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Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet 2013 Dec;45(12):1494-8

Date

10/22/2013

Pubmed ID

24141364

Pubmed Central ID

PMC4039076

DOI

10.1038/ng.2803

Scopus ID

2-s2.0-84888311432 (requires institutional sign-in at Scopus site)   273 Citations

Abstract

Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome-positive ALL and poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a susceptibility locus for Ph-like ALL (GATA3, rs3824662; P = 2.17 × 10(-14), odds ratio (OR) = 3.85 for Ph-like ALL versus non-ALL; P = 1.05 × 10(-8), OR = 3.25 for Ph-like ALL versus non-Ph-like ALL), with independent validation. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (CRLF2 rearrangement, JAK gene mutation and IKZF1 deletion) and with variation in GATA3 expression. Finally, genotype at the GATA3 SNP was also associated with early treatment response and risk of ALL relapse. Our results provide insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis.

Author List

Perez-Andreu V, Roberts KG, Harvey RC, Yang W, Cheng C, Pei D, Xu H, Gastier-Foster J, E S, Lim JY, Chen IM, Fan Y, Devidas M, Borowitz MJ, Smith C, Neale G, Burchard EG, Torgerson DG, Klussmann FA, Villagran CR, Winick NJ, Camitta BM, Raetz E, Wood B, Yue F, Carroll WL, Larsen E, Bowman WP, Loh ML, Dean M, Bhojwani D, Pui CH, Evans WE, Relling MV, Hunger SP, Willman CL, Mullighan CG, Yang JJ

Author

Bruce m. Camitta Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Case-Control Studies
Child
GATA3 Transcription Factor
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Inheritance Patterns
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Risk