Tumor cells are a mosaic of different cell types

For the last decade or so, progressive cancer treatments involved taking samples of tumors, testing the cells to determine the genetic makeup, and then prescribing medicines targeted to specific mutations. There are many benefits to this approach, but it doesn’t always work.

It turns out that tumors aren’t uniform; they are mosaics of cells that can be genetically very different. A recent paper in the New England Journal of Medicine showed that a cell in one area may not be the same as a call in another area (a phenomenon called “intratumor heterogeneity”). So a treatment based on a sample from one area may not work for the whole tumor. Some tumor cells may be resistant to the drug so the cancer persists, or even grows.

In this British pilot study, cells from 9 different locations within a primary kidney tumor, and several metastatic tumors, were analyzed using next generation DNA sequencing. Only 34% of the 118 mutations identified were present in all the samples, and several of the major cancer genes were mutated in different ways in different locations. This turned traditional ideas about cancer cells being “clones” of a single, mutated cell on its head.

Previously, it was thought that a tumor develops when a single cell accumulates sufficient mutations over time that eventually lead to it dividing uncontrollably. Therefore if you could find the original mutation, and target treatment to that, then every cell would react to the treatment. But if the tumor is made up of a mosaic of cells, then they could all react differently to the drug. The researchers then created a phylogenetic “tree,” identifying which cells were more persistent, being in the trunk of the tree. They proposed that if those cells were receptive to a targeted medicine, the treatment might be more effective; if not, less so.

Although this study only involved four patients, the results provide a new way of thinking for researchers and clinicians. If we remove the presumption that all tumor cells are identical, we open the way for more creative thinking about how to tackle the problem.

Of course, we also know that environment can play a strong role in determining a disease outcome. For identical twins in their first environment,  the womb, each individual had slight environmental differences the moment the zygote split into two.  As identical twins develop, there will always be some environmental differences, many of which are still not fully understood. Before we explain this mystery of differences between identical (or more accurately “semi-identical”) twins as a matter of nature vs. nurture, there is another component that requires consideration.

There are other ways that DNA can be modified which don’t involve changes in DNA sequence (the order of the DNA’s A, C, T, G chemical “spelling”). These modifications often involve enzymes that can, for example, alter how, or if DNA is transcribed into mRNA. One type these DNA modifying enzymes is methyltransferase, which can add methyl modifications to cytosine (C), often resulting in the suppression of a gene. These types of non-sequence based changes are referred to as epigenetic modifications. Taking the sum of all of the epigenetic modifications gives us the term epigenome, the additional heritable information content of the DNA genome.

In a recent study published in the journal Human Molecular Genetics a paper by E.L. Dempster et.al at the Institute of Psychiatry Kings College in London showed that epigenetic DNA modifications between sets of identical twins can vary by as much as 20%. This study is highly significant in its demonstrating why researches will have to go beyond sequencing the DNA genome of patients and start paying more attention to the epigenome. The Kings College study is the first wide-scale study that brings recent technological advances in epigenetic investigation to understanding psychiatric disorder. The study found epigenetic modifications not only in gene regions already known to be involved in disorders like schizophrenia and bipolar disorder, but has revealed new genes that could be potential targets for drugs. Because epigenetic modification involves chemical modification of DNA, aberrant epigenetic modifications can often be targeted by drugs.  Hopefully further exploration of the epigenome will  yield more clues about these often devastating conditions.