Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Mol Carcinog. 2013 Jun;52(6):475-87. doi: 10.1002/mc.21881. Epub 2012 Feb 7.
Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array-CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre-malignant phenotypes.
启动子甲基化作为肿瘤抑制基因在肿瘤进展过程中失活的主要机制之一，其作用正不断得到增强。在其启动子中，经常发现有三个肿瘤抑制基因发生甲基化，与表达缺失一致，这三个基因分别是 RASSF1A、SLIT2 和 WIF1。此外，我们小组之前的 array-CGH 分析显示，这些基因存在于遗传性乳腺癌肿瘤中观察到的缺失基因组区域。在本工作中，我们分析了 47 例遗传性乳腺癌肿瘤中这三个肿瘤抑制基因启动子的甲基化状态。对遗传性乳腺癌肿瘤的启动子甲基化状态分析显示，这三个基因的甲基化频率很高（RASSF1A 为 67%，SLIT2 为 80%，WIF1 为 72%）。此外，三个基因的甲基化 PCR 产物的存在与蛋白表达缺失相关，且与 RASSF1A 和 WIF1 具有统计学意义。有趣的是，在 6 例 1 级浸润性导管癌肿瘤中有 4 例存在所有三个基因的甲基化。还发现 RASSF1A 甲基化与 DCIS 肿瘤之间存在关联。这些结果表明，这些肿瘤抑制基因的失活是遗传性乳腺癌的早期事件，并且可能是恶性前表型的标志物。
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