Padar Asha, Sathyanarayana Ubaradka G, Suzuki Makoto, Maruyama Riichiroh, Hsieh Jer-Tsong, Frenkel Eugene P, Minna John D, Gazdar Adi F
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Clin Cancer Res. 2003 Oct 15;9(13):4730-4.
Loss or abnormal expression of Cyclin D2, a crucial cell cycle-regulatory gene, has been described in human cancers; however, data for prostate tumors are lacking. We investigated the epigenetic silencing of Cyclin D2 gene in prostate cancers and correlated the data with clinicopathological features.
Cyclin D2 promoter methylation was analyzed in 101 prostate cancer samples by methylation-specific PCR. In addition, we analyzed 32 nonmalignant prostate tissue samples, which included 24 samples of benign disease, benign prostatic hypertrophy, or prostatitis and 7 normal tissues adjacent to cancer. The methylation status of Cyclin D2 was correlated with the methylation of nine other tumor suppressor genes published previously from our laboratory on the same set of samples (R. Maruyama et al., Clin. Cancer Res., 8: 514-519, 2002). The methylation index was determined as a reflection of the methylated fraction of the genes examined.
The frequency of methylation of Cyclin D2 promoter was significantly higher in prostate cancers (32%) than in nonmalignant prostate tissues (6%; P = 0.004), and it was not age related. Aberrant methylation was present at insignificant levels in peripheral blood lymphocytes (8%). We also compared methylation of cyclin D2 with methylation of nine tumor suppressor genes [published previously from our laboratory (R. Maruyama et al., Clin. Cancer Res., 8: 514-519, 2002)] studied in the same set of samples. The concordances between methylation of Cyclin D2 and the methylation of RARbeta, GSTP1, CDH13, RASSF1A, and APC were statistically significant, whereas methylation of P16, DAPK, FHIT, and CDH1 were not significant. The differences in methylation index between malignant and nonmalignant tissues for all 10 genes were statistically significant (P < 0.0001). Among clinicopathological correlations, the high Gleason score group had significantly greater methylation frequency of Cyclin D2 (42%; P = 0.004). Although the high preoperative serum prostate-specific antigen (PSA) group did not have significantly greater methylation frequency, methylation of Cyclin D2 had higher mean PSA value. Also, the prostate cancers in the high Gleason score group had high mean values of PSA.
Our results indicate that methylation of Cyclin D2 in prostate cancers correlates with clinicopathological features of poor prognosis. These findings are of biological and potential clinical importance.
细胞周期蛋白D2（Cyclin D2）是一种关键的细胞周期调控基因，其缺失或异常表达在人类癌症中已有报道；然而，前列腺肿瘤的数据尚缺乏。我们研究了前列腺癌中Cyclin D2基因的表观遗传沉默，并将数据与临床病理特征相关联。
采用甲基化特异性PCR分析101例前列腺癌样本中Cyclin D2启动子甲基化情况。此外，我们分析了32例非恶性前列腺组织样本，其中包括24例良性疾病、良性前列腺增生或前列腺炎样本以及7例癌旁正常组织样本。Cyclin D2的甲基化状态与我们实验室之前发表的同一组样本中其他9个肿瘤抑制基因的甲基化情况相关（R. Maruyama等人，《临床癌症研究》，8：514 - 519，2002年）。甲基化指数作为所检测基因甲基化部分的反映来确定。
前列腺癌中Cyclin D2启动子的甲基化频率（32%）显著高于非恶性前列腺组织（6%；P = 0.004），且与年龄无关。外周血淋巴细胞中异常甲基化水平较低（8%）。我们还将Cyclin D2的甲基化与同一组样本中研究的9个肿瘤抑制基因的甲基化情况进行了比较[我们实验室之前发表的（R. Maruyama等人，《临床癌症研究》，8：514 - 519，2002年）]。Cyclin D2的甲基化与视黄酸受体β（RARβ）、谷胱甘肽S - 转移酶P1（GSTP1）、钙黏蛋白13（CDH13）、RAS相关结构域家族1A（RASSF1A）和腺瘤性息肉病基因（APC）的甲基化之间的一致性具有统计学意义，而与P16、死亡相关蛋白激酶（DAPK）、脆性组氨酸三联体基因（FHIT）和钙黏蛋白1（CDH1）的甲基化无显著差异。所有10个基因在恶性和非恶性组织中的甲基化指数差异具有统计学意义（P < 0.0001）。在临床病理相关性方面，高Gleason评分组中Cyclin D2的甲基化频率显著更高（42%；P = 0.004）。虽然术前血清前列腺特异性抗原（PSA）高值组的甲基化频率没有显著更高，但Cyclin D2的甲基化组的PSA平均值更高。此外，高Gleason评分组的前列腺癌PSA平均值也较高。
我们的结果表明，前列腺癌中Cyclin D2的甲基化与预后不良的临床病理特征相关。这些发现具有生物学和潜在的临床重要性。
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