Unité de Recherche Génétique du Cancer et Production de Protéines Thérapeutiques, Centre de Biotechnologie de Sfax, BP 1177, Route Sidi Mansour, Sfax, Tunisia.
J Cancer Res Clin Oncol. 2010 Feb;136(2):203-10. doi: 10.1007/s00432-009-0649-6. Epub 2009 Aug 6.
Epigenetic gene silencing is one of the major causes of inactivation of tumor-suppressor genes in many human cancers.
The aim of the present study was to determine the methylation status of the promoter region CpG islands of four cancer-related genes RASSF1A, RARbeta2, CDH1, and p16 ( INK4a ) in 78 breast cancer specimens and to evaluate whether the methylation status is associated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) together with the major clinico-pathological parameters.
We showed that the methylation frequencies ranged from 19.6% (p16 ( INK4a )) to 87% (RASSF1A) in primary breast tumors of Tunisian patients. Aberrant methylation of RARbeta2 was observed in 66.6% of cases and associated with age at diagnosis (P = 0.043), while CDH1 was methylated in 47.4% of tumors and was correlated with tumor size (P = 0.013). RASSF1A presented the highest percentage of methylation (87%) and was strongly associated with poor survival (P = 0.014), with age (P = 0.048), and tumor stage (P = 0.033). Loss of ER and PR was strongly associated with GIII tumors (P = 0.000 and 0.037 respectively) while HER2/neu was associated with lymph node involvement (P = 0.026) and 5-year survival rate (P = 0.028).
Our preliminary findings suggested that aberrant methylation of RASSF1A and RARbeta2 occurs frequently in Tunisian breast cancer patients compared with others. Furthermore, RASSF1A hypermethylation could be used as a potential marker of poor prognosis.
表观基因的基因沉默是许多人类癌症中肿瘤抑制基因失活的主要原因之一。
本研究的目的是确定 78 例乳腺癌标本中四个与癌症相关基因（RASSF1A、RARβ2、CDH1 和 p16（INK4a））启动子区 CpG 岛的甲基化状态，并评估其甲基化状态是否与雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体 2（HER2/neu）以及主要临床病理参数相关。
我们发现，突尼斯患者原发性乳腺癌中，RASSF1A 的甲基化频率为 19.6%（p16（INK4a））至 87%（RASSF1A），RARβ2 的异常甲基化发生率为 66.6%，与诊断时的年龄有关（P = 0.043），而 CDH1 的甲基化发生率为 47.4%，与肿瘤大小有关（P = 0.013）。RASSF1A 的甲基化率最高（87%），与不良预后显著相关（P = 0.014），与年龄（P = 0.048）和肿瘤分期（P = 0.033）相关。ER 和 PR 的缺失与 GIII 型肿瘤强烈相关（分别为 P = 0.000 和 0.037），而 HER2/neu 与淋巴结受累（P = 0.026）和 5 年生存率（P = 0.028）相关。
我们的初步研究结果表明，与其他地区相比，突尼斯乳腺癌患者中 RASSF1A 和 RARβ2 的异常甲基化更为常见。此外，RASSF1A 的高甲基化可能成为不良预后的潜在标志物。
