FAS Promoter Polymorphism: Etiology and Outcome of Childhood Acute Myeloid Leukemia

FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine (G→A) transition in the FAS promoter region (position –1377) is thought to reduce stimulatory protein 1 (SP1) transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. We hypothesized that FAS genotype would also increase risk of childhood AML and, by altering susceptibility to apoptosis might also impact outcome of AML therapy. 440 children treated for de novo AML on a uniform protocol were genotyped for FAS 1377. Similar to adult AML data, genotype frequencies in our study were significantly different between white patients and white controls, suggesting that the variant allele at this site increases susceptibility to developing childhood AML. There were no significant differences in overall survival (OS), event-free survival (EFS), treatment-related mortality (TRM), or relapse rate between patients with FAS 1377GG genotype vs. 1377GA/1377AA genotypes. There was a trend towards improved OS and EFS in children homozygous for the variant genotype (AA cases) but small numbers (n=12 AA) make interpretation of this observation difficult.