Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia.
The FAS (TNFRSF6/CD95/APO-1) gene is silenced in many tumor types, resulting in an inability to respond to proapoptotic signals. The FAS promoter is polymorphic, including a G to A substitution at -1377 bp and an A to G substitution at -670 bp, which occur within SP1 and signal transducers and activators of transcription 1 transcription factor binding sites, respectively. In a case-control study of adult acute myeloid leukemia (AML), we show a significantly increased risk of AML associated with heterozygotes (GA) and homozygote variants (AA) at position -1377 bp (32.3% in cases versus 22.0% in controls; odds ratio, 1.69; 95% confidence interval, 1.32-2.16). Extended haplotype analysis revealed that the -1377A/-670A haplotype was significantly associated with disease (3% versus 0.5%; odds ratio, 6.72; 95% confidence interval, 3.13-14.51). These data suggest that variation in the FAS gene promoter may affect FAS gene expression and modulate apoptotic signaling, contributing to an increased risk of AML.
Sibley
Kathryn
K
Leukaemia Research Fund, Epidemiology and Genetics Unit, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom. k.sibley@lrf.leeds.ac.uk
Rollinson
Sara
S
Allan
James M
JM
Smith
Alexandra G
AG
Law
Graham R
GR
Roddam
Philippa L
PL
Skibola
Christine F
CF
Smith
Martyn T
MT
Morgan
Gareth J
GJ
D000208:Acute Disease; D000328:Adult; D000483:Alleles; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D019014:fas Receptor / Q000235:genetics*
D004273:DNA, Neoplasm; D019014:fas Receptor