title: Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.
abstract: Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) - the most common chromosomal translocation observed in childhood ALL - which leads to an ETV6-RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, P(CMH)=8.94 × 10(-9), OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10(-11), OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10(-9), OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10(-7), OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6-RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Ellinghaus
authors.forename: M
authors.initials: M
authors.lastname: Stanulla
authors.forename: G
authors.initials: G
authors.lastname: Richter
authors.forename: D
authors.initials: D
authors.lastname: Ellinghaus
authors.forename: G
authors.initials: G
authors.lastname: te Kronnie
authors.forename: G
authors.initials: G
authors.lastname: Cario
authors.forename: G
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: M
authors.initials: M
authors.lastname: Horstmann
authors.forename: R
authors.initials: R
authors.lastname: Panzer Grümayer
authors.forename: H
authors.initials: H
authors.lastname: Cavé
authors.forename: J
authors.initials: J
authors.lastname: Trka
authors.forename: O
authors.initials: O
authors.lastname: Cinek
authors.forename: A
authors.initials: A
authors.lastname: Teigler-Schlegel
authors.forename: A
authors.initials: A
authors.lastname: ElSharawy
authors.forename: R
authors.initials: R
authors.lastname: Häsler
authors.forename: A
authors.initials: A
authors.lastname: Nebel
authors.forename: B
authors.initials: B
authors.lastname: Meissner
authors.forename: T
authors.initials: T
authors.lastname: Bartram
authors.forename: F
authors.initials: F
authors.lastname: Lescai
authors.forename: C
authors.initials: C
authors.lastname: Franceschi
authors.forename: M
authors.initials: M
authors.lastname: Giordan
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.forename: B
authors.initials: B
authors.lastname: Heinzow
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.forename: A
authors.initials: A
authors.lastname: Franke
mesh_terms: D016022:Case-Control Studies; D002648:Child; D002893:Chromosomes, Human, Pair 3; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human
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