EGAGenomicsOtherhttps://ega-archive.org/studies/EGAS00001002761EGAEGA study EGAS00001002761Comprehensive genetic analysis of uveal melanoma heterogeneity during metastatic progressionEGArestrictedMetastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.Rodrigues Manuel M, Mobuchon Lenha L, Houy Alexandre A, Fiévet Alice A, Gardrat Sophie S, Barnhill Raymond L RL, Popova Tatiana T, Servois Vincent V, Rampanou Aurore A, Mouton Aurore A, Dayot Stéphane S, Raynal Virginie V, Galut Michèle M, Putterman Marc M, Tick Sarah S, Cassoux Nathalie N, Roman-Roman Sergio S, Bidard François-Clément FC, Lantz Olivier O, Mariani Pascale P, Piperno-Neumann Sophie S, Stern Marc-Henri MHChoroidal, metastatic., Ciliochoroidal Melanoma, Intraocular, Ocular, determination, Uveal, Melanoma Of The Uvea, familial, Choroidal Melanomas, Iris, Ciliary, Ciliochoroidal, genetic, Ciliary Body Melanomas, Intraocular Melanoma, Melanomas, Melanoma, Ciliary Body Melanoma, chemical analysis, Body Melanoma, heterogeneity, iris melanoma, Ciliary Body, inherited genetic, assay, Ocular Melanoma, Iris Melanoma, constitutitional genetic, Intraocular melanoma, hereditary, Choroidal MelanomaAntemortem Diagnosis, Uveal, Complete Exome, Neoplasms, drug susceptibility/resistance, Iris, Benign Neoplasm, Tumor, Malignant, Diagnosis, interbrain, between brain, Client., Roles, Ciliary Body Melanoma, Mass, symptoms, Screening, Concepts, Whole Transcriptome, Transcriptome Sequencing, Antemortem, Iris Melanoma, drug resistance, adult, Choroidal Melanoma, Choroidal, treatment, DiE, WES, Complete, Exome Sequencings, Malignancy, Complete Exome Sequencing, Whole Transcriptome Sequencing, Diagnoses and Examinations, Ciliochoroidal, Sequencing, Neoplasias, Whole Exome, Clients, Whole, heterogeneity, Role Concepts, disease management, Therapies, Ciliary Body, Malignancies, Diagnose, Cancer, Tumors, Therapy, Antemortem Diagnoses, screening, Ciliochoroidal Melanoma, Ocular, findings, Malignant Neoplasm, Complete Exome Sequencings, Drug resistance, Exome, diencephalon, Ciliary, thalamencephalon, Client, Examination and Diagnoses, Diagnoses, metastatic neoplasm, Ciliary Body Melanomas, betweenbrain, Concept, Melanomas, mature diencephalon, Exome Sequencing, metastatic disease, Melanoma, MT, Benign, Postmortem, Screenings, Role Concept, Mass Screenings, Examinations and Diagnoses, Body Melanoma, Neoplasm, Resistance, Role, iris melanoma, Postmortem Diagnosis, Adults, Diagnoses and Examination, Intraocular, Postmortem Diagnoses, Complete Transcriptome, Complete Transcriptome Sequencing, Melanoma Of The Uvea, Choroidal Melanomas, response to drug, signs, common, Benign Neoplasms, Cancers, Treatments, Malignant Neoplasms, Drug, Intraocular Melanoma, metastatic, Therapeutic, Patient, metastatic tumor, metastatic tumour, Whole Exome Sequencing, Treatment, Ocular Melanoma, Intraocular melanoma, other neoplasm, Transcriptome Sequencings, NeoplasiaPARK1, Ciliochoroidal Melanoma, Ocular, Malignant Neoplasm, SLEB2, Uveal, PARK4, Neoplasms, Iris, Benign Neoplasm, Ciliary, Tumor, Malignant, Ciliary Body Melanomas, MED1, Med1, Mutations, Melanomas, methyl-CPG-binding domain 4, Melanoma, Benign, Ciliary Body Melanoma, Body Melanoma, Neoplasm, iris melanoma, Iris Melanoma, PD1, PD-1, Choroidal Melanoma, Choroidal, NACP, Intraocular, Malignancy, Melanoma Of The Uvea, Choroidal Melanomas, Benign Neoplasms, Cancers, Ciliochoroidal, CD279, hPD-1, Neoplasias, Intraocular Melanoma, hPD-l, PPP1R145, hSLE1, Ciliary Body, Malignancies, Ocular Melanoma, tamo, Intraocular melanoma, Neoplasia, Cancer, Tumors, Malignant Neoplasms.other disease, Care Standards, Uveal, Neoplasms, Iris, Benign Neoplasm, Tumor, Malignant, Mutations, MED1, Med1, RPL23, diseases, Ciliary Body Melanoma, sensitive, Heterozygosity, disease or disorder, diseases and disorders, Carrying, Iris Melanoma, sensitivity, Choroidal Melanoma, Choroidal, Ly101, human disease, Malignancy, Genomes, C1, inhibiteur, Ciliochoroidal, CD279, non-neoplastic, allergic reaction, Neoplasias, Pdc1, inhibidor, malignant neoplasm, Clients, disorder, Sensitivity, Ciliary Body, Homo sapiens disease, L17, Malignancies, Allelic Loss, Cancer, Tumors, inhibitors, Ciliochoroidal Melanoma, Ocular, Malignant Neoplasm, SLEB2, disorders, Phenotypes., l17, Ciliary, inhibitor, medical condition, Loss of, Client, Ciliary Body Melanomas, Allelic Losses, Melanomas, methyl-CPG-binding domain 4, Melanoma, Benign, MT, rpl17a, pd-1, Body Melanoma, Diseases, Neoplasm, iris melanoma, condition, Standards of Care, PD1, PD-1, antagonists, Intraocular, primary cancer, Heterozygosity Loss, Melanoma Of The Uvea, Choroidal Melanomas, Specificity, 60S ribosomal protein L23, Benign Neoplasms, rpl23, patient, Cancers, whole genome, malignant tumor, hPD-1, Malignant Neoplasms, Atlases, disease, metastatic, Intraocular Melanoma, hPD-l, Patient, Specificity and Sensitivity, antagonists and inhibitors, hSLE1, rpl17, Ocular Melanoma, Intraocular melanoma, other neoplasm, Care Standard, NeoplasiafalseComprehensive genetic analysis of uveal melanoma heterogeneity during metastatic progressionUveal melanoma (UM) is the most common primary intraocular malignancy in adults. Despite improvement of diagnosis and treatment of the primary tumor, there is no effective treatment of metastatic disease and approximately half of patients will die within one year or less following metastases detection. Tumor heterogeneity has been proposed as a key factor of drug resistance. However, it has been scarcely studied in UM. The present project aims searching for specific drivers of the metastatic progression, describing the genomic and transcriptomic landscape of metastatic UM, exploring tumor heterogeneity and investigating its role in drug resistance. Thus whole exome sequencing and transcriptomics have been performed on constitutional, primary tumor and metastatic samples from 28 UM patients.2019-07-25 15:53:56EGAS00001002761960629760383EGAD00001004554EGAC00001000670