Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

被引：168

作者：

Reinert, Thomas ^{[1
]}

Modin, Charlotte ^{[1
]}

Castano, Francisco M. ^{[1
]}

Lamy, Philippe ^{[1
]}

Wojdacz, Tomasz K. ^{[4
]}

Hansen, Lise Lotte ^{[4
]}

Wiuf, Carsten ^{[3
]}

Borre, Michael ^{[2
]}

Dyrskjot, Lars ^{[1
]}

Orntoft, Torben F. ^{[1
]}

机构：

[1] Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus N, Denmark

[2] Aarhus Univ Hosp, Dept Urol, DK-8200 Aarhus N, Denmark

[3] Univ Aarhus, Bioinformat Res Ctr BiRC, Aarhus C, Denmark

[4] Univ Aarhus, Inst Human Genet, Aarhus C, Denmark

来源：

CLINICAL CANCER RESEARCH | 2011年 / 17卷 / 17期

关键词：

DNA METHYLATION; PROMOTER HYPERMETHYLATION; EPIGENETIC INACTIVATION; MULTIPLE GENES; CPG-ISLANDS; PROGRESSION; ASSOCIATION; EXPRESSION; GRADE; RISK;

D O I：

10.1158/1078-0432.CCR-10-2659

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Epigenetic alterations are common and can now be addressed in a parallel fashion. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers. Experimental Design: A microarray assay was utilized to analyze methylation in 56 samples. Independent validation was conducted in 63 samples by a PCR-based method and bisulfite sequencing. The methylation levels in 174 urine specimens were quantified. Transcript levels were analyzed using expression microarrays and pathways were analyzed using dedicated software. Results: Global methylation patterns were established within and outside CpG islands. We validated methylation of the eight tumor markers genes ZNF154 (P < 0.0001), HOXA9 (P < 0.0001), POU4F2 (P < 0.0001), EOMES (P = 0.0005), ACOT11 (P = 0.0001), PCDHGA12 (P = 0.0001), CA3 (P = 0.0002), and PTGDR (P = 0.0110), the candidate marker of disease progression TBX4 (P < 0.04), and other genes with stage-specific methylation. The methylation of metachronous tumors was stable and targeted to certain pathways. The correlation to expression was not stringent. Chromosome 21 showed most differential methylation (P < 0.0001) and specifically hypomethylation of keratins, which together with keratin-like proteins were epigenetically regulated. In DNA from voided urine, we detected differential methylation of ZNF154 (P < 0.0001), POU4F2 (P < 0.0001), HOXA9 (P < 0.0001), and EOMES (P < 0.0001), achieving 84% sensitivity and 96% specificity. Conclusions: We initiated a detailed mapping of the methylome in metachronous bladder cancer. Novel genes with tumor, chromosome, as well as pathway-specific differential methylation in bladder cancer were identified. The methylated genes were promising cancer markers for early detection of bladder cancer. Clin Cancer Res; 17(17); 5582-92. (C)2011 AACR.

引用

页码：5582 / 5592

页数：11

共 49 条

[21] Promoter Hypermethylation in Tumour Suppressor Genes Shows Association with Stage, Grade and Invasiveness of Bladder Cancer [J].