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Blood, 1 August 2008, Vol. 112, No. 3, pp. 741-749. Prepublished online as a Blood First Edition Paper on April 21, 2008; DOI 10.1182/blood-2007-11-126508. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2007-11-126508v1 112/3/741    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 Ellis, N. A Articles by Onel, K. Search for Related Content PubMed PubMed Citation Articles by Ellis, N. A Articles by Onel, K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 29, 2007 Accepted March 28, 2008 MDM2 SNP309 and TP53 Arg72Pro interact to alter therapy-related acute myeloid leukemia susceptibility Nathan A Ellis, Dezheng Huo, Ozlem Yildiz, Lisa J Worrillow, Mekhala Banerjee, Michelle M Le Beau, Richard A Larson, James M Allan, and Kenan Onel* Department of Medicine, University of Chicago, Chicago, IL, United States Department of Health Studies, University of Chicago, Chicago, IL, United States Section of Hematology/Oncology, Department of Pediatrics, University of Chicago, Chicago, IL, United States Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom University of Chicago Cancer Research Center, University of Chicago, Chicago, IL, United States * Corresponding author; email: konel{at}uchicago.edu. The p53 tumor suppressor directs the cellular response to many mechanistically distinct DNA damaging agents and is selected against during the pathogenesis of therapy-related acute myeloid leukemia (t-AML). We hypothesized that constitutional genetic variation in the p53 pathway would affect t-AML risk. Therefore, we tested associations between patients with t-AML (n=171) and two common functional p53-pathway variants, the MDM2 SNP309 and the TP53 codon 72 polymorphism. Although neither polymorphism alone influenced the risk of t-AML, an interactive effect was detected such that MDM2 TT TP53 Arg/Arg double homozygotes, and individuals carrying both a MDM2 G allele and a TP53 Pro allele were at increased risk of t-AML (p for interaction=0.009). This interactive effect was observed in patients previously treated with chemotherapy but not in patients treated with radiotherapy, and in patients with loss of chromosomes 5 and/or 7, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Additionally, there was a trend towards shorter latency to t-AML in MDM2 GG versus TT homozygotes in females but not in males, and in younger but not older patients. These data indicate that the MDM2 and TP53 variants interact to modulate responses to genotoxic therapy and are determinants of risk for t-AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Taking a SNPshot of t-AML Jane Liesveld Blood 2008 112: 458-459. [Full Text] [PDF] This article has been cited by other articles: J. A. Knight, A. D. Skol, A. Shinde, D. Hastings, R. A. Walgren, J. Shao, T. R. Tennant, M. Banerjee, J. M. Allan, M. M. Le Beau, et al. Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility Blood, May 28, 2009; 113(22): 5575 - 5582. [Abstract] [Full Text] [PDF]

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