EGAGenomicsOtherhttps://ega-archive.org/studies/EGAS00001001113EGAEGA study EGAS00001001113Whole-exome sequencing of BCP HD ALL on Illumina HiSeq 2000, 100 bp paired-endDeep sequencing of 60 genes from BCP HD ALL samples on Illumina HiSeq 2000, 100 bp paired-endrestrictedEGAHigh hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia.Malinowska-Ozdowy K K, Frech C C, Schönegger A A, Eckert C C, Cazzaniga G G, Stanulla M M, zur Stadt U U, Mecklenbräuker A A, Schuster M M, Kneidinger D D, von Stackelberg A A, Locatelli F F, Schrappe M M, Horstmann M A MA, Attarbaschi A A, Bock C C, Mann G G, Haas O A OA, Panzer-Grümayer R RLymphoblastic Leukemia, ALL, Lymphocytic, Childhood., whole exome, pre-B-cell, B-cell precursor, Leukemia, precursor lymphoblastic lymphoma/leukemia, lymphoblastic leukaemia, Lymphocytic Leukemia, pre-B cell, Exomes, Lymphoblastic, acute lymphoblastic leukaemia, Childhood, Acute Lymphoblastic Leukemia, Lymphoid Leukemia, Philadelphia-Positive, Adult, L1 Lymphocytic Leukemia, Lymphoblastic Lymphoma, L2 Lymphocytic, Acute Lymphoblastic, B cell precursor, L1, lymphoblastic leukemia, Acute, L2, L1 Lymphocytic, Acute Lymphoid Leukemia, Precursor Cell Lymphoblastic Leukemia Lymphoma, Lymphoma, Acute Lymphocytic, L2 Lymphocytic Leukemia, Acute lymphoblastic leukemia, Lymphoid, Acute Lymphoid, acute lymphocytic leukaemia, Acute Lymphocytic Leukemia, Childhood ALLRas1/RAs85D, RAS, Ras, Antemortem Diagnosis, l(1)G0098, Materials, c-rasHa, E(sev)3C, Ras-1, Diagnosis, CG11485, Mutations, Relative, ras, relapse, c-ras2, symptoms, 1, Relapses, Fs(3)Hor, C-K-RAS, k-ras, D-Ras1, Chromatins, rask2, increased, me75, skeletal, DmelCG2684, Receptor tyrosine kinase, RTK, proportionality to, Recurrences, l(1)G0436, Iprit, RTS, ras85B, ras85D, NTef2, D17Mit170, T1, genetic, high frequency, D-ras-2, CG14648, chromosome scaffold, mustard gas, Diagnose, CG1799, nuclear chromatin, Relapse, screening, l(3)s1747, Growl, Ras2, RAS2, Ras1, RAS1, Ki-ras, familial, KAT3A, Tl3, Tl2, results, Diagnoses, Fs(3)Sz11, RSTS, Postmortem, Screenings, bis(2-chloroethyl)sulfane, Recrudescence, Examinations and Diagnoses, Relative Risks, p21, dRas85D, Genetic Materials, p21[Ras1], rsts, dRas1, dRAS1, Postmortem Diagnosis, ras1, Dras85D, ras2, Genetic Material, ras-2, BcDNA:RE36103, Diagnoses and Examination, Postmortem Diagnoses, acute lymphoblastic leukemia (ALL), l(1)G0351, LD02673, Risk, DmelCG1799, c-Ha-ras, D-ras1, l(1)G0238, D-ras2, proportionality, Hras-1, Exomes, signs, C-ras1, rate, Dm Ras1, Dras64B, C-ras2, l(3)06677, early, l(1)G0002, RasI, l(1)G0482, RASK2, Material, c-H-ras, Horka, l(1)G0127, CG2684, Fs(3)Horka, Cistron, inherited genetic, Harvey-ras, kat3a, accessory, Hras1, KI-RAS, whole exome, cytoplasmic chromatin, RasV12, dRas, Kras2, NS3, CG1167, H-ras, Gene, DRAS1, DRas2, DmelCG9375, IMPDH, Yperite, supernumerary, LD06825, Dras2, Dras1, l(1)G0388, D-Ras, Mass, Screening, Kras-2, Low, Mustard gas, DmF2, Antemortem, IMPdH, 1'-thiobis(2-chloroethane), Ha-ras, l(1)G0380, KRAS2, KRAS1, Dras, p21B, lod, ras 1, proportion, dras1, Dm-ras-64B, Genetic, Recrudescences, raspberry/impd, K-RAS4B, anon-WO0118547.126, K-RAS4A, Diagnoses and Examinations, Ras[V12], growl, l(1)G0391, Recurrences., EK3-4, DRas, bis(2-chloroethyl) sulphide, Lost, DRas85D/Ras, Ras 85D, Dmras64B, heterogeneity, DmelCG14648, ras-l, constitutitional genetic, receptor tyrosine kinase, sulfur mustard, l(1)G0056, Antemortem Diagnoses, findings, cou, 1-chloro-2-[(2-chloroethyl)thio]ethane, CG9375, K-RAS2B, K-RAS2A, K-ras, D-ras-1, c-Ki-ras, Muscle, Cistrons, Examination and Diagnoses, Cell, nev, E(faf), DmelCG1167, fs(3)05703, Lr, Mass Screenings, EP(X)1093, S35097, AI929937, Relative Risk, susceptibility, RAS85D, NS, Dmras85D, frequent, l(1)9Eb, increased number, Risks, CBP, Senfgas, Lds, Su(tor)3-2, present in greater numbers in organism, kras, CFC2, Bra, quotient, cbp, acute