthritis, Cistron, Interferon, pERK, accessory, the brain, ribosomal S6 protein kinase activity, calcium/phospholipid-dependent protein kinase activity, d230, SGCG_HUMAN, GroupII, Monocyte Derived Macrophages, Benign Neoplasm, Gene, dTAFII250, disfunctional, Malignant, EfW1, supernumerary, TYPE, zone of skin melanoma (disease), froggy, Gyltl1a, protrusion, l(3)10419, DAGA4, dmTAF8, dmTAF1, Taf230, resistance, 35DAG, HL-VIII, Mast, serine(threonine) protein kinase activity, anon-WO0140519.15, F15E12.6, Malignant melanoma of skin NOS (disorder), Stage Unspecified, juvenile, SCG3, melanoma of skin, Malignant melanoma of skin, T-antigen kinase activity, TAF250, galactosyltransferase-associated kinase activity, tumor cell migration, PROS, Taf200, 0585/13, Genetic, Malignancy, xp42, NR3A1, Basophil, CG7128, inhibiteur, ERalpha, metastasis, Taf1p, zone of skin melanoma, LARGE, clumped, p42 mitogen-activated protein kinase activity, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, BPFD#36, protein kinase (phosphorylating) activity, prod, Immune Response, inhibidor, lamellocyte, Raf-1, Clients, genetic recombination, DmERK-A, TAF, 0563/18, casein kinase (phosphorylating) activity, Immune Process, HHT1, ESRA, macrophagocyte, Mast Cell, ert1, TAF[[II]]250, Edg, malignant, prkm2, prkm1, CT39192, inhibitor, l(3)84Ab, Monocyte Derived, malignant melanoma of skin stage unspecified, Cistrons, Client, 1810036E18Rik, LGMD2C, l(3)rJ806, Pros, p38delta, Melanomas, twitchin kinase activity, ERAL1A, p230, AP50 kinase activity, MBP kinase I activity, TFIID, T-Lymphocyte Exhaustions, malignant melanoma (of skin), Xp42, antagonists, threonine-specific protein kinase activity, TAF[[II]]230, Foundation., mitogen activated kinase activity, malignant melanoma of ear and/or external auricular canal, Su(Raf)2B, Bone Marrow Derived Macrophages, EY2-2, TAF[II]250, cutaneous melanoma (disease), malignant melanoma of skin of lower limb, enthesitis-related arthritis, present in greater numbers in organism, D-ERK, DmelCG17603, DmelCG7128, Therapeutic, Bal, malignant upper limb melanoma, Estr, BAL, SCARMD2, Response, Treatment, malignant melanoma, CD8, ORW1, TAF8, ER-alpha, MAP kinase 1 activity, A-kinase activity, glycosyltransferase-like protein LARGE1, TAF1falseMulti-organ landscape of terminal, therapy-resistant, cutaneous melanomaPatients 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.2023-04-19 16:10:05EGAS000010066449606EGAD00001009499EGAD00001009513EGAC00000000011EGAC00001002884