EGAGenomicsCancer Genomicshttps://ega-archive.org/studies/EGAS00001007383EGAEGA study EGAS00001007383dic(9;20) pediatric ALL with DNMT3B rearrangement - arrayCGH experimentRecurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALLrestrictedEGADNA MTase MmuIIIB, Bcp., AW551857, DNA methyltransferase HsaIIIB, DNA MTase HsaIIIB, Materials, DNA methyltransferase MmuIIIB, Genetic, 2.1.1.37, M.MmuIIIB, Gene, CBT, INSDC_feature:gene, Cistrons, BOP, ICF1, Dnmt3b, Material, M.HsaIIIB, ICF, BCP, Genetic Materials, Cistron, Genetic Material, MmuIIIBp15ink4b, Dic19B, H2S(D2S), Dic19C, Ribonucleic, l(4)13, Materials, p19<ARF>, dP60, odd(Oz), Vps34, Zfpn1a1, Hs.54452, Sequence Determination, BcDNA:LD15217, p21[dacapo], Tumor, VPS34, 11621, LEF-1, PI-3 kinase, l(1)AA33, p110-alpha, Relative, KL receptor activity, Dmel_CG32005, hnRNP A2/B1, BCP, Bcp, ten-m, LEF1/TCF, SCO5, 1, 2, ARF-INK4a, 3, SCO1, Analysis, Gsfsow3, p16(INK4a), Non Polyadenylated, treatment, EBB-1, Crtac1B, thymus nucleic acid, Dp60, B-cell-specific transcription factor, l(3)rP126, DNA methyltransferase MmuIIIB, Analyses, Genomes, PI3K_59F, hrp40, hnRNP36, nucleic acid library preparation, HardwareType, PI3-kinase activity, W, Hrb87Fa, amlcr1, cTCF, BcDNA:AT25108, Sequence Determinations, PI3Kgamma, Hrb85CD, DIC, Dic, BSAP, MCAP, DNA Sequence Analysis, Acute Lymphoblastic, high frequency, Cgh, hrp36, Human Genomes, l(1)B2/13.1, Dnmt3b, AA409961, Precursor Cell Lymphoblastic Leukemia Lymphoma, PI3K 68D, Red, Bs, Lymphoid, AW557856, Pan, PAN, NSC 45388, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, dic, Ten-mc, Tumors, dVps34, DNA methyltransferase HsaIIIB, l(1)LB9, rea, CG5723, e(Pc), p50alpha, Hematopoiesis, CG2699, DmelCG5373, signal transduction by trans-phosphorylation, Hrb87f, PBT, C530050K14, Benign, Recrudescence, Acute Lymphoid Leukemia, PAX5, 5832432G11Rik, type-1 PI3K, Relative Risks, CG5974, Ikaros, Lymphoid Cell, Ribonucleic acids, DNA Sequence, desoxyribose nucleic acid, evi-1, S100 calcium-binding protein A10, CG11621, Acid, pbt, DmelCG7776, death rate, instrument, F24J5.12, Classical Polyarteritis Nodosa, Panarteritis Nodosa, DTCF, DTcf, Benign Neoplasms, INSDC_feature:gene, whole genome, Acute Lymphoblastic Leukemia, ANX2LG, DmelCG4141, INK4b, F8A5_4, F24J5_12, Malignant Neoplasms, APDS, CDKN2B, array CGH, GP11, signaling pathway, congenital generalised, Chromosome, Material, Decarbazine, DmelLcp3, PI3KBETA, Lymphoma, BG:DS02740.11, Cells, ds DNA, ink4b, CG18000, Nerve growth factor-induced protein 42C, 2017, DNA, Dncic1, INK4A, Pax-5, PEP, Acute Lymphocytic Leukemia, INK4B, dTCF, dTcf, CDKN2, krk1, Dimethyl, CG34403, Macias-Flores Garcia-Cruz Rivera syndrome, GH05739, l(2)04454, 5301, DNS, PELLE/IL-1, (Deoxyribonucleotide)n, INK4, Periarteritis Nodosa, Neoplasms, M.MmuIIIB, haemopoiesis, IC, p15(INK4b), Human, cdi4, Odz, PIK3, IKAROS, Lotus corniculatus, dVps34/PI3K59F, Pi3Kp60, Deoxyribonucleic