Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility.
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.
Knight
Jeffrey A
JA
Committee on Cancer Biology, University of Chicago, IL 60637, USA.
Skol
Andrew D
AD
Shinde
Abhijit
A
Hastings
Darcie
D
Walgren
Richard A
RA
Shao
Jin
J
Tennant
Thelma R
TR
Banerjee
Mekhala
M
Allan
James M
JM
Le Beau
Michelle M
MM
Larson
Richard A
RA
Graubert
Timothy A
TA
Cox
Nancy J
NJ
Onel
Kenan
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000209:etiology; D055106:Genome-Wide Association Study; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D055815:Young Adult