Inherited GATA3 Variants Are Associated with Ph-like Childhood Acute Lymphoblastic Leukemia and Risk of Relapse

Overview

Journal Nat Genet

Specialty Genetics

Date 2013 Oct 22

PMID 24141364

Citations 156

Authors

Virginia Perez-Andreu

Kathryn G Roberts

Richard C Harvey

Wenjian Yang

Cheng Cheng

Deqing Pei

Heng Xu

Julie Gastier-Foster

Shuyu E

Joshua Yew-Suang Lim

I-Ming Chen

Yiping Fan

Meenakshi Devidas

Michael J Borowitz

Colton Smith

Geoffrey Neale

Esteban G Burchard

Dara G Torgerson

Federico Antillon Klussmann

Cesar Rolando Najera Villagran

Naomi J Winick

Bruce M Camitta

Elizabeth Raetz

Brent Wood

Feng Yue

William L Carroll

Eric Larsen

W Paul Bowman

Mignon L Loh

Michael Dean

Deepa Bhojwani

Ching-Hon Pui

William E Evans

Mary V Relling

Stephen P Hunger

Cheryl L Willman

Charles G Mullighan

Jun J Yang

Affiliations

Soon will be listed here.

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.

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