title: Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse.
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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Perez-Andreu
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Roberts
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Wenjian
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authors.lastname: Yang
authors.forename: Cheng
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authors.lastname: Cheng
authors.forename: Deqing
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authors.forename: Julie
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authors.lastname: Gastier-Foster
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authors.forename: Joshua Yew-Suang
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authors.forename: I-Ming
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authors.forename: Meenakshi
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authors.lastname: Devidas
authors.forename: Michael J
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authors.lastname: Borowitz
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authors.lastname: Neale
authors.forename: Esteban G
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authors.lastname: Burchard
authors.forename: Dara G
authors.initials: DG
authors.lastname: Torgerson
authors.forename: Federico Antillon
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authors.lastname: Klussmann
authors.forename: Cesar Rolando Najera
authors.initials: CR
authors.lastname: Villagran
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.forename: Elizabeth
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authors.lastname: Raetz
authors.forename: Brent
authors.initials: B
authors.lastname: Wood
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authors.initials: F
authors.lastname: Yue
authors.forename: William L
authors.initials: WL
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authors.forename: Eric
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authors.lastname: Larsen
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Michael
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authors.lastname: Dean
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
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
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D016022:Case-Control Studies; D002648:Child; D050990:GATA3 Transcription Factor / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012008:Recurrence; D012306:Risk
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human