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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5575-5582. Prepublished online as a Blood First Edition Paper on March 18, 2009; DOI 10.1182/blood-2008-10-183244. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2008-10-183244v1 113/22/5575    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Knight, J. A. Articles by Onel, K. PubMed PubMed Citation Articles by Knight, J. A. Articles by Onel, K. Related Collections Myeloid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility Jeffrey A. Knight1,*, Andrew D. Skol2,*, Abhijit Shinde2, Darcie Hastings3, Richard A. Walgren4, Jin Shao4, Thelma R. Tennant2, Mekhala Banerjee2, James M. Allan5, Michelle M. Le Beau1,2,6, Richard A. Larson2,6, Timothy A. Graubert4, Nancy J. Cox1,2,6, and Kenan Onel1,3,6 1 Committee on Cancer Biology, 2 Department of Medicine, and 3 Department of Pediatrics, University of Chicago, IL; 4 Department of Medicine, Washington University School of Medicine, St Louis, MO; 5 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; and 6 University of Chicago Cancer Research Center, IL Therapy-related acute myeloid leukemia (t-AML) is a rare but fatal complication of cytotoxic therapy. Whereas sporadic cancer results from interactions between complex exposures and low-penetrance alleles, t-AML results from an acute exposure to a limited number of potent genotoxins. Consequently, we hypothesized that the effect sizes of variants associated with t-AML would be greater than in sporadic cancer, and, therefore, that these variants could be detected even in a modest-sized cohort. To test this, we undertook an association study in 80 cases and 150 controls using Affymetrix Mapping 10K arrays. Even at nominal significance thresholds, we found a significant excess of associations over chance; for example, although 6 associations were expected at P less than .001, we found 15 (Penrich = .002). To replicate our findings, we genotyped the 10 most significantly associated single nucleotide polymorphisms (SNPs) in an independent t-AML cohort (n = 70) and obtained evidence of association with t-AML for 3 SNPs in the subset of patients with loss of chromosomes 5 or 7 or both, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Thus, we conclude that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in t-AML compared with sporadic cancer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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