功能性FAS启动子多态性与急性髓系白血病风险增加相关。

Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia.

作者信息

Sibley Kathryn, Rollinson Sara, Allan James M, Smith Alexandra G, Law Graham R, Roddam Philippa L, Skibola Christine F, Smith Martyn T, Morgan Gareth J

机构信息

Leukaemia Research Fund, Epidemiology and Genetics Unit, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.

出版信息

Cancer Res. 2003 Aug 1;63(15):4327-30.

PMID:12907599

Abstract

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.

摘要

FAS（TNFRSF6/CD95/APO-1）基因在许多肿瘤类型中沉默，导致无法对促凋亡信号作出反应。FAS启动子具有多态性，包括在-1377 bp处由G到A的替换以及在-670 bp处由A到G的替换，它们分别发生在SP1以及信号转导和转录激活因子1转录因子结合位点内。在一项针对成人急性髓系白血病（AML）的病例对照研究中，我们发现-1377 bp处杂合子（GA）和纯合子变体（AA）与AML风险显著增加相关（病例组为32.3%，对照组为22.0%；比值比为1.69；95%置信区间为1.32 - 2.16）。扩展单倍型分析显示，-1377A/-670A单倍型与疾病显著相关（3%对0.5%；比值比为6.72；95%置信区间为3.13 - 14.51）。这些数据表明，FAS基因启动子的变异可能影响FAS基因表达并调节凋亡信号传导，从而增加AML的风险。