Identification of novel tumor-suppressor genes by Outlier approach

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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.