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

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

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Odds Ratio
Philadelphia Chromosome
Gene Rearrangement
Sequence Deletion
Genome-Wide Association Study
Single Nucleotide Polymorphism
Alleles
Genotype

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Perez-Andreu, V., Roberts, K. G., Harvey, R. C., Yang, W., Cheng, C., Pei, D., ... 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
Perez-Andreu, Virginia ; Roberts, Kathryn G. ; Harvey, Richard C. ; Yang, Wenjian ; Cheng, Cheng ; Pei, Deqing ; Xu, Heng ; Gastier-Foster, Julie ; Shuyu, E. ; 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. / Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. In: Nature Genetics. 2013 ; Vol. 45, No. 12. pp. 1494-1498.
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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.}",
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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

Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. / Perez-Andreu, Virginia; Roberts, Kathryn G.; Harvey, Richard C.; Yang, Wenjian; Cheng, Cheng; Pei, Deqing; Xu, Heng; Gastier-Foster, Julie; Shuyu, E.; 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, Vol. 45, No. 12, 01.12.2013, p. 1494-1498.

Research output: Contribution to journalArticle

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.

PY - 2013/12/1

Y1 - 2013/12/1

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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JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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