Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse by Perez-Andreu Virginia, Roberts Kathryn G, Harvey Richard C, Yang Wenjian, Cheng Cheng, Pei Deqing, Xu Heng, Gastier-Foster Julie, E Shuyu, Lim Joshua Yew-Suang, Chen I-Ming, Fan Yiping, Devidas Meenakshi, Borowitz Michael J, Smith Colton, Neale Geoffrey, Burchard Esteban G, Torgerson Dara G, Klussmann Federico Antillon, Villagran Cesar Rolando Najera, Winick Naomi J, Camitta Bruce M, Raetz Elizabeth, Wood Brent, Yue Feng, Carroll William L, Larsen Eric, Bowman W Paul, Loh Mignon L, Dean Michael, Bhojwani Deepa, Pui Ching-Hon, Evans William E, Relling Mary V, Hunger Stephen P, Willman Cheryl L, Mullighan Charles G, Yang Jun J in Nature genetics (2013).

[PMID: 24141364] PubMed


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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