Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia

Jun J. Yang, Cheng Cheng, Meenakshi Devidas, Xueyuan Cao, Dario Campana, Wenjian Yang, Yiping Fan, Geoff Neale, Nancy Cox, Paul Scheet, Michael J. Borowitz, Naomi J. Winick, Paul L. Martin, W. Paul Bowman, Bruce Camitta, Gregory H. Reaman, William L. Carroll, Cheryl L. Willman, Stephen P. Hunger, William E. Evans & 3 others Ching Hon Pui, Mignon Loh, Mary V. Relling

Research output: Contribution to journalArticle

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Abstract

With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 × 10 -9). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host disposition of antileukemic drugs.

Original languageEnglish (US)
Pages (from-to)4197-4204
Number of pages8
JournalBlood
Volume120
Issue number20
DOIs
StatePublished - Nov 15 2012

Fingerprint

Genome-Wide Association Study
Polymorphism
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genes
Recurrence
Nucleotides
Single Nucleotide Polymorphism
Residual Neoplasm
Pharmacodynamics
Pharmacokinetics
Alleles
Remission Induction
Pharmaceutical Preparations
Therapeutics
Genotype
Genome

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Yang, J. J., Cheng, C., Devidas, M., Cao, X., Campana, D., Yang, W., ... Relling, M. V. (2012). Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia. Blood, 120(20), 4197-4204. https://doi.org/10.1182/blood-2012-07-440107

Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia. / Yang, Jun J.; Cheng, Cheng; Devidas, Meenakshi; Cao, Xueyuan; Campana, Dario; Yang, Wenjian; Fan, Yiping; Neale, Geoff; Cox, Nancy; Scheet, Paul; Borowitz, Michael J.; Winick, Naomi J.; Martin, Paul L.; Bowman, W. Paul; Camitta, Bruce; Reaman, Gregory H.; Carroll, William L.; Willman, Cheryl L.; Hunger, Stephen P.; Evans, William E.; Pui, Ching Hon; Loh, Mignon; Relling, Mary V.

In: Blood, Vol. 120, No. 20, 15.11.2012, p. 4197-4204.

Research output: Contribution to journalArticle

Yang, JJ, Cheng, C, Devidas, M, Cao, X, Campana, D, Yang, W, Fan, Y, Neale, G, Cox, N, Scheet, P, Borowitz, MJ, Winick, NJ, Martin, PL, Bowman, WP, Camitta, B, Reaman, GH, Carroll, WL, Willman, CL, Hunger, SP, Evans, WE, Pui, CH, Loh, M & Relling, MV 2012, 'Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia', Blood, vol. 120, no. 20, pp. 4197-4204. https://doi.org/10.1182/blood-2012-07-440107
Yang, Jun J. ; Cheng, Cheng ; Devidas, Meenakshi ; Cao, Xueyuan ; Campana, Dario ; Yang, Wenjian ; Fan, Yiping ; Neale, Geoff ; Cox, Nancy ; Scheet, Paul ; Borowitz, Michael J. ; Winick, Naomi J. ; Martin, Paul L. ; Bowman, W. Paul ; Camitta, Bruce ; Reaman, Gregory H. ; Carroll, William L. ; Willman, Cheryl L. ; Hunger, Stephen P. ; Evans, William E. ; Pui, Ching Hon ; Loh, Mignon ; Relling, Mary V. / Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia. In: Blood. 2012 ; Vol. 120, No. 20. pp. 4197-4204.
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