TY - JOUR
T1 - Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse
AU - Perez-Andreu, Virginia
AU - Roberts, Kathryn G.
AU - Harvey, Richard C.
AU - Yang, Wenjian
AU - Cheng, Cheng
AU - Pei, Deqing
AU - Xu, Heng
AU - Gastier-Foster, Julie
AU - Shuyu, E.
AU - Lim, Joshua Yew Suang
AU - Chen, I. Ming
AU - Fan, Yiping
AU - Devidas, Meenakshi
AU - Borowitz, Michael J.
AU - Smith, Colton
AU - Neale, Geoffrey
AU - Burchard, Esteban G.
AU - Torgerson, Dara G.
AU - Klussmann, Federico Antillon
AU - Villagran, Cesar Rolando Najera
AU - Winick, Naomi J.
AU - Camitta, Bruce M.
AU - Raetz, Elizabeth
AU - Wood, Brent
AU - Yue, Feng
AU - Carroll, William L.
AU - Larsen, Eric
AU - Bowman, W. Paul
AU - Loh, Mignon L.
AU - Dean, Michael
AU - Bhojwani, Deepa
AU - Pui, Ching Hon
AU - Evans, William E.
AU - Relling, Mary V.
AU - Hunger, Stephen P.
AU - Willman, Cheryl L.
AU - Mullighan, Charles G.
AU - Yang, Jun J.
N1 - Funding Information:
We thank the patients and parents who participated in the COG protocols included in this study, the clinicians and research staff at COG institutions and J. Pullen (University of Mississippi at Jackson) for assistance in the classification of patients with ALL. Genome-wide genotyping of COG P9905 samples was performed by the Center for Molecular Medicine with generous financial support from the Jeffrey Pride Foundation and the National Childhood Cancer Foundation. V.P.-A. is supported by a Spanish Ministry of Education Fellowship Grant and by a St. Jude Children’s Research Hospital Academic Programs Special Fellowship. J.J.Y. is supported by an American Society of Hematology Scholar Award, an Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Grant and by the Order of St. Francis Foundation. K.G.R. is supported by a National Health and Medical Research Council (Australia) Overseas Training Fellowship and by a Haematology Society of Australia and New Zealand Novartis New Investigator Scholarship. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick’s Scholar. We thank M. Shriver (Pennsylvania State University) for sharing SNP genotype data for the Native American references, J. Pritchard and J. Degner (University of Chicago) for sharing DNase I hypersensitivity data for HapMap YRI cell lines, R.C. Ribeiro (St. Jude Children’s Research Hospital) and P. De Alarcon (University of Illinois College of Medicine at Peoria) for coordinating collaborations in Guatemala and S. Naron for her editorial assistance. This work was supported by the US National Institutes of Health (grant numbers CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729 and GM92666), in part by the intramural Program of the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). Study sponsors were not directly involved in the design of the study, the collection, analysis and interpretation of data, the writing of the manuscript or the decision to submit the manuscript. Detailed acknowledgments for the dbGaP data sets are provided in the Supplementary Note.
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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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U2 - 10.1038/ng.2803
DO - 10.1038/ng.2803
M3 - Article
C2 - 24141364
AN - SCOPUS:84888311432
SN - 1061-4036
VL - 45
SP - 1494
EP - 1498
JO - Nature genetics
JF - Nature genetics
IS - 12
ER -