Association of the ABCG2 C421A polymorphism with prostate cancer risk and survival.
Association of the ABCG2 C421A polymorphism with prostate cancer risk and survival.
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DOI：
10.1111/j.1464-410x.2008.07913.x
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发表时间：
2008-12
影响因子：
4.5
通讯作者：
Figg WD
中科院分区：
文献类型：
--
作者：
Gardner ER;Ahlers CM;Shukla S;Sissung TM;Ockers SB;Price DK;Hamada A;Robey RW;Steinberg SM;Ambudkar SV;Dahut WL;Figg WD
确定ATP结合盒转运蛋白ABCG 2中的C421 A单核苷酸多态性（SNP）是否增加前列腺癌风险或影响生存。许多研究表明，饮食、激素和环境因素都在前列腺癌的发生中起作用;其中，致癌的杂环胺2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP）是ABCG 2的已知底物。ABCG 2的SNP C421 A导致氨基酸141处谷氨酰胺变为赖氨酸，已显示导致蛋白质功能降低。由于ABCG 2在前列腺中的表达，以及饮食致癌物和类固醇在前列腺癌的发展和进展中的作用，311名个体被基因分型为ABCG 2 C421 A SNP，170名雄激素非依赖性前列腺癌（AIPC）患者和141名“健康”对照。我们还评估了这种SNP对PhIP和睾酮在体外细胞内积累的影响。在该人群中，基于ABCG 2遗传变异的前列腺癌患病率无显著差异。然而，与C421 A SNP杂合子或纯合子相比，野生型ABCG 2个体的生存期显著延长（7.4年vs 5.3年，P = 0.044）。在用Q141 K ABCG 2转染的HEK 293细胞中，PhIP的细胞内积累比野生型细胞高80%，证实该SNP降低了PhIP的转运。相反，睾酮不被野生型或变体转染细胞转运，也不作为ABCG 2的抑制剂在随后的转运试验中起作用。
To determine if the C421A single nucleotide polymorphism (SNP) in the ATP-binding cassette transporter ABCG2 increases prostate cancer risk or affects survival. Numerous studies have suggested that dietary, hormonal and environmental factors all play a role in the initiation in prostate cancer; among these, the carcinogenic heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a known substrate of the ABCG2. A SNP of ABCG2, C421A, resulting in a glutamine to lysine change at amino acid 141, has been shown to result in decreased function of the protein. Due to the expression of ABCG2 in the prostate, together with the purported role of dietary carcinogens and steroids in the development and progression of prostate cancer, 311 individuals were genotyped for the ABCG2 C421A SNP, 170 patients with androgen-independent prostate cancer (AIPC) and 141 ‘healthy’ controls. We also evaluated the effect of this SNP on the intracellular accumulation of PhIP and testosterone in vitro. There were no significant differences in the prevalence of prostate cancer based on ABCG2 genetic variation in this population. However, survival was significantly longer for individuals with wild-type ABCG2, as compared with those hetero- or homozygous for the C421A SNP (7.4 years vs 5.3 years, P = 0.044). Intracellular accumulation of PhIP was 80% higher in HEK293 cells transfected with Q141K ABCG2 than in wild-type cells, confirming that this SNP decreases transport of PhIP. In contrast, testosterone was not transported by either wild-type or variant transfected cells, nor did it act as in inhibitor of ABCG2 in subsequent transport assays.