Identification of novel tumor-suppressor genes by Outlier approach

启动子CpG岛(CGI)的异常DNA甲基化与人类癌症的发生密切相关。虽然在癌细胞中有成千上万的基因发生异常甲基化，但大多数基因是癌变的结果，很难从众多甲基化基因中识别出肿瘤抑制基因(TSG)。在这项研究中，我们开发了一种新的方法来识别TSG，基于我们之前的发现，正常细胞中带有RNA聚合酶II(POL II)的基因对异常甲基化诱导具有抵抗力，而已知的TSG在癌症中被甲基化，这违反了这一普遍规律。首先，我们在人类乳腺癌中确定了280个甲基化敏感基因。从这些基因中，通过分析正常细胞中的Pol II结合，分离出14个违反一般规则的甲基化基因(异常值基因)。在这些基因中，DZIP1是一个新的TSG，FBN2和HOXA5是已知的TSG。这些结果表明，该方法可以有效地识别TSG。

Aberrant DNA methylation of promoter CpG islands (CGIs) is deeply involved in human carcinogenesis. Although hundreds to thousands of genes are aberrantly methylated in cancer cells, the majority is methylated as a consequence of carcinogenesis, and it is difficult to identify tumor-suppressor genes (TSGs) from numerous methylated genes. In this study, we developed a novel method to identify TSGs based on our previous findings that genes with RNA polymerase II (Pol II) in normal cells are resistant to aberrant methylation induction and that known TSGs were methylated in cancers against this general rule. First, we identified 280 methylation-sensitive genes in human breast cancers. From these genes, 14 genes methylated against the general rule (outlier genes) were isolated by analyzing Pol II binding in normal cells. Among these genes, DZIP1 was a novel TSG, and FBN2 and HOXA5 were known TSGs. These results showed that TSGs can be efficiently identified by this approach.