{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"study_type":["Cancer Genomics"],"full_dataset_link":["https://ega-archive.org/studies/EGAS00001005579"],"host":["EGA"],"description":["EGA study EGAS00001005579"],"dataset_title":["Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency: An Observational Registry Study"],"repository":["EGA"],"category":["restricted"],"name_synonyms":["Ly101, SLEB2, l17, study., 60S ribosomal protein L23, rpl23, Children, CD279, Autonomous, hPD-1, Mutations, hPD-l, RPL23, Pdc1, Replications, rpl17a, pd-1, hSLE1, rpl17, Autonomous Replications, L17, DNA, Autonomous Replication, Replication, DNA Replications, PD1, PD-1"],"description_synonyms":["PD L1 Inhibitor, PPAC, T22F8.160, and rna binding 2, neoplasia, Chronic Airflow Obstructions, chronic obstructive pulmonary disease (COPD), CCN6, Progress Reports, Tumor, HPPDASE, Mutations, T22F8_160, Summary Report, responsivity, ATGPR7, chronic obstructive airways disease NOS (disorder), Chronic irreversible airway obstruction, 10.5, GRP8, GRP7, PD L1 Inhibitors, Chronic Obstructive Pulmonary Disease (COPD), Summary Reports, eIF2C 2, 10.9, Protein slicer, treatment, increased, PPCD, thymus nucleic acid, PPD, PD-1 Inhibitors, F, COLD (chronic obstructive lung disease), Man (Taxonomy), Programmed Death-Ligand 1 Inhibitors, Progress Report, DmelCG2328, NEC in ICD9CM_2006, cell process disease, tumor disease, neoplasm (disease), CAFL - Chronic airflow limitation, V, LIBC, Chronic airflow limitation, Progress, Immune, RINX, Field Reports, disease (COPD), GLYCINE RICH PROTEIN 7, PD-L1 Inhibitor, disease management, Therapies, PPD-F, Double-Stranded DNA, PPD-B, deoxyribonucleic acids, Argonaute2, tumor, DNAn, glycine-rich RNA-binding protein 8, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, Tumors, Therapy, CHRONIC, chronic obstructive lung disease [Ambiguous], obstructive lung disease, Checkpoint Blockade, CTLA-4 Inhibitors, Modern, neoplastic disease, Double-Stranded, tumours, Airflow Obstructions, predicted, (Deoxyribonucleotide)n+m, CHRONIC OBSTRUCTIVE AIRWAY DIS, pulmonary disease (COPD), Immune Checkpoint Blockers, Investigative Report, CTLA 4 Inhibitor, CHRONIC OBSTRUCTIVE, chronic obstructive pulmonary disease and allied conditions, Chronic airway disease, VI, NOS, Programmed Cell Death Protein 1 Inhibitors, progressive pseudorheumatoid chondrodysplasia, desoxyribose nucleic acid, Airflow Obstruction, activation, PD-1, COPD NOS, CHRONIC OBSTRUCTIVE LUNG DIS, GLYCINE-RICH PROTEIN 8, Chronic Obstructive Airways Disease, Chronic airway obstruction, Chronic obstructive lung disease, 20.35, Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitors, death rate, PPD CG, cold, Field, common, PD 1 Inhibitor, Children, Treatments, Cytotoxic T Lymphocyte Associated Protein 4 Inhibitor, Chronic Airflow Obstruction, Report, F2G1.4, Patient, OBSTRUCTIVE PULMONARY DISEASE (COPD), progressive pseudorheumatoid, COPD - Chronic obstructive pulmonary disease, ds DNA, chronic obstructive airways disease, eve2, arthropathy, Checkpoint Inhibitors, DNA, obstructive pulmonary disease (COPD), other neoplasm, Inhibitor, COLD, chronic obstructive lung disease, humans, accessory, CG2328, 14.10, DNS, hAgo2, (Deoxyribonucleotide)n, DISEASE (COPD), Neoplasms, CAO - Chronic airflow obstruction, CHRONIC OBSTRUCTIVE PULM DIS, circadian rhythm, Chronic obstructive pulmonary disease NOS, PD-L1 Inhibitors, PD 1 PD L1 Blockade, supernumerary, Deoxyribonucleic acids, and RNA binding 1, NEOPL, Human, Chronic obstructive pulmonary disease finding, Cold, PULMONARY DISEASE (COPD), Blockade, Investigative, Pulmonary Disease, Deoxyribonucleic Acid, Homo sapiens, 3.1.26.n2, even, PD-1 Inhibitor, neoplasm, Man, Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitor, study, reactivity, Cold Temperatures, Eukaryotic translation initiation factor 2C 2, CNS, eIF-2C 2, Double Stranded, KTCN1, Deoxyribonucleic acid, tumour, Chronic Obstructive, Checkpoint Blockers, Programmed Death Ligand 1 Inhibitors, CTLA-4 Inhibitor, Immune Checkpoint Blockade, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), ATGRP7, ATGRP8, time of survival, Clients, NEC, PD-1-PD-L1, Chronic, SEDT-PA, (Deoxyribonucleotide)m, Investigative Reports, progressive pseudorheumatoid dysplasia, PPCD1, Neoplastic Growth, COPD, Argonaute RISC catalytic component 2, PD-1-PD-L1 Blockade, spondyloepiphyseal dysplasia tarda - progressive arthropathy, COAD - Chronic obstructive airways disease, PPD-S, PPD-CG, neuraxis, chronic obstructive airways disease NOS, DNAn+1, not elsewhere classified, PPD-L, COAD, Immunotherapies., Checkpoint Inhibitor, CAASDS, COLD - Chronic obstructive lung disease, Client, chronic, PULM DIS CHRONIC OBSTRUCTIVE, of childhood, Chronic obstructive pulmonary disease finding (finding), Cytotoxic T Lymphocyte Associated Protein 4 Inhibitors, CTLA 4 Inhibitors, neoplastic growth, survival, Temperatures, PD 1 Inhibitors, 4-HPPD, Research Reports, cerebrospinal axis, Eve, EVE, GLYCINE-RICH RNA-BINDING PROTEIN 7, (COPD), ds-DNA, KTCN, chronic airway obstruction, chronic obstructive, CAL - Chronic airflow limitation, chronic obstructive airway disease, Temperature, Immune Checkpoint Inhibitor, increased number, 4HPPD, Dops, INS, GR-RBP7, GR-RBP8, l(2)46Ce, Programmed Cell Death Protein 1 Inhibitor, Neuraxis, disease of cellular proliferation, l(2)46Cg, l(2)46CFj, present in greater numbers in organism, l(2)46CFh, PAZ Piwi domain protein, PPD F, Reports, Therapeutic, PPD B, DEL, l(2)46CFp, Checkpoint Inhibition, Modern Man, chronic obstructive lung disease (disorder), Desoxyribonukleinsaeure, spondyloepiphyseal dysplasia tarda with progressive arthropathy, Purified Protein Derivative of Tuberculin, Treatment, cold (chronic obstructive lung disease), GLOD3, Chronic Obstructive Lung Disease, response, Summary, E(eve), PPD L, NEOPLASMS BENIGN, Neoplasia, Immune Checkpoint Inhibition, Field Report, l(2)46CFg, chronic obstructive pulmonary disease"],"additional_accession":[]},"is_claimable":false,"name":"Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency: An Observational Registry Study","description":"Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive/recurrent tumours from 38 patients, that revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold†tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.","dates":{"updated":"2021-10-12 18:09:36"},"accession":"EGAS00001005579","cross_references":{"TAXONOMY":["9606"],"EGA":["EGAD00001008036","EGAC00001001936"]}}