Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia

Jun J. Yang, Cheng, Wenjian Yang, Deqing Pei, Xueyuan Cao, Yiping Fan, Stanley B. Pounds, Geoffrey Neale, Lisa R. Trevino, Deborah French, Dario Campana, James R. Downing, William E. Evans, Ching Hon Pui, Meenakshi Devidas, W. P. Bowman, Bruce M. Camitta, Cheryl L. Willman, Stella M. Davies, Michael J. Borowitz & 3 others William L. Carroll, Stephen P. Hunger, Mary V. Relling

Research output: Contribution to journalArticle

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Abstract

Context Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. Objectives To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. Design, Setting, and Patients Genome-wide interrogation of 476796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. Main Outcome Measures Minimal residual disease at the end of induction therapy, measured by flow cytometry. Results There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P≤ .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P< .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. Conclusion Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.

Original languageEnglish (US)
Pages (from-to)393-403
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume301
Issue number4
DOIs
StatePublished - Jan 28 2009
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Single Nucleotide Polymorphism
Residual Neoplasm
Genome
Pharmaceutical Preparations
Therapeutics
Disease Eradication
Remission Induction
Recurrence
Interleukin-15
Induction Chemotherapy
Cell Biology
Flow Cytometry
Leukemia
Odds Ratio
Genotype
Outcome Assessment (Health Care)
Pediatrics
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. / Yang, Jun J.; Cheng; Yang, Wenjian; Pei, Deqing; Cao, Xueyuan; Fan, Yiping; Pounds, Stanley B.; Neale, Geoffrey; Trevino, Lisa R.; French, Deborah; Campana, Dario; Downing, James R.; Evans, William E.; Pui, Ching Hon; Devidas, Meenakshi; Bowman, W. P.; Camitta, Bruce M.; Willman, Cheryl L.; Davies, Stella M.; Borowitz, Michael J.; Carroll, William L.; Hunger, Stephen P.; Relling, Mary V.

In: JAMA - Journal of the American Medical Association, Vol. 301, No. 4, 28.01.2009, p. 393-403.

Research output: Contribution to journalArticle

Yang, JJ, Cheng, Yang, W, Pei, D, Cao, X, Fan, Y, Pounds, SB, Neale, G, Trevino, LR, French, D, Campana, D, Downing, JR, Evans, WE, Pui, CH, Devidas, M, Bowman, WP, Camitta, BM, Willman, CL, Davies, SM, Borowitz, MJ, Carroll, WL, Hunger, SP & Relling, MV 2009, 'Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia', JAMA - Journal of the American Medical Association, vol. 301, no. 4, pp. 393-403. https://doi.org/10.1001/jama.2009.7
Yang, Jun J. ; Cheng ; Yang, Wenjian ; Pei, Deqing ; Cao, Xueyuan ; Fan, Yiping ; Pounds, Stanley B. ; Neale, Geoffrey ; Trevino, Lisa R. ; French, Deborah ; Campana, Dario ; Downing, James R. ; Evans, William E. ; Pui, Ching Hon ; Devidas, Meenakshi ; Bowman, W. P. ; Camitta, Bruce M. ; Willman, Cheryl L. ; Davies, Stella M. ; Borowitz, Michael J. ; Carroll, William L. ; Hunger, Stephen P. ; Relling, Mary V. / Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. In: JAMA - Journal of the American Medical Association. 2009 ; Vol. 301, No. 4. pp. 393-403.
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abstract = "Context Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80{\%}, considerable unexplained interindividual variability exists in treatment response. Objectives To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. Design, Setting, and Patients Genome-wide interrogation of 476796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. Main Outcome Measures Minimal residual disease at the end of induction therapy, measured by flow cytometry. Results There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P≤ .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P< .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. Conclusion Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.",
author = "Yang, {Jun J.} and Cheng and Wenjian Yang and Deqing Pei and Xueyuan Cao and Yiping Fan and Pounds, {Stanley B.} and Geoffrey Neale and Trevino, {Lisa R.} and Deborah French and Dario Campana and Downing, {James R.} and Evans, {William E.} and Pui, {Ching Hon} and Meenakshi Devidas and Bowman, {W. P.} and Camitta, {Bruce M.} and Willman, {Cheryl L.} and Davies, {Stella M.} and Borowitz, {Michael J.} and Carroll, {William L.} and Hunger, {Stephen P.} and Relling, {Mary V.}",
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T1 - Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia

AU - Yang, Jun J.

AU - Cheng,

AU - Yang, Wenjian

AU - Pei, Deqing

AU - Cao, Xueyuan

AU - Fan, Yiping

AU - Pounds, Stanley B.

AU - Neale, Geoffrey

AU - Trevino, Lisa R.

AU - French, Deborah

AU - Campana, Dario

AU - Downing, James R.

AU - Evans, William E.

AU - Pui, Ching Hon

AU - Devidas, Meenakshi

AU - Bowman, W. P.

AU - Camitta, Bruce M.

AU - Willman, Cheryl L.

AU - Davies, Stella M.

AU - Borowitz, Michael J.

AU - Carroll, William L.

AU - Hunger, Stephen P.

AU - Relling, Mary V.

PY - 2009/1/28

Y1 - 2009/1/28

N2 - Context Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. Objectives To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. Design, Setting, and Patients Genome-wide interrogation of 476796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. Main Outcome Measures Minimal residual disease at the end of induction therapy, measured by flow cytometry. Results There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P≤ .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P< .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. Conclusion Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.

AB - Context Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. Objectives To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. Design, Setting, and Patients Genome-wide interrogation of 476796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. Main Outcome Measures Minimal residual disease at the end of induction therapy, measured by flow cytometry. Results There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P≤ .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P< .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. Conclusion Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.

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U2 - 10.1001/jama.2009.7

DO - 10.1001/jama.2009.7

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JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

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