Disorder in epigenetics is a defining characteristic of cancer.


The genetic tumult within cancerous tumours is more than matched by the disorder in one of the mechanisms for switching cells’ genes on and off, scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT & Harvard report in a new study. Their findings indicate that the disarray in the on-off mechanism, known as methylation, is one of the defining characteristics of cancer and helps tumours adapt to changing circumstances.  Their opensource study is published in the journal Cancer Cell.

The researchers also showed that derangement in the methylation process has a direct bearing on the effectiveness of cancer therapy. In patients with chronic lymphocytic leukemia (CLL), they found that treatment produced shorter remissions if the tumour tissue showed signs of highly disorganized methylation. The findings demonstrate that such disorganization can actually benefit tumours and render them less vulnerable to anti-cancer drugs.

The behaviour of a cancer cell is dictated not only genetics, by the particular set of mutated genes within it, but also by epigenetics, the system for controlling the expression of genes.  Expressed genes are active, their information is being used by the cell. One of the ways that cells control gene expression is by attaching chemical units called methyl groups to sections of DNA in a process called methylation. The exact arrangement of methyl groups helps determine which genes are expressed.

The medical community knows that tumours are composed of many subgroups of cells, each with its own array of gene mutations.  In the current study the team wanted to see if that type of genetic diversity coincides with epigenetic diversity.  In other words, does the range of methylation patterns mirror the genetic variety found in tumours?

To find out the researchers used a new technology known as bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder. They also devised a simple measure called PDR, percent discordant reads, for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.

The team measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells (CLL is a cancer of B cells, which help fight disease).  The team theorised that the epigenetic structure would map right onto the genetic structure, that is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.

To their surprise, the methylation patterns showed a tremendous degree of random disarray.  It is known that individual tumours are checkered with genetically distinct groups of cells. Bisulfite sequencing enabled the group to see that the placement of methyl groups across tumour cell DNA also varies substantially among cells in the same tumour. In fact, disorderly methylation pervades the entire tumour.

The results revealed that the diversity within individual tumours apparently proceeds along two independent, yet interrelated tracks; one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.

The methylation irregularities, technically known as local methylation disorder, were highly evident in CLL and, the researchers found, in other types of cancer as well.

Because methyl groups control the expression of genes, disorderly methylation might be expected to cause gene activity to be wildly inconsistent even within a single tumour. This, in fact, is what the research team found.

The disruption of methylation machinery might seem hazardous to tumour survival, but the researchers theorise that tumours can turn the ‘disorderliness’ to their own advantage.

Just as in the case of genetic heterogeneity within tumours, increased random variation of the epigenetic profile may augment the diversity of malignant cells.  The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.

The team state that this research presents a compelling argument for how disrupted methylation leads to increased cancer progression and heterogeneity.  Cancer survives through some wildly inventive ways. Methylation disorder is one of the ways it creates the conditions that enable it to adapt.

Source:  Dana-Farber Cancer Institute

Proposed Interaction between Methylation Disorder and Clonal Evolution A novel somatic mutation (depicted with lightning bolts) would have to coincide with an epigenetic state that will be permissive to the propagation of the new genotype to a progeny population. In a cellular population with limited stochastic methylation changes (top), the proportion of cells that are therefore able to actively participate in the evolutionary process is small. However, in a more malleable epigenetic landscape, such as expected to result from a high level of locally disordered methylation, a greater proportion of cells can give birth to new subclones, increasing the diversity and the adaptive capacity of the cancer population, resulting in adverse clinical outcome with therapy.  Locally Disordered Methylation Forms the Basis of Intratumor Methylome Variation in Chronic Lymphocytic Leukemia.  Wu et al 2014.

Proposed Interaction between Methylation Disorder and Clonal Evolution A novel somatic mutation (depicted with lightning bolts) would have to coincide with an epigenetic state that will be permissive to the propagation of the new genotype to a progeny population. In a cellular population with limited stochastic
methylation changes (top), the proportion of cells that are therefore able to actively participate in the evolutionary process is small. However, in a more malleable epigenetic landscape, such as expected to result from a high level of locally disordered methylation, a greater proportion of cells can give birth to new subclones, increasing the diversity and the adaptive capacity of the cancer population, resulting in adverse clinical outcome with therapy. Locally Disordered Methylation Forms the Basis of Intratumor Methylome Variation in Chronic Lymphocytic Leukemia. Wu et al 2014.

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