01 April 2015
By David Wedge
Figure shows the relationships between subclones in each patient. Each line is associated with a subclone; the length of each line represents the number of genetic variations in the subclone and the thickness shows the proportion of the sample made up of that subclone. Credit: doi:10.1038/ng.3221
Many types of cancer can arise from a field effect, a poorly understood but often observed change in normal tissue that predisposes it to the development of tumours.
In our research, we wanted to find evidence for a field effect within the normal tissue that frequently lies between different tumours in prostate cancer. If we could find the field effect, we hoped to be able to identify a genetic basis for it and, by doing so, learn more about how tumours spread in the prostate.
The field effect was first discovered in 1953, in a type of mouth cancer called oral squamous cell carcinoma, and has since been identified in most tissues, including lung, breast, colon, oesophagus, bladder and prostate. It results in the occurrence of multiple tumours within a single organ.
For some types of cancer, including prostate cancer, we are unsure what causes the field effect, but it’s thought that it is probably genetic (arising from mutations in DNA) or epigenetic (arising from other changes that affect the ability of a cell to produce RNA and proteins, such as changes in methylation of regions of the DNA).
Prostate cancer is very commonly multifocal, meaning that multiple tumours develop in the prostate. These tumours tend to appear at around the same time and are separated by healthy tissue. If a field effect is operative, we would, over time, expect to see the healthy tissue between and around the tumours acquire mutations and become cancerous.
We sequenced the genomes of cells taken from multiple tumour sites and healthy prostate tissue in three men with prostate cancer. By comparing the different genomes, we were able to identify groups of cells with different mutations, known as subclones, in each sample. Subclones compete with one another to expand fastest and take over a tumour, so we often find multiple subclones in one organ.
To learn more about how the field effect might be operating in prostate cancers, we investigated the relationships between these subclones within different regions of the prostate. What we found surprised us. What we thought was normal tissue distant from the tumours actually contained clusters of mutated cells, suggesting that a subclone had expanded. However, none of the mutations were known drivers of cancer and the normal cells shared no more than 10 mutations with the cancerous cells in the tumours.
It seems that the field effect, whatever it is, causes mutations in normal prostate tissue but does not necessarily lead to cancer in this tissue. No driver mutations were shared by the normal and cancer cells, suggesting that the field effect in prostate cancer may not be a genetic effect. Further study will be needed to find out whether, for example, it is an epigenetic effect and whether the field effect is exacerbated by any environmental or lifestyle factors.
Another interesting finding was that tumours contained genetically distinct subclones from different regions of the prostate, suggesting that individual cancer cells can travel across regions of apparently normal tissue.
Fascinatingly, although the different tumours found within a single prostate were almost completely independent, they each contained a similar genetic defect, a deletion of a small part of DNA resulting in the fusion of two genes, TMPRESS2 and ERG. This gene fusion is common, occurring in around half of all prostate cancers and appears to have occurred independently multiple times in different regions of a single prostate.
Although cells in different locations of the prostate are evolving almost completely independently, they are subject to the same selective pressures and it seems that the TMPRESS2-ERG fusion gives such a large advantage to cells that many cells that have acquired this aberration may clonally expand simultaneously.
What does this tell us about treatment and diagnosis of prostate cancer? Firstly, since prostate cancers may be composed of multiple unrelated tumours, it is important to biopsy multiple regions of the tumour, and possibly of the apparently normal prostate, when diagnosing prostate cancers.
Treatment of prostate cancers is often performed on targeted tumours only. Our study suggests that it may be necessary to look at the entire prostate when designing therapy as the field effect may have an impact on wider regions of tissue.
This research was funded by Cancer Research UK
David Wedge is a Senior Staff Scientist in the Cancer Genome Project at the Wellcome Trust Sanger Institute, working on heterogeneity and evolution within prostate and other cancers.
References
- Cooper CS, Eeles R, Wedge DC, Van Loo P, et al (2015). Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nature Genetics. DOI:10.1038/ng.3221
- Slaughter DP, Southwick HW, Smejkal W. (1953). Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. DOI: 10.1002/1097-0142(195309)6:5 963::AID-CNCR2820060515 3.0.CO;2-Q
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