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

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
Blood. 2009 113 (22): 5575-82

PMID: 19299336 · PMCID: PMC2689055 · DOI:10.1182/blood-2008-10-183244

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.

MeSH Terms (17)

Adolescent Adult Aged Aged, 80 and over Case-Control Studies Cohort Studies Female Genetic Predisposition to Disease Genome-Wide Association Study Humans Leukemia, Myeloid Male Middle Aged Neoplasms, Second Primary Polymorphism, Single Nucleotide Quantitative Trait Loci Young Adult

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