Acid, GH14582, PI3K-dp110, Gene Products, hypertrichosis, Classic Polyarteritis Nodosa, Znfn1a1, Cdi4, CDI4, dPI3K, cDIC, anon-92Ed, Yellow, class I, DmelCG2043, Cdic, odz, Hrp36, 1H-Imidazole-4-carboxamide, Leukemia, Methyltransferase, lcp3, Recrudescences, Lotus japonicus, Dimethyl Imidazole, LCP-3, nucleic acid library construction, Cal1l, Double Stranded, IC74, Deoxyribonucleic acid, Pi3Kp110, l(3)rJ307, Expressions, pebp2ab, Biocarbazine, Sequencing, P110BETA, Neoplasias, l(3)05301, L2 Lymphocytic, CG12749, L1, L2, PI3K21B, L1 Lymphocytic, CP3, MiSeq, p19ARF, Ca[1], HRP36, Expression, (Deoxyribonucleotide)m, MCM, TEL|ABL, Methylations, LB5, NSC45388, Cpk, Sequence Analyses, Cancer, CAL12, ALL, proto-oncogene c-Kit, RNA, 42C, TP16, TP15, LcpIII, Malignant Neoplasm, AA414921, whole blood, DTIC, hydrosulfite, DmelCG18000, ZNFN1A1, class II, DNAn+1, type III phosphoinositide 3-kinase activity, D10Wsu136e, tp15, RNS, Rnt, p19-lt-ARF-gt-, L1 Lymphocytic Leukemia, p16INK4a, Cell, PI(3)K, Ten79E, cpk, PI3K-92E/Dp110, lLB5, BOP, Lymphoblastic Lymphoma, prophase chromosome, PIK3C1, AV083695, CAL1L, MT, CWS5, medulla ossium, Human Genome, KIT ligand receptor activity, P14ARF, Dimethyl Imidazole Carboxamide, chemical analysis, DNA Rearrangements, Neoplasm, AI462102, Acute Lymphoid, aml1-evi-1, signalling cascade, TEL/ABL, LCP3, Tcf/LEF, 5-(3, Library, Lymphoid Cells, Relative Risk, XKrk1, P16INK4A, cdk4l, aml, periarteritis, susceptibility, Yellow Marrow, 3-dimethyl-1-triazenyl)-, AML1-EVI-1, primary cancer, CT16449, Peripheral Blood, DMLCP3, library construction, medullary bone, l(2)28-28-12, interphase chromosome, Ntup1, hematopoiesis, survival analysis, DTIC Dome, Haematopoiesis, DmelCG11621, Childhood, CBFA2, Ribonucleic Acid, Cancers, CD117, malignant tumor, CG32005, INK4a-ARF, Reticuloendothelial System, DmelCG5861, caPI3K, CLOVE, DNA Sequence Analyses, Acute, DmVps34, C-Kit, hMtr3p, IMD14, PI3K_68D, Ssm, Lotus, Lef, PI3K-92D, Fusions, Desoxyribonukleinsaeure, xkl-1, 2810454P21Rik, Dimethyl Triazeno Imidazole Carboxamide, ten(m), acute lymphoblastic leukaemia (ALL), Dmp110, CG2043, PE, AI450383, Neoplasia, CG11452, DNA MTase MmuIIIB, MTS1, MTS2, DmelCG5974, CG5373, Polyarteritis Nodosa, determination, ATVPS34, PreP, Feature, Blood, leg, instrument configuration, PI3K, Dp110, Pctr1, DmelCG34403, Xkl-1, Medullary, AA410010, IA5, Medullary Hematopoiesis, DmelCG5723, relapse, PHOSPHATIDYLINOSITOL 3-KINASE, Cbfa2, Gsfsco1, hlk-1, DmelCG2699, F8A5.4, MTR3, medulla ossea, Pop, l(1)19Bb, AW047536, p110alpha, Arf, Q14, ARF, mts2, Relapses, phosphatidylinositol 3-kinase activity, Q16, Gsfsco5, Fusion, RNA Gene Products, SOW3, NSC-45388, signal transduction by protein phosphorylation, Pebp2a2, TCF/LEF, Gene Expressions, l(3)rL201, Survival Analyses, Pi3K92D, CG4141, Determination, Recurrences, catalyst activity, MTS-1, E(Sev-CycE)2B, ten-m/odz, Pi3k, chromatid, PI[[3]]K, Adult, ten[m], free, aml1, p10 