环氧化酶-2、视黄酸受体β、内皮素受体B及其他基因位点的CpG岛高甲基化在接受根治性前列腺切除术患者中的预后价值

Prognostic value of CpG island hypermethylation at PTGS2, RAR-beta, EDNRB, and other gene loci in patients undergoing radical prostatectomy.

作者信息

Bastian Patrick J, Ellinger Jörg, Heukamp Lukas C, Kahl Philip, Müller Stefan C, von Rücker Alexander

机构信息

Klinik und Poliklinik für Urologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms Universität Bonn, Germany.

出版信息

Eur Urol. 2007 Mar;51(3):665-74; discussion 674. doi: 10.1016/j.eururo.2006.08.008. Epub 2006 Aug 23.

DOI:10.1016/j.eururo.2006.08.008

PMID:16956712

Abstract

OBJECTIVES

To evaluate CpG island hypermethylation in a set of candidate genes in prostate cancer (pCA) and its relationship to clinicopathologic parameters and a nomogram predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy.

MATERIALS AND METHODS

Tissues of 78 prostate carcinomas, 32 benign prostate hyperplasias (BPHs), and prostate cell lines (LNCaP, DU145, PC3, BPH-1) were examined with MethyLight polymerase chain reaction at 13 gene loci (APC, CDC6, CTNNB1, E-Cadherin, EDNRB, FGFR2, GSTP1, NAB2, PKCmu, PTGS2, RAR-beta, RASL11A, WWOX).

RESULTS

APC, RAR-beta, PTGS2, GSTP1, EDNRB, and CTNNB1 (83%, 71%, 65%, 33%, 14%, 9%, respectively) were methylated in pCA but rarely or not methylated in BPH. NAB2 and CDC6 were hypermethylated frequently in pCA (92%, 67%, respectively) and in BPH (91%, 59%, respectively). FGFR2, WWOX, E-Cadherin, PKCmu, and RASLL1A did not display noteworthy methylation in pCA (0-1%) or in BPH. CpG island hypermethylation at APC, retinoic acid receptor beta (RAR-beta), and PTGS2 discriminated with a sensitivity of 65-83% and a specificity of 97-100% between BPH and pCA. The combination of various genes increased the diagnostic expressiveness. PTGS2 hypermethylation correlated with seminal vesicle infiltration (p=0.047), capsular penetration (p=0.004), and pT stage (p=0.014). RAR-beta methylation was accompanied by a higher cumulative Gleason score (p=0.042). The probability of PSA-free-survival calculated with a Kattan nomogram correlated inversely with CpG island hypermethylation at EDNRB, RAR-beta, and PTGS2. All prostate cancer cell lines displayed a varying degree of demethylation after 5-aza-2'deoxycytidine treatment.

CONCLUSIONS

CpG island hypermethylation at various gene loci is frequent in prostate cancer and can distinguish between neoplastic and noncancerous tissue. Furthermore, hypermethylation at PTGS2, RAR-beta, and EDNRB inversely correlated with PSA-free-survival according to a Kattan nomogram and has potential prognostic value.

摘要

目的

评估一组前列腺癌（pCA）候选基因中的CpG岛高甲基化及其与临床病理参数的关系，以及与预测前列腺癌根治术后前列腺特异性抗原（PSA）复发的列线图之间的关系。

材料与方法

采用甲基化荧光定量聚合酶链反应检测78例前列腺癌组织、32例良性前列腺增生（BPH）组织及前列腺癌细胞系（LNCaP、DU145、PC3、BPH-1）中13个基因位点（APC、CDC6、CTNNB1、E-钙黏蛋白、EDNRB、FGFR2、GSTP1、NAB2、PKCμ、PTGS2、视黄酸受体β（RAR-β）、RASL11A、WWOX）的甲基化情况。

结果

APC、RAR-β、PTGS2、GSTP1、EDNRB和CTNNB1在pCA中发生甲基化（分别为83%、71%、65%、33%、14%、9%），而在BPH中很少或未发生甲基化。NAB2和CDC6在pCA（分别为92%、67%）和BPH（分别为91%、59%）中频繁发生高甲基化。FGFR2、WWOX、E-钙黏蛋白、PKCμ和RASL1A在pCA（0-1%）或BPH中未显示出明显的甲基化。APC、视黄酸受体β（RAR-β）和PTGS2的CpG岛高甲基化在区分BPH和pCA时，灵敏度为65-83%，特异性为97-100%。多种基因的联合可提高诊断效能。PTGS2高甲基化与精囊浸润（p=0.047）、包膜侵犯（p=0.004）及pT分期（p=0.014）相关。RAR-β甲基化与更高的累积Gleason评分相关（p=0.042）。根据Kattan列线图计算的无PSA生存概率与EDNRB、RAR-β和PTGS2的CpG岛高甲基化呈负相关。所有前列腺癌细胞系在5-氮杂-2'-脱氧胞苷处理后均表现出不同程度的去甲基化。