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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4752-4758. Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-11-4544. This Article Full Text (PDF) All Versions of this Article: 2004-11-4544v1 105/12/4752    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rocha, J. C Articles by Relling, M. V Search for Related Content PubMed PubMed Citation Articles by Rocha, J. C Articles by Relling, M. V Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 2, 2004 Accepted February 3, 2005 Pharmacogenetics of outcome in children with acute lymphoblastic leukemia Jose C Rocha, Cheng Cheng, Wei Liu, Shinji Kishi, Soma Das, Edwin H Cook, John T Sandlund, Jeffrey Rubnitz, Raul Ribeiro, Dario Campana, Ching-Hon Pui, William E Evans, and Mary V Relling* Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA Hematologic Malignancies Program, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA Department of Psychiatry, Pediatrics, and Human Genetics, University of Chicago, Chicago, IL, USA Hematologic Malignancies Program, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennessee, Memphis, TN, USA Hematologic Malignancies Program, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennessee, Memphis, TN, USA * Corresponding author; email: mary.relling{at}stjude.org. Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germline genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St. Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematological relapse (P = 0.03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = 0.03). These genotypes were also predictive in multivariate analyses (P = 0.0002 and 0.0031, respectively). No genotypes were predictive in the LR arm. Expression of these two genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = 0.02) and intron 8 genotypes (P = 0.04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = 0.04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome, and represent determinants of response that can be used to optimize therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Toward individualized dosing in pediatric ALL Michel Zwaan Blood 2005 105: 4544-4545. [Full Text] [PDF] This article has been cited by other articles: A. Ongaro, M. De Mattei, M. G. Della Porta, G. Rigolin, C. Ambrosio, F. Di Raimondo, A. Pellati, F. F. Masieri, A. Caruso, L. Catozzi, et al. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival Haematologica, October 1, 2009; 94(10): 1391 - 1398. [Abstract] [Full Text] [PDF] M. Ansari, G. Sauty, M. Labuda, V. Gagne, C. Laverdiere, A. Moghrabi, D. Sinnett, and M. Krajinovic Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia Blood, August 13, 2009; 114(7): 1383 - 1386. [Abstract] [Full Text] [PDF] J. J. Yang, C. Cheng, W. Yang, D. Pei, X. Cao, Y. Fan, S. B. Pounds, G. Neale, L. R. Trevino, D. French, et al. Genome-wide Interrogation of Germline Genetic Variation Associated With Treatment Response in Childhood Acute Lymphoblastic Leukemia JAMA, January 28, 2009; 301(4): 393 - 403. [Abstract] [Full Text] [PDF] N. Barahmani, S. Carpentieri, X.-N. Li, T. Wang, Y. Cao, L. Howe, L. Kilburn, M. Chintagumpala, C. Lau, and M. F. Okcu Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma Neuro-oncol, January 1, 2009; 11(3): 292 - 300. [Abstract] [Full Text] [PDF] S. Dulucq, G. St-Onge, V. Gagne, M. Ansari, D. Sinnett, D. Labuda, A. Moghrabi, and M. Krajinovic DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL Blood, April 1, 2008; 111(7): 3692 - 3700. [Abstract] [Full Text] [PDF] S. M. Davies, M. J. Borowitz, G. L. Rosner, K. Ritz, M. Devidas, N. Winick, P. L. Martin, P. Bowman, J. Elliott, C. Willman, et al. Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group Blood, March 15, 2008; 111(6): 2984 - 2990. [Abstract] [Full Text] [PDF] D. Campana Molecular Determinants of Treatment Response in Acute Lymphoblastic Leukemia Hematology, January 1, 2008; 2008(1): 366 - 373. [Abstract] [Full Text] [PDF] G. J.L. 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