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Lookup NU author(s): Professor James Allan
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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 (P-enrich = .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. (Blood. 2009; 113: 5575-5582)
Author(s): Knight JA, Skol AD, Shinde A, Hastings D, Walgren RA, Shao J, Tennant TR, Banerjee M, Allan JM, Le Beau MM, Larson RA, Graubert TA, Cox NJ, Onel K
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2009
Volume: 113
Issue: 22
Pages: 5575-5582
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: http://dx.doi.org/10.1182/blood-2008-10-183244
DOI: 10.1182/blood-2008-10-183244
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