protein, Red Marrow, XAML, Trefoil, p55alpha, blood cell formation, RUN, Run, malignant neoplasm, PrEP, ICF, disease management, DmelCG12749, Therapies, P11, Calpactin I light chain, P14, P16, Pi3K, PI3k, Acute lymphoblastic leukemia, Double-Stranded DNA, CG7776, Malignancies, P15, deoxyribonucleic acids, DNAn, TL, P19, Sl, MCMTC, HTC2, Loteae, polyarteritis, P16-INK4A, Therapy, AW551857, Relapse, PI3K68D, CBF-alpha-2, chromosome Xq27.1 Interchromosomal insertion syndrome, total RNA extract, ribose nucleic acid, P110DELTA, PtdIns-3-kinase activity, p10, Aml1, RGD1562979, MLM, AML1, p11, ribonucleic acids, signal transduction by conformational transition, Exosome component 6, RNA-seq, p16, Tr-kit, p15, Philadelphia-Positive, Lotus arabicus, Hrb2, Double-Stranded, l(3)05309, L[[3]]CP3, LEF/TCF, vacuolar protein sorting 34, AA33, Determinations, Dm Pan, dPIK, 1-phosphatidylinositol 3-kinase activity, (Deoxyribonucleotide)n+m, congenital generalized, MP-1, signaling cascade, EVI-1, PEBP2aB, M.HsaIIIB, PERIANTHIA, Ribonukleinsaeure, p21, DNA Sequence Determinations, Gene Fusions, kl1-A, Genetic Materials, Acute Lymphocytic, pentosenucleic acids, CLP11, p27, KIT, PRO0758, Genetic Material, HRB87F/hrp36, DNA sequencing, Lymphoblastic Leukemia, tyrosine-protein kinase Kit, acute lymphoblastic leukemia (ALL), DNA Rearrangement, Drives, Risk, p85alpha, ALL3, medulla of bone, hCG, HRB87F, p38, AI047692, AW123102, kit, mKIAA1104, PI3K 68_D, CG17964, Features, LYF1, Treatments, ANX2L, DHIC-1, loss of, p110D, p27[Dap], Patient, hypertrichosis congenital generalized X-linked, E(PC), PBMCs, anon-48Ac, aml-1, MP1, microarray, Cistron, L2 Lymphocytic Leukemia, p120-PI3K, Bone, droPIK57, Gene Rearrangements, DmelCG1772, CG1849, ICDT, WGBS, CIB1, Lymphocytic Leukemia, KLP, PI3K92E, Rearrangements, LEF/TCF-1, Benign Neoplasm, hIk-1, SCF receptor activity, mRNA transport regulator 3 homolog, Gene, Pi3K_59F, Ten[m], type I phosphatidylinositol kinase activity, Mtr3p, Malignant, Deoxyribonucleic acids, phosphatidylinositol 3-kinase, hardware, AL024248, III, scfr, p60, Survival, Marrow, PBMC, Whole Transcriptome Shotgun Sequencing, PHOSPATIDYLINOSITOL 3-KINASE, Decapo, SCFR, Childhood ALL, Dp110/PI3K, PI3K-68D/E, Runx-1, Lymphocytic, study, whole genome bisulfite sequencing, Fdc, DNA MTase HsaIIIB, Genetic, lymphoblastic leukaemia, AMLCR1, Malignancy, IK1, Runt, 3-Dimethyl-1-triazeno)imidazole-4-carboxamide, bisulfite, 17-234, Tcf-1, PI3'K, d-TCF, NovaSeq 6000, DTIC-Dome, Non-Polyadenylated RNA, PI3K-68D, signalling pathway, lymphoblastic leukemia, Ink4a|Arf, Dac, ICF1, dacapo/cyclin-dependent kinase interactor 4, time of survival, Pebpa2b, Clients, odz/ten-m, TCF/LEF1, CMM2, Dap, signal transduction by cis-phosphorylation, chimpanzees, Characteristics, hypertrichosis congenital generalised X-linked, Lymphocyte, whole-genome shotgun bisulfite