Loss of blood group A antigen expression in bladder cancer caused by allelic loss and/or methylation of the ABO gene
Loss of blood group A antigen expression in bladder cancer caused by allelic loss and/or methylation of the ABO gene
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DOI：
10.1038/labinvest.3700268
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发表时间：
2005-07-01
影响因子：
5
通讯作者：
Hirao, Y
中科院分区：
文献类型：
--
作者：
Chihara, Y;Sugano, K;Hirao, Y
据报道，膀胱移行细胞癌 (TCC) 中 ABO 血型抗原表达缺失。 ABO 血型抗原的合成由分配在 9q34.1 上的 ABO 基因的等位基因变体遗传决定。我们分析了 TCC 中 ABO 基因的杂合性丢失 (LOH) 和启动子高甲基化，并将其与 TCC、不典型增生和正常尿路上皮中 A 抗原表达的改变进行比较。对经尿道切除术 (TUR) (n = 44) 和根治性膀胱切除术 (n = 37) 获得的总共 81 个膀胱 TCC 样本进行了检查。使用抗A抗原单克隆抗体通过免疫组织化学染色(IHC)评估A抗原的表达。使用基于荧光的自动测序仪通过平端单链 DNA 构象多态性 (SSCP) 分析检查 ABO 基因位点的 LOH。通过亚硫酸氢盐 PCR-SSCP (BiPS) 分析和/或甲基化特异性 PCR (MSP) 检查 ABO 基因的启动子高甲基化。在接受 TUR (P = 0.02) 和根治性膀胱切除术 (P = 0.0005) 的病例中，A 等位基因的缺失和/或高甲基化与 A 抗原的异常表达显着相关。对于 23 例膀胱 TCC 伴发不典型增生的分析，无论肿瘤中 A 等位基因缺失或甲基化状态如何，A 抗原的表达均得以维持。总之，ABO基因启动子区的A等位基因缺失和高甲基化与TCC中A抗原表达的减少显着相关，而在伴发的不典型增生或正常尿路上皮中A抗原的表达得以维持，表明ABO基因的缺失和/或其启动子高甲基化是TCC的特异性标志物。
Loss of ABO blood group antigen expression has been reported in transitional cell carcinoma ( TCC) of the bladder. Synthesis of the ABO blood group antigen was genetically determined by allelic variants of the ABO gene assigned on 9q34.1. We analyzed loss of heterozygosity ( LOH) and promoter hypermethylation of the ABO gene in TCC and compared them with alterations of A antigen expression in TCC, dysplasia and normal urothelium. A total of 81 samples of TCC of the bladder obtained from transurethral resection ( TUR) ( n = 44) and radical cystectomy ( n = 37) were examined. Expression of the A antigen was evaluated by immunohistochemical staining ( IHC) using anti-A antigen monoclonal antibody. LOH of the ABO gene locus was examined by blunt-end single-strand DNA conformational polymorphism ( SSCP) analysis using flouresence-based auto sequencer. Promoter hypermethylation of the ABO gene were examined by bisulfite PCR-SSCP ( BiPS) analysis and/or methylation-specific PCR ( MSP). Loss of A allele and/or hypermethylation were significantly associated with abnormal expression of the A antigen in cases undergoing TUR ( P = 0.02) and radical cystectomy ( P = 0.0005). For the analysis of the concomitant dysplasia in 23 cases with TCC of the bladder, the expression of the A antigen was maintained, regardless of the A allelic loss or methylation status in the tumor. In conclusion, A allelic loss and hypermethylation in the promoter region of the ABO gene showed significant correlation with reduction of A antigen expression in TCC, while the expression of the A antigen is maintained in concomitant dysplasia or normal urothelium, suggesting that loss of the ABO gene and/or its promoter hypermethylation is a specific marker for TCC.