As new research finds tumor cells don’t like to be tied to just one methylation pattern, they prefer a variety. In fact, that variation within tumors gives cells a big leg-up in challenging environments, and possibly even helps them avoid detection and treatment.
Building on their earlier work on CpG shores and stochastic variation, the Feinberg lab at Johns Hopkins University used whole-genome bisulfite sequencing to study the DNA methylation differences between cancer types and normal cells. Here’s what their analysis revealed:
- Increased stochastic variation was found in several cancer types compared to normal tissues.
- Large (5kb to 10Mb) DNA hypomethylation “blocks” in cancer that cover roughly half of the genome.
- Other smaller, differentially methylated regions (DMRs) are involved in the loss of methylation boundaries.
- Variable gene expression is increased in hypomethylated blocks and DMRs.
As Dr. Andrew Feinberg explains, he and his crew believe that they’ve uncovered two new features of a cancer mechanism. “First is a loss of stability of normal boundaries of methylation around CpG islands. What people referred to as hypermethylated islands, or hypomethylated or hypermethylated shores was really a loss of stability of the boundaries of a low methylation in islands and high methylation next to them. So the regulation of those boundaries would appear to be the key target of disruption in cancer. The second thing going on is a large scale hypomethylation of large blocks (10s of kb to megabases). This is not due to hypomethylation of repeats, it just looks that way since repeats are somewhat enriched in the blocks. But 1/3 of genes are in the blocks.”
This epigenetic instability allows cancers to quickly adapt and keep on their destructive path. “Cancers need to survive in a changing environment and stochastic variation in methylation would enhance that survival. But here’s the thing–the same sites of stochastic variation are critically important in normal development. …(As our work shows) the most variable sites in colon cancer, are also the most variable in the other common cancers, and ALSO are able to discriminate the normal tissues from each other.” Says Feinberg. Epigenetic stability may also be a major reason for so much heterogeneity found within tumors.
Based on cancer variability between types, and even cells within the same tumor, the Feinberg team suggests that some of the conventional wisdom around the epigenetic diagnosis and treatment of cancer may need to be re-thought. According to Feinberg, “Our data show that there is stochastic deviation from normal caused by the loss of stability of methylation at island boundaries, and the hypomethylation of large blocks–rather than a cancer-specific pattern, per se.” So taking the usual approach of identifying a “cancer profile” instead of looking for differences from normal tissue may not be the way to go.
Find out how this study might change your own cancer research at Nature Genetics, July 2011.