E-Cadherin, NFATC3, and PLP2 Are Differentially Methylated in Multiple Cancers

It is well documented that cancer cells have abnormal methylation patterns often caused by faulty methylating machinery. Specifically, E-cadherin, NFATC3, and PLP2 are 3 genes known to be aberrantly methylated in cancer cells. These genes are well documented for their role in signaling pathways involved with cell proliferation, adhesion, migration, and other signs of tumor progression. Therefore, changes in gene expression of CDH1, NFATC3, and PLP2 due to aberrant methylation can lead to profound changes in cellular function and tumor formation. In order to ensure that previous in vitro and in vivo methylation studies match what is observed in the clinic, we utilized a bioinformatics approach to complete an extensive analysis of methylation patterns of these 3 genes, analyzing over 5000 patient samples, across all cancers for which both normal and tumor tissues were available. Specifically, we analyzed overall and site-specific methylation patterns, at CpG islands and shores, of all 3 genes across 14 cancer types. Furthermore, we compared these methylation levels in normal and tumor samples of both matched and unmatched patient samples in order to determine any differences between groups. Finally, we examined whether an aberrant DNA methyltransferase, DNMT3B7, known to be expressed in cancer cells and to alter methylation patterns in vitro correlated with altered overall and site-specific methylation of CDH1, NFATC3, and PLP2 in these patient samples. Our results indicate that methylation patterns of CDH1 and NFATC3 were unexpectedly varied across tumors, contrary to previous studies performed in vitro, while PLP2 showed the expected hypomethylation pattern in tumor tissues. We also observed some correlation between DNMT3B7 expression and methylation patterns of these genes, but patterns were inconsistent. Taken together, these results emphasize the necessity for in vivo and patient studies rather than a complete reliance on in vitro data and provide multiple areas of future research.