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 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

doi:10.1038/ng.2803

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^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

253 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 language	English (US)
Pages (from-to)	1494-1498
Number of pages	5
Journal	Nature Genetics
Volume	45
Issue number	12
DOIs	https://doi.org/10.1038/ng.2803
State	Published - Dec 2013

Funding

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.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2803

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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

@article{0b11c10fdeb64ce3816df604c7e49e6d,

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.",

author = "Virginia Perez-Andreu and Roberts, {Kathryn G.} and Harvey, {Richard C.} and Wenjian Yang and Cheng Cheng and Deqing Pei and Heng Xu and Julie Gastier-Foster and E. Shuyu and Lim, {Joshua Yew Suang} and Chen, {I. Ming} and Yiping Fan and Meenakshi Devidas and Borowitz, {Michael J.} and Colton Smith and Geoffrey Neale and Burchard, {Esteban G.} and Torgerson, {Dara G.} and Klussmann, {Federico Antillon} and Villagran, {Cesar Rolando Najera} and Winick, {Naomi J.} and Camitta, {Bruce M.} and Elizabeth Raetz and Brent Wood and Feng Yue and Carroll, {William L.} and Eric Larsen and Bowman, {W. Paul} and Loh, {Mignon L.} and Michael Dean and Deepa Bhojwani and Pui, {Ching Hon} and Evans, {William E.} and Relling, {Mary V.} and Hunger, {Stephen P.} and Willman, {Cheryl L.} and Mullighan, {Charles G.} and Yang, {Jun J.}",

note = "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{\textquoteright}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{\textquoteright}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{\textquoteright}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.",

year = "2013",

month = dec,

doi = "10.1038/ng.2803",

language = "English (US)",

volume = "45",

pages = "1494--1498",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

Perez-Andreu, V, Roberts, KG, Harvey, RC, Yang, W, Cheng, C, Pei, D, Xu, H, Gastier-Foster, J, Shuyu, E, Lim, JYS, Chen, IM, Fan, Y, Devidas, M, Borowitz, MJ, Smith, C, Neale, G, Burchard, EG, Torgerson, DG, Klussmann, FA, Villagran, CRN, Winick, NJ, Camitta, BM, Raetz, E, Wood, B, Yue, F, Carroll, WL, Larsen, E, Bowman, WP, Loh, ML, Dean, M, Bhojwani, D, Pui, CH, Evans, WE, Relling, MV, Hunger, SP, Willman, CL, Mullighan, CG & Yang, JJ 2013, 'Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse', Nature Genetics, vol. 45, no. 12, pp. 1494-1498. https://doi.org/10.1038/ng.2803

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

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AN - SCOPUS:84888311432

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VL - 45

SP - 1494

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JO - Nature Genetics

JF - Nature Genetics

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ER -

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

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