Clinical Cancer Epigenetics

cancer_normal_mds1bWe have published work showing that there is a universal dysregulation of epigenetic state in cancer compared to normal tissue. When differentially methylated regions (DMRs), previously identified in colorectal cancer, were explored in other types of cancer (specifically, breast, lung, kidney and thyroid), we found methylation differences in the same regions. Pictured to the left is a multidimensional scaling of the methylation signatures for the different tissues and their corresponding cancer samples. Two major findings are apparent. First – the normal tissues seem to be very consistant between samples – showing very similar methylation profiles to others from the same tissue. Different tissues are clearly distinguished by their methylation profiles from these regions. Secondly, we find that in cancer samples, there is a loss of these tightly regulated signatures – different cancer samples show a dramatically increased intra-sample variance when compared to their normal counterparts.

smallDMR1

In addition, we performed full genome bisulfite sequencing on three paired normal colon and colon cancer samples. From the subsequent analysis, many DMRs were identified (example shown to the left). Many of the DMRs show a loss of the tightly controlled methylation signature present in the normal sample.

cancer_blocks1

Performing a lower-frequency analysis on the methylation profile, we found that there were large regions of altered methylation in the cancer samples compared to the normal sample – an example is pictured to the left. Note that these regions are on the scale of megabases.

genome_scale_blocks1

These large methylation blocks are distributed widely throughout the genome, as pictured ot the left.  Shown is the distribution of blocks on chromosome 11, along with the distribution of Large Organized heteroChromatin K9 modifications (LOCKs), Lamina Associated Domains (LADs), genes and CGs.

cancer_block_meth_hist_web1

 

In fact, throughout the entire genome, we find that the majority of methylation changes occur inside blocks. As shown in the histograms to the left, outside blocks the majority of CGs are either completely methylated or completely unmethylated in both normal and cancer samples.  In contrast, inside blocks,  normal samples methylation show a tight distribution centered around ~80% methylated. Cancer samples, however, show an overall hypomethylation, but with a broader distribution and a large variation between samples. This suggests a dysregulation of methylation occurring in cancer.