EGA00190GenomicsIllumina HiSeq 2000Otherhttps://ega-archive.org/studies/EGAS00001001387EGAEGA study EGAS00001001387Exome sequencing of primary and relapse neuroblastomaEGArestrictedNeuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.Mutational dynamics between primary and relapse neuroblastomas.Schramm Alexander A, Köster Johannes J, Assenov Yassen Y, Althoff Kristina K, Peifer Martin M, Mahlow Ellen E, Odersky Andrea A, Beisser Daniela D, Ernst Corinna C, Henssen Anton G AG, Stephan Harald H, Schröder Christopher C, Heukamp Lukas L, Engesser Anne A, Kahlert Yvonne Y, Theissen Jessica J, Hero Barbara B, Roels Frederik F, Altmüller Janine J, Nürnberg Peter P, Astrahantseff Kathy K, Gloeckner Christian C, De Preter Katleen K, Plass Christoph C, Lee Sangkyun S, Lode Holger N HN, Henrich Kai-Oliver KO, Gartlgruber Moritz M, Speleman Frank F, Schmezer Peter P, Westermann Frank F, Rahmann Sven S, Fischer Matthias M, Eggert Angelika A, Schulte Johannes H JHprojections, malignant Growth, RAS, Ras, target gene, l(1)G0098, Materials, tumor suppressor, YY1AP, Visible Light, sympathetic part of autonomic division of nervous system, DNA Methylations, Diagnosis, Mutations, dmTAF[[II]]230, cell cycle regulator, OTTMUSG00000022087, ras, c-ras2, whole exome sequencing, hnu, symptoms, Whole Transcriptome, Transcriptome Sequencing, C130080N23Rik, C-K-RAS, Progression, TFIID TAF250, cel, cell process disease, tumor disease, CA, decreased, regulation of cell cycle progression, 1200017A24Rik, Diagnose, CG1799, single organism signaling, screening, Neuroblastoma (Schwannian Stroma-Poor), malignancy, dTAF[[II]]230, anatomical protrusion, Radiation, Ras2, RAS2, Exome, familial, TAF200, neuroblastoma (Schwannian Stroma-poor), Light, Sympathicoblastoma, Diagnoses, Postmortem, LIGHT, arrest of mitotic cell cycle progression, HCCA1, shelf, HCCA2, modulation of cell cycle progression, ras2, BcDNA:RE36103, Complete Transcriptome, protein_coding_transcript, HVEML, Sympathetic, CHDS5, Hras-1, signs, projection, ridge, 4930532L22Rik, array CGH, light quantum, Chromosome, HRAS1, RASK2, Taf250, Material, Whole Exome Sequencing, H-Ras, DNA, MRD2, other neoplasm, cancer, Harvey-ras, TAF230, Hras1, PEZ, DmelCG4005, lamellae, cell type cancer, Central neuroblastoma, CG1167, H-ras, DRas2, IMPDH, hras1, process of organ, LD06825, DUET, Ly113, Dras2, lamella, Kras-2, Antemortem, IMPdH, C-BAS/HAS, neoplasm, Ha-ras, malignant tumour, Complete, Exome Sequencings, dTAF[[II]]250, Clinical, 5530402J05Rik, cell, raspberry/impd, Lichtquant, K-RAS4B, K-RAS4A, messenger RNA, Diagnoses and Examinations, Sequencing, C030018G21Rik, Dmras64B, dTAF250, template RNA, Whole Exome, control of cell cycle progression, C-BAS|HAS, Clinical Course, regulation of progression through cell cycle, Whole, photon, (neuroblastoma NOS) or (sympathicoblastoma), RIGB, TR2, laminae, constitutitional genetic, Methylations, negative regulation of cell cycle arrest, Cancer, Antemortem Diagnoses, cell cycle modulation, COB1, findings, Complete Exome Sequencings, K-RAS2B, anatomical process, K-RAS2A, BG:DS00004.13, rash1, c-Ki-ras, CD258, Cell, dTAF230, DNA methylation maintenance following DNA replication, Exome Sequencing, positive regulation of cell cycle arrest, prophase chromosome, DmelCG1167, neoplastic growth, MT, CTLO, chemical analysis, CG4005, INSDC_feature:mRNA, TAF[[II]]250/230, NB, CHD-5, CHD-6, organ process, ZIR8, Taf[[II]]250, primary