EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100265357EGA dataset EGAD00001002653EGAHigh 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 RfalseWES - samplesGenomic DNA from leukemic and remission bone marrow mononuclear cells was isolated with the QIAamp DNA Blood Extraction Kit (Qiagen, Venlo, The Netherlands). Libraries were prepared with the Illumina TruSeq DNA Sample Prep and TruSeq Exome Enrichment Kits (Illumina, San Diego, CA, USA) according to the manufacturer's recommendations. 100 bp paired-end sequencing was performed on a HiSeq 2000 (Illumina) to about 80x coverage.2017-07-26 15:39:28EGAD00001002653960625917266EGAC00001000262EGAS00001001113