Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

Virginia Perez-Andreu; Kathryn G. Roberts; Heng Xu; Colton Smith; Hui Zhang; Wenjian Yang; Richard C. Harvey; Debbie Payne-Turner; Meenakshi Devidas; I. Ming Cheng; William L. Carroll; Nyla A. Heerema; Andrew J. Carroll; Elizabeth A. Raetz; Julie M. Gastier-Foster; Guido Marcucci; Clara D. Bloomfield; Krzysztof Mrózek; Jessica Kohlschmidt; Wendy Stock; Steven M. Kornblau; Marina Konopleva; Elisabeth Paietta; Jacob M. Rowe; Selina M. Luger; Martin S. Tallman; Michael Dean; Esteban G. Burchard; Dara G. Torgerson; Feng Yue; Yanli Wang; Ching Hon Pui; Sima Jeha; Mary V. Relling; William E. Evans; Daniela S. Gerhard; Mignon L. Loh; Cheryl L. Willman; Stephen P. Hunger; Charles G. Mullighan; Jun J. Yang

doi:10.1182/blood-2014-09-595744

Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

Virginia Perez-Andreu, Kathryn G. Roberts, Heng Xu, Colton Smith, Hui Zhang, Wenjian Yang, Richard C. Harvey, Debbie Payne-Turner, Meenakshi Devidas, I. Ming Cheng, William L. Carroll, Nyla A. Heerema, Andrew J. Carroll, Elizabeth A. Raetz, Julie M. Gastier-Foster, Guido Marcucci, Clara D. Bloomfield, Krzysztof Mrózek, Jessica Kohlschmidt, Wendy StockSteven M. Kornblau, Marina Konopleva, Elisabeth Paietta, Jacob M. Rowe, Selina M. Luger, Martin S. Tallman, Michael Dean, Esteban G. Burchard, Dara G. Torgerson, Feng Yue, Yanli Wang, Ching Hon Pui, Sima Jeha, Mary V. Relling, William E. Evans, Daniela S. Gerhard, Mignon L. Loh, Cheryl L. Willman, Stephen P. Hunger, Charles G. Mullighan, Jun J. Yang

Oncology

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Abstract

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms(SNPs) in 308AYAALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10^-8 in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10^-10) and rs3781093, OR, 1.73 (P = 3.2 × 10^-9). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10^-11). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

Original language	English (US)
Pages (from-to)	680-686
Number of pages	7
Journal	Blood
Volume	125
Issue number	4
DOIs	https://doi.org/10.1182/blood-2014-09-595744
State	Published - Jan 22 2015

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Perez-Andreu, V., Roberts, K. G., Xu, H., Smith, C., Zhang, H., Yang, W., Harvey, R. C., Payne-Turner, D., Devidas, M., Cheng, I. M., Carroll, W. L., Heerema, N. A., Carroll, A. J., Raetz, E. A., Gastier-Foster, J. M., Marcucci, G., Bloomfield, C. D., Mrózek, K., Kohlschmidt, J., ... Yang, J. J. (2015). Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults. Blood, 125(4), 680-686. https://doi.org/10.1182/blood-2014-09-595744

Perez-Andreu, V, Roberts, KG, Xu, H, Smith, C, Zhang, H, Yang, W, Harvey, RC, Payne-Turner, D, Devidas, M, Cheng, IM, Carroll, WL, Heerema, NA, Carroll, AJ, Raetz, EA, Gastier-Foster, JM, Marcucci, G, Bloomfield, CD, Mrózek, K, Kohlschmidt, J, Stock, W, Kornblau, SM, Konopleva, M , Paietta, E, Rowe, JM, Luger, SM, Tallman, MS, Dean, M, Burchard, EG, Torgerson, DG, Yue, F, Wang, Y, Pui, CH, Jeha, S, Relling, MV, Evans, WE, Gerhard, DS, Loh, ML, Willman, CL, Hunger, SP, Mullighan, CG & Yang, JJ 2015, 'Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults', Blood, vol. 125, no. 4, pp. 680-686. https://doi.org/10.1182/blood-2014-09-595744

@article{957736b226d44e9c94501e76c1ffebed,

title = "Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults",

abstract = "Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms(SNPs) in 308AYAALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10-8 in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10-10) and rs3781093, OR, 1.73 (P = 3.2 × 10-9). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10-11). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.",

author = "Virginia Perez-Andreu and Roberts, {Kathryn G.} and Heng Xu and Colton Smith and Hui Zhang and Wenjian Yang and Harvey, {Richard C.} and Debbie Payne-Turner and Meenakshi Devidas and Cheng, {I. Ming} and Carroll, {William L.} and Heerema, {Nyla A.} and Carroll, {Andrew J.} and Raetz, {Elizabeth A.} and Gastier-Foster, {Julie M.} and Guido Marcucci and Bloomfield, {Clara D.} and Krzysztof Mr{\'o}zek and Jessica Kohlschmidt and Wendy Stock and Kornblau, {Steven M.} and Marina Konopleva and Elisabeth Paietta and Rowe, {Jacob M.} and Luger, {Selina M.} and Tallman, {Martin S.} and Michael Dean and Burchard, {Esteban G.} and Torgerson, {Dara G.} and Feng Yue and Yanli Wang and Pui, {Ching Hon} and Sima Jeha and Relling, {Mary V.} and Evans, {William E.} and Gerhard, {Daniela S.} and Loh, {Mignon L.} and Willman, {Cheryl L.} and Hunger, {Stephen P.} and Mullighan, {Charles G.} and Yang, {Jun J.}",

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month = jan,

day = "22",

doi = "10.1182/blood-2014-09-595744",

language = "English (US)",

volume = "125",

pages = "680--686",

journal = "Blood",

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publisher = "American Society of Hematology",

number = "4",

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T1 - Lymphoid neoplasia

T2 - A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

AU - Perez-Andreu, Virginia

AU - Roberts, Kathryn G.

AU - Xu, Heng

AU - Smith, Colton

AU - Zhang, Hui

AU - Yang, Wenjian

AU - Harvey, Richard C.

AU - Payne-Turner, Debbie

AU - Devidas, Meenakshi

AU - Cheng, I. Ming

AU - Carroll, William L.

AU - Heerema, Nyla A.

AU - Carroll, Andrew J.

AU - Raetz, Elizabeth A.

AU - Gastier-Foster, Julie M.

AU - Marcucci, Guido

AU - Bloomfield, Clara D.

AU - Mrózek, Krzysztof

AU - Kohlschmidt, Jessica

AU - Stock, Wendy

AU - Kornblau, Steven M.

AU - Konopleva, Marina

AU - Paietta, Elisabeth

AU - Rowe, Jacob M.

AU - Luger, Selina M.

AU - Tallman, Martin S.

AU - Dean, Michael

AU - Burchard, Esteban G.

AU - Torgerson, Dara G.

AU - Yue, Feng

AU - Wang, Yanli

AU - Pui, Ching Hon

AU - Jeha, Sima

AU - Relling, Mary V.

AU - Evans, William E.

AU - Gerhard, Daniela S.

AU - Loh, Mignon L.

AU - Willman, Cheryl L.

AU - Hunger, Stephen P.

AU - Mullighan, Charles G.

AU - Yang, Jun J.

PY - 2015/1/22

Y1 - 2015/1/22

N2 - Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms(SNPs) in 308AYAALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10-8 in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10-10) and rs3781093, OR, 1.73 (P = 3.2 × 10-9). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10-11). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

AB - Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms(SNPs) in 308AYAALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10-8 in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10-10) and rs3781093, OR, 1.73 (P = 3.2 × 10-9). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10-11). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

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Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

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