cancer, NS, mRNA, underdeveloped, B230399N07Rik, l(1)9Eb, HAPIP, cell cycle control, HVEM-L, increased number, interphase chromosome, Cancers, AI325207, disease of cellular proliferation, malignant tumor, signalling, neuroblastoma NOS (morphologic abnormality), DUO, mitotic cell cycle arrest, processes, sympathetic nervous system, Photoradiations, signalling process, (Neuroblastoma NOS) or (sympathicoblastoma), neuroblastoma NOS (morphologic abnormality)., hereditary, General activity, 5830472H07Rik, YAP65, Antemortem Diagnosis, Activity, determination, pars sympathica divisionis autonomici systematis nervosi, selection process, neoplasia, Yap65, c-rasHa, genome methylation maintenance following DNA replication, CG11485, relapse, Nervous Systems, present in fewer numbers in organism, k-ras, foton, rask2, increased, DNA methylation maintenance, Yap, YAP, H-RASIDX, Complete Exome Sequencing, neoplasm (disease), Whole Transcriptome Sequencing, l(1)G0436, hypoplasia, chromatid, DNA methylation, neuroblastoma (morphologic abnormality), Sympathetic Nervous Systems, [M]Neuroblastoma NOS (morphologic abnormality), genetic, reaction, N-RAS, D-ras-2, yap, malignant neoplasm, papilla, signaling process, Exacerbation, NB - Neuroblastoma, neuroblastoma (Schwannian Stroma-Poor), tumor, gamma, Ki-ras, lamina, Disease Exacerbation, flanges, neoplastic disease, TAFII-250, TAF250/230, PTP36, TAFII250, Examinations and Diagnoses, p21, organ system cancer, Genetic Materials, NOS, Postmortem Diagnosis, Genetic Material, ras-2, Visible Radiations, Diagnoses and Examination, DNA methylation maintenance following cell division, AW060752, YAP2, Postmortem Diagnoses, Visible Radiation, l(1)G0351, LD02673, Neuroblastomas, DmelCG1799, c-Ha-ras, System, shelves, l(1)G0238, D-ras2, Dras64B, CG17603, TAF[[II]], C-ras2, l(1)G0002, p21ras, Sympathetic Nervous, l(1)G0482, Patient, spine, c-H-ras, SR3-5, l(1)G0127, regulation of cell cycle arrest, Cistron, inherited genetic, Transcriptome Sequencings, Methylation, cell cycle regulation, accessory, KI-RAS, d230, biological signaling, TRAD, neuroblastoma, Complete Exome, Kras2, NS3, Gene, dTAFII250, HEL-205, EfW1, supernumerary, protrusion, l(1)G0388, reduced, dmTAF1, subnumerary, Taf230, AI461977, Clinical Progression, light, tiny, l(1)G0380, KRAS2, KRAS1, TAF250, p21B, ARHGEF24, Nervous System, WES, Taf200, Dm-ras-64B, pattern, Genetic, distribution, RASH1, Taf1p, ridges, Visible, decreased number, l(1)G0391, Clients, [M]Neuroblastoma NOS, heterogeneity, Yki, YKI, ras-l, TAF, Yorkie, small, l(1)G0056, targeted exome capture, Disease, data, TAF[[II]]250, CHD5, cell cycle arrest, malignant, neural Crest tumor, l(3)84Ab, K-ras, Cistrons, Client, Examination and Diagnoses, A130095G14Rik, EP(X)1093, p230, malignant neoplasm (disease), Systems, TFIID, K-Ras, K-RAS, methylation, Chd5, AI929937, flange, C-HA-RAS1, Radiations, HAMSV, Complete Transcriptome Sequencing, TAF[[II]]230, Neuroblastoma, Photoradiation, patient, TAF[II]250, LTg, process, present in greater numbers in organism, C-H-RAS, DmelCG17603, malignant neoplastic disease, kras, CFC2, processus, assay, TAF1[M]Neuroblastoma NOS (morphologic abnormality), Neuroblastoma (Schwannian Stroma-Poor), relapse, neuroblastoma, (Neuroblastoma NOS) or (sympathicoblastoma), Neuroblastomas, Neuroblastoma, [M]Neuroblastoma NOS, malignant, neuroblastoma NOS (morphologic abnormality)., Central neuroblastoma, neural Crest tumor, (neuroblastoma NOS) or (sympathicoblastoma), NOS, NB, NB - Neuroblastoma, neuroblastoma (Schwannian Stroma-poor), neuroblastoma (Schwannian Stroma-Poor), neuroblastoma (morphologic abnormality), Sympathicoblastomamalignant Growth, YAP65, RAS, Ras, Antemortem Diagnosis, l(1)G0098, Materials, tumor suppressor, Activity, determination, pars sympathica divisionis autonomici systematis nervosi, selection process, neoplasia, YY1AP, Yap65, c-rasHa, Visible Light, sympathetic part of autonomic division of nervous system, DNA Methylations, genome methylation maintenance following DNA replication, Diagnosis, CG11485, Mutations, dmTAF[[II]]230, relapse, cell cycle regulator, OTTMUSG00000022087, ras, c-ras2, Nervous Systems, whole exome sequencing, hnu, symptoms, Whole Transcriptome, Transcriptome Sequencing, C130080N23Rik, present in fewer numbers in organism, C-K-RAS, k-ras, foton, rask2, Progression, increased, DNA methylation maintenance, Yap, YAP, TFIID TAF250, H-RASIDX, cel, cell process disease, tumor disease, Complete Exome Sequencing, neoplasm (disease), Whole Transcriptome Sequencing, l(1)G0436, hypoplasia, chromatid, DNA methylation, neuroblastoma (morphologic abnormality), CA, Sympathetic Nervous Systems, [M]Neuroblastoma NOS (morphologic abnormality), genetic, reaction, N-RAS, decreased, D-ras-2, yap, malignant neoplasm, regulation of cell cycle progression, signaling process, Exacerbation, 1200017A24Rik, NB - Neuroblastoma, neuroblastoma (Schwannian Stroma-Poor), tumor, Diagnose, CG1799, single organism signaling, gamma, screening, Neuroblastoma (Schwannian Stroma-Poor), malignancy, dTAF[[II]]230, Radiation, Ras2, RAS2, Ki-ras, Exome, Disease Exacerbation, familial, TAF200, neuroblastoma (Schwannian Stroma-poor), neoplastic disease, Light, TAFII-250, TAF250/230, Sympathicoblastoma, Diagnoses, PTP36, TAFII250, Postmortem, LIGHT, arrest of mitotic cell cycle progression, Examinations and Diagnoses, HCCA1, p21, organ system cancer, HCCA2, modulation of cell cycle progression, Genetic Materials, NOS, Postmortem Diagnosis, ras2, Genetic Material, ras-2, BcDNA:RE36103, Visible Radiations, Diagnoses and Examination, DNA methylation maintenance following cell division, AW060752, YAP2, Complete Transcriptome, Postmortem Diagnoses, Visible Radiation, l(1)G0351, LD02673, protein_coding_transcript, HVEML, Neuroblastomas, DmelCG1799, c-Ha-ras, System, Sympathetic, l(1)G0238, D-ras2, CHDS5, Hras-1, signs, Dras64B, CG17603, TAF[[II]], C-ras2, 4930532L22Rik, l(1)G0002, p21ras, Sympathetic Nervous, array CGH, l(1)G0482, light quantum, Chromosome, HRAS1, RASK2, Taf250, c-H-ras, Material, SR3-5, l(1)G0127, Whole Exome Sequencing, regulation of cell cycle arrest, H-Ras, Cistron, inherited genetic, DNA, MRD2, other neoplasm, cancer, Transcriptome Sequencings, Harvey-ras, Methylation, cell cycle regulation, accessory, TAF230, Hras1, KI-RAS, PEZ, d230, biological signaling, TRAD, DmelCG4005, neuroblastoma, Complete Exome, cell type cancer, Central neuroblastoma, Kras2, NS3, CG1167, H-ras, Gene, dTAFII250, DRas2, IMPDH, HEL-205, hras1, EfW1, supernumerary, LD06825, DUET, Ly113, Dras2, l(1)G0388, reduced, dmTAF1, subnumerary, Taf230, AI461977, Clinical Progression, Kras-2, light, tiny, Antemortem, IMPdH, C-BAS/HAS, neoplasm, Ha-ras, l(1)G0380, malignant tumour, KRAS2, KRAS1, TAF250, p21B, ARHGEF24, Nervous System, WES, Taf200, Complete, Exome Sequencings, Dm-ras-64B, dTAF[[II]]250, Clinical, pattern, Genetic, 5530402J05Rik, distribution, cell, raspberry/impd, Lichtquant, RASH1, K-RAS4B, K-RAS4A, messenger