lymphoblastic leukaemia (ALL), hereditary, crebbpKI-RAS, ALL, Relapse, Childhood., precursor lymphoblastic lymphoma/leukemia, Lymphocytic Leukemia, Ki-ras, K-RAS2B, K-RAS2A, Kras2, NS3, KAT3A, K-ras, acute lymphoblastic leukaemia, Lymphoid Leukemia, Philadelphia-Positive, c-Ki-ras, L1 Lymphocytic Leukemia, Mutations, Lymphoblastic Lymphoma, ras, relapse, RSTS, Recrudescence, Acute Lymphoid Leukemia, p21, Kras-2, Acute Lymphocytic, rsts, Relapses, Acute Lymphoid, AI929937, acute lymphocytic leukaemia, C-K-RAS, k-ras, Childhood ALL, KRAS2, KRAS1, rask2, p21B, Lymphoblastic Leukemia, Lymphocytic, NS, Leukemia, lymphoblastic leukaemia, Recrudescences, K-RAS4B, Recurrences, K-RAS4A, CBP, RTS, Lymphoblastic, Childhood, Acute Lymphoblastic Leukemia, Adult, L2 Lymphocytic, Acute Lymphoblastic, L1, lymphoblastic leukemia, Acute, L2, L1 Lymphocytic, RASK2, kras, Precursor Cell Lymphoblastic Leukemia Lymphoma, CFC2, Lymphoma, cbp, L2 Lymphocytic Leukemia, Acute lymphoblastic leukemia, Lymphoid, Acute Lymphocytic Leukemia, kat3a, crebbpRas1/RAs85D, RAS, Ras, Antemortem Diagnosis, l(1)G0098, Materials, c-rasHa, E(sev)3C, Ras-1, Diagnosis, CG11485, Mutations, Relative, ras, relapse, c-ras2, symptoms, 1, Relapses, Fs(3)Hor, C-K-RAS, k-ras, D-Ras1, Chromatins, rask2, increased, me75, skeletal, DmelCG2684, Receptor tyrosine kinase, RTK, proportionality to, Recurrences, l(1)G0436, Iprit, RTS, ras85B, ras85D, NTef2, D17Mit170, T1, genetic, high frequency, D-ras-2, CG14648, chromosome scaffold, mustard gas, Diagnose, CG1799, nuclear chromatin, Relapse, screening, l(3)s1747, Growl, Ras2, RAS2, Ras1, RAS1, Ki-ras, familial, KAT3A, Tl3, Tl2, results, Diagnoses, Fs(3)Sz11, RSTS, Postmortem, Screenings, bis(2-chloroethyl)sulfane, Recrudescence, Examinations and Diagnoses, Relative Risks, p21, dRas85D, Genetic Materials, p21[Ras1], rsts, dRas1, dRAS1, Postmortem Diagnosis, ras1, Dras85D, ras2, Genetic Material, ras-2, BcDNA:RE36103, Diagnoses and Examination, Postmortem Diagnoses, acute lymphoblastic leukemia (ALL), l(1)G0351, LD02673, Risk, DmelCG1799, c-Ha-ras, D-ras1, l(1)G0238, D-ras2, proportionality, Hras-1, Exomes, signs, C-ras1, rate, Dm Ras1, Dras64B, C-ras2, l(3)06677, early, l(1)G0002, RasI, l(1)G0482, RASK2, Material, c-H-ras, Horka, l(1)G0127, CG2684, Fs(3)Horka, Cistron, inherited genetic, Harvey-ras, kat3a, accessory, Hras1, KI-RAS, whole exome, cytoplasmic chromatin, RasV12, dRas, Kras2, NS3, CG1167, H-ras, Gene, DRAS1, DRas2, DmelCG9375, IMPDH, Yperite, supernumerary, LD06825, Dras2, Dras1, l(1)G0388, D-Ras, Mass, Screening, Kras-2, Low, Mustard gas, DmF2, Antemortem, IMPdH, 1'-thiobis(2-chloroethane), Ha-ras, l(1)G0380, KRAS2, KRAS1, Dras, p21B, lod, ras 1, proportion, dras1, Dm-ras-64B, Genetic, Recrudescences, raspberry/impd, K-RAS4B, anon-WO0118547.126, K-RAS4A, Diagnoses and Examinations, Ras[V12], growl, l(1)G0391, Recurrences., EK3-4, DRas, bis(2-chloroethyl) sulphide, Lost, DRas85D/Ras, Ras 85D, Dmras64B, heterogeneity, DmelCG14648, ras-l, constitutitional genetic, receptor tyrosine kinase, sulfur mustard, l(1)G0056, Antemortem Diagnoses, findings, cou, 1-chloro-2-[(2-chloroethyl)thio]ethane, CG9375, K-RAS2B, K-RAS2A, K-ras, D-ras-1, c-Ki-ras, Muscle, Cistrons, Examination and Diagnoses, Cell, nev, E(faf), DmelCG1167, fs(3)05703, Lr, Mass Screenings, EP(X)1093, S35097, AI929937, Relative Risk, susceptibility, RAS85D, NS, Dmras85D, frequent, l(1)9Eb, increased number, Risks, CBP, Senfgas, Lds, Su(tor)3-2, present in greater numbers in organism, kras, CFC2, Bra, quotient, cbp, acute lymphoblastic leukaemia (ALL), hereditary, crebbpfalseWhole-exome and targeted sequencing of pediatric hyperdiploid B-cell precursor acute lymphoblastic leukemiaHigh hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.2017-07-26 15:39:28EGAS00001001113960625917266EGAD00001002652EGAD00001002653EGAC00001000262