Germline genomic variants associated with childhood acute lymphoblastic leukemia.
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.
Treviño
Lisa R
LR
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Yang
Wenjian
W
French
Deborah
D
Hunger
Stephen P
SP
Carroll
William L
WL
Devidas
Meenakshi
M
Willman
Cheryl
C
Neale
Geoffrey
G
Downing
James
J
Raimondi
Susana C
SC
Pui
Ching-Hon
CH
Evans
William E
WE
Relling
Mary V
MV
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
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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