title: Germline genomic variants associated with childhood acute lymphoblastic leukemia.
abstract: Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 x 10(-5)) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 x 10(-15), odds ratio (OR) = 1.91; rs10994982, P = 5.7 x 10(-9), OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 x 10(-5), OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n = 124 children with ALL; P = 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes.
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Treviño
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Deborah
authors.initials: D
authors.lastname: French
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Cheryl
authors.initials: C
authors.lastname: Willman
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: James
authors.initials: J
authors.lastname: Downing
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10; D002897:Chromosomes, Human, Pair 7; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D004296:Dopa Decarboxylase / Q000235:genetics; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005854:Germ Cells; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D015810:Linkage Disequilibrium; D008727:Methotrexate / Q000378:metabolism / Q000627:therapeutic use; D016017:Odds Ratio; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011099:Polyglutamic Acid / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification* / Q000188:drug therapy / Q000235:genetics*; D011336:Probability; D015203:Reproducibility of Results; D012307:Risk Factors; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C503805:ARID5B protein, human; D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D051740:Ikaros Transcription Factor; D011099:Polyglutamic Acid; D004296:Dopa Decarboxylase; D008727:Methotrexate
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