Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse

Virginia Perez-Andreu, Kathryn G. Roberts, Richard C. Harvey, Wenjian Yang, Cheng Cheng, Deqing Pei, Heng Xu, Julie Gastier-Foster, E. Shuyu, 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 VillagranNaomi 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

Research output: Contribution to journalArticle

140 Scopus 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.

Original languageEnglish (US)
Pages (from-to)1494-1498
Number of pages5
JournalNature Genetics
Volume45
Issue number12
DOIs
StatePublished - Dec 1 2013

All Science Journal Classification (ASJC) codes

  • Genetics

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    Perez-Andreu, V., Roberts, K. G., Harvey, R. C., Yang, W., Cheng, C., Pei, D., Xu, H., Gastier-Foster, J., Shuyu, E., Lim, J. Y. S., Chen, I. M., Fan, Y., Devidas, M., Borowitz, M. J., Smith, C., Neale, G., Burchard, E. G., Torgerson, D. G., Klussmann, F. A., ... Yang, J. J. (2013). Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nature Genetics, 45(12), 1494-1498. https://doi.org/10.1038/ng.2803