sequencing, Rearrangement, dP110, WGS, P16INK4, 6330412C24Rik, 2.1.1.37, p120, Calpactin-1 light chain, DTICDome, Dmel_CG17964, DmelCG1849, p110, P11/Hrb87F, Vps34p, Lymphoid Leukemia, Cellular ligand of annexin II, Cistrons, Client, PPP1R92, EAP4, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, Characteristic, survival, pan.dTCF, Imidazole Carboxamide, vps34, yeast nucleic acid, DNA Sequencing, hMtr3, dp110, chromosome Xq27.1 interchromosomal insertion syndrome, Ink4a/Arf, CG1772, DH IC-1, Trefoils, methylation, Tcf, TCF, PI3CG, ds-DNA, Carboxamide, cbfa2, MmuIIIB, Shotgun bisulfite sequencing, PI-3-K, Lef1, ribonucleic acid, PI3K-59F, c-KIT, NovaSeq 6000., LEF1, frequent, PI3K-Dp110, Xaml1, Non Polyadenylated RNA, CDK4I, p15INK4b, Risks, class III, Lymphoblastic, Non-Polyadenylated, 2310012C15Rik, CBT, anon-35Fa, l(1)19Ea, tcf, p110gamma, l(4)102ABb, DNA Sequence Determination, P235, Deticene, c-kit, Therapeutic, anon-35Fc, P19ARF, blood cell biosynthesis, Treatment, assay, lef1, mKIAA4227, LyF-1, TEL, Tel, Runnings, l(3)00844, WGSBSfalseRecurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALLThe dicentric chromosome dic(9;20)(p11∼13;q11), occurs in 2% of pediatric acute lymphoblastic leukemia (ALL) cases. However, the prognostic significance of the dic(9;20) alterations and the mechanism in which these alterations drive leukemogenesis remains elusive. Our study describes the demographic, clinical, prognostic, and molecular characteristics of the dic(9;20)-positive ALL in a cohort of 57 pediatric BCP-ALL patients. Targeted RNA-seq and Array CGH analysis unraveled heterogeneous breakpoints on chromosomes 9 and 20 and frequent deletions of the IKZF1 gene. Together with the intrinsic susceptibility for deletions in CDKN2A, CDKN2B, and PAX5 genes in the dic(9;20)-positive ALL, these patients are eligible for treatment escalation in the AIEOP-BFM ALL 2017 clinical study. Survival analysis revealed poor 5-year event-free survival (pEFS) of 69% in dic(9;20)-positive ALL cases, compared to BCP-ALL patients enrolled in modern treatment studies. Strikingly, we identified six dic(9;20)-positive cases with rearrangements involving the DNMT3B gene, and poor 5-year pEFS of 25% (SE = 20%), compared to 79% (SE = 9%) for the remaining cohort (P = 0.011). Despite the loss of the methyltransferase domain of the DNMT3B gene in most cases with DNMT3B rearrangements, we did not observe major changes in the global methylation patterns. Differential gene expression analysis of DNMT3B-rearranged ALL unraveled a dysregulation of genes involved in hematopoiesis, lymphocyte maturation, and the PI3K/AKT signaling pathway. After confirmation in an independent cohort, DNMT3B-rearranged ALL cases should be considered high-risk for relapse and treated accordingly. We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.2023-07-27 14:35:03EGAS000010073839606EGAD00010002564EGAD00001011122EGAC00001003324