RNA, Taf1p, Diagnoses and Examinations, Visible, decreased number, l(1)G0391, Sequencing, C030018G21Rik, Dmras64B, dTAF250, template RNA, Whole Exome, control of cell cycle progression, C-BAS|HAS, Clinical Course, regulation of progression through cell cycle, [M]Neuroblastoma NOS, Whole, heterogeneity, photon, (neuroblastoma NOS) or (sympathicoblastoma), RIGB, TR2, Yki, YKI, ras-l, TAF, constitutitional genetic, Methylations, Yorkie, negative regulation of cell cycle arrest, Cancer, small, l(1)G0056, Antemortem Diagnoses, targeted exome capture, cell cycle modulation, Disease, COB1, data, TAF[[II]]250, findings, Complete Exome Sequencings, CHD5, cell cycle arrest, malignant, K-RAS2B, K-RAS2A, neural Crest tumor, l(3)84Ab, K-ras, BG:DS00004.13, rash1, c-Ki-ras, Cistrons, CD258, Examination and Diagnoses, Cell, dTAF230, DNA methylation maintenance following DNA replication, Exome Sequencing, positive regulation of cell cycle arrest, prophase chromosome, DmelCG1167, neoplastic growth, A130095G14Rik, MT, CTLO, EP(X)1093, p230, malignant neoplasm (disease), Systems, chemical analysis, CG4005, INSDC_feature:mRNA, TAF[[II]]250/230, TFIID, NB, K-Ras, K-RAS, methylation, CHD-5, Chd5, AI929937, CHD-6, C-HA-RAS1, ZIR8, Radiations, Taf[[II]]250, HAMSV, primary cancer, NS, Complete Transcriptome Sequencing, TAF[[II]]230, mRNA, underdeveloped, B230399N07Rik, l(1)9Eb, Neuroblastoma, HAPIP, cell cycle control, HVEM-L, increased number, interphase chromosome, Photoradiation, patient, TAF[II]250, Cancers, AI325207, disease of cellular proliferation, malignant tumor, signalling, LTg, neuroblastoma NOS (morphologic abnormality), DUO, mitotic cell cycle arrest, present in greater numbers in organism, C-H-RAS, sympathetic nervous system, DmelCG17603, Photoradiations, signalling process, (Neuroblastoma NOS) or (sympathicoblastoma), malignant neoplastic disease, kras, CFC2, neuroblastoma NOS (morphologic abnormality)., assay, hereditary, General activity, 5830472H07Rik, TAF1[M]Neuroblastoma NOS (morphologic abnormality), Neuroblastoma (Schwannian Stroma-Poor), neuroblastoma, (Neuroblastoma NOS) or (sympathicoblastoma), Genomes, Neuroblastomas, Neuroblastoma, [M]Neuroblastoma NOS, malignant, neuroblastoma NOS (morphologic abnormality)., Central neuroblastoma, neural Crest tumor, (neuroblastoma NOS) or (sympathicoblastoma), NOS, NB, NB - Neuroblastoma, neuroblastoma (Schwannian Stroma-poor), neuroblastoma (Schwannian Stroma-Poor), neuroblastoma (morphologic abnormality), Sympathicoblastoma190.00.00.00.00.005860579888957434falseGenomes of Relapsing NeuroblastomaNeuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs, but the molecular mechanisms behind this process are poorly defined. We here used whole-exome sequencing, mRNA expression, array CGH and DNA methylation analysis to holistically characterize 16 paired samples from neuroblastoma patients at diagnosis and relapse. The mutational burden significantly increased in relapsing tumors accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and patient-specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target gene, YAP. Recurrent new mutations in HRAS, KRAS, DOCK8 and genes mediating cell-cell interaction in 13/16 relapse tumors also indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed first light on genetic alteration frequency, identity and evolution in neuroblastoma.2017-07-26 15:39:26EGAS00001001387960626121086EGAD00001001607EGAC00001000373