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Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility

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)

Publication metadata

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


DOI: 10.1182/blood-2008-10-183244


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Funder referenceFunder name
Barnes Jewish Hospital Foundation (St Louis)
Bear Necessities Pediatric Cancer Foundation (Chicago, IL)
Leukaemia Research (London, United Kingdom)
CA101937National Institutes of Health (Bethesda)
CA40046National Institutes of Health (Bethesda)
CA14599National Institutes of Health (Bethesda)
HD0433871National Institutes of Health (Bethesda)
HL007088National Institutes of Health (Bethesda)