A novel XPF −357A>C polymorphism predicts risk and recurrence of bladder cancer
A novel XPF −357A>C polymorphism predicts risk and recurrence of bladder cancer
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DOI：
10.1038/onc.2009.484
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发表时间：
2010-04
期刊：
影响因子：
8
通讯作者：
M. Wang;L. Yuan;D. Wu;Z. Zhang;C. Yin;G. Fu;Q. Wei
中科院分区：
文献类型：
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作者：
M. Wang;L. Yuan;D. Wu;Z. Zhang;C. Yin;G. Fu;Q. Wei
着色性干皮病F组（XPF）在核苷酸切除修复途径中具有重要作用，该途径可去除各种DNA损伤。我们假设XPF的遗传变异与膀胱癌的风险和复发相关。我们从中国人的HapMap数据库中选择了三个标记单核苷酸多态性（tagSNP），并在两阶段病例对照研究中对它们进行基因分型，以评估其相关性，并进一步检查启动子中新型多态性的功能。两阶段分析发现，XPF内含子1中的rs744154 tagSNP与启动子区的-357 A> C多态性连锁不平衡，与膀胱癌风险的保护作用相关。电泳迁移率变动分析（EMSA）进一步揭示，-357C等位基因降低转录因子的结合能力的XPF启动子。含有-357C等位基因的载体构建体具有比-357A等位基因更低的荧光素酶表达。转录因子结合位点的-357C等位基因也与膀胱癌组织中XPF mRNA和蛋白表达水平的降低相关。此外，携带-357C等位基因的患者总体无复发生存期短于携带-357A等位基因的患者。本研究结果提示XPF启动子-357A> C多态性可能通过调节XPF的表达而影响膀胱癌的易感性和预后。需要对不同人群进行更大规模的研究来证实这些发现。
Xeroderma pigmentosum group F (XPF) has an essential role in the nucleotide excision repair pathway that removes a wide variety of DNA lesions. We hypothesized that genetic variants in XPF are associated with bladder cancer risk and recurrence. We selected three tagging single nucleotide polymorphisms (tagSNPs) from the HapMap database for the Chinese and genotyped them in a two-stage case–control study to evaluate the association and further examined the functionality of a novel polymorphism in the promoter. The two-stage analysis found that the rs744154 tagSNP in the XPF intron 1, which was linkage disequilibrium with the–357A> C polymorphism in the promoter region, was associated with a protective effect on bladder cancer risk. Electrophoretic mobility shift assay (EMSA) further revealed that the–357C allele decreased the binding ability of transcriptional factors to the XPF promoter. The vector construct containing the–357C allele had a lower luciferase expression than did the–357A allele. The–357C allele in the transcription factor-binding site was also associated with decreased expression levels of both XPF mRNA and protein in bladder cancer tissues. Furthermore, patients with the–357C allele had a shorter overall recurrence-free survival than did patients with the–357A allele. Our results suggest that the XPF promoter–357A> C polymorphism may regulate the expression of XPF and thereby contribute to susceptibility to and prognosis of bladder cancer. Further larger studies with different populations are warranted to confirm these findings.