Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

Shawn H.R. Lee; Maoxiang Qian; Wentao Yang; Jonathan D. Diedrich; Elizabeth Raetz; Wenjian Yang; Qian Dong; Meenakshi Devidas; Deqing Pei; Allen Yeoh; Cheng Cheng; Ching Hon Pui; William E. Evans; Charles G. Mullighan; Stephen P. Hunger; Daniel Savic; Mary V. Relling; Mignon L. Loh; Jun J. Yang

doi:10.1093/jnci/djaa133

Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

Shawn H.R. Lee, Maoxiang Qian, Wentao Yang, Jonathan D. Diedrich, Elizabeth Raetz, Wenjian Yang, Qian Dong, Meenakshi Devidas, Deqing Pei, Allen Yeoh, Cheng Cheng, Ching Hon Pui, William E. Evans, Charles G. Mullighan, Stephen P. Hunger, Daniel Savic, Mary V. Relling, Mignon L. Loh, Jun J. Yang

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12 Scopus citations

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

Original language	English
Pages (from-to)	933-937
Number of pages	5
Journal	Journal of the National Cancer Institute
Volume	113
Issue number	7
DOIs	https://doi.org/10.1093/jnci/djaa133
State	Published - 1 Jul 2021
Externally published	Yes

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Lee, S. H. R., Qian, M., Yang, W., Diedrich, J. D., Raetz, E., Yang, W., Dong, Q., Devidas, M., Pei, D., Yeoh, A., Cheng, C., Pui, C. H., Evans, W. E., Mullighan, C. G., Hunger, S. P., Savic, D., Relling, M. V., Loh, M. L., & Yang, J. J. (2021). Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children. Journal of the National Cancer Institute, 113(7), 933-937. https://doi.org/10.1093/jnci/djaa133

@article{5dff3312a509496ea1fbe17d4cdede71,

title = "Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children",

abstract = "Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.",

author = "Lee, {Shawn H.R.} and Maoxiang Qian and Wentao Yang and Diedrich, {Jonathan D.} and Elizabeth Raetz and Wenjian Yang and Qian Dong and Meenakshi Devidas and Deqing Pei and Allen Yeoh and Cheng Cheng and Pui, {Ching Hon} and Evans, {William E.} and Mullighan, {Charles G.} and Hunger, {Stephen P.} and Daniel Savic and Relling, {Mary V.} and Loh, {Mignon L.} and Yang, {Jun J.}",

year = "2021",

month = jul,

day = "1",

doi = "10.1093/jnci/djaa133",

language = "English",

volume = "113",

pages = "933--937",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

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Lee, SHR, Qian, M, Yang, W, Diedrich, JD, Raetz, E, Yang, W, Dong, Q, Devidas, M, Pei, D, Yeoh, A, Cheng, C, Pui, CH, Evans, WE, Mullighan, CG, Hunger, SP, Savic, D, Relling, MV, Loh, ML & Yang, JJ 2021, 'Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children', Journal of the National Cancer Institute, vol. 113, no. 7, pp. 933-937. https://doi.org/10.1093/jnci/djaa133

TY - JOUR

T1 - Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

AU - Lee, Shawn H.R.

AU - Qian, Maoxiang

AU - Yang, Wentao

AU - Diedrich, Jonathan D.

AU - Raetz, Elizabeth

AU - Yang, Wenjian

AU - Dong, Qian

AU - Devidas, Meenakshi

AU - Pei, Deqing

AU - Yeoh, Allen

AU - Cheng, Cheng

AU - Pui, Ching Hon

AU - Evans, William E.

AU - Mullighan, Charles G.

AU - Hunger, Stephen P.

AU - Savic, Daniel

AU - Relling, Mary V.

AU - Loh, Mignon L.

AU - Yang, Jun J.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

AB - Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

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U2 - 10.1093/jnci/djaa133

DO - 10.1093/jnci/djaa133

M3 - Article

C2 - 32882024

AN - SCOPUS:85109920535

SN - 0027-8874

VL - 113

SP - 933

EP - 937

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 7

ER -

Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

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