Prostate cancer mutations identified

Behind the Headlines

Thursday February 10 2011

The study looked at mutations in prostate cancer cells

The genetic map of prostate cancer has been “cracked”, The Daily Telegraph reported. The newspaper said that new research into prostate cancer has provided a “breakthrough that could transform our understanding of the disease”.

The research scanned the entire genetic sequences of prostate tumours and compared them to the genetics of healthy cells from the same patient. The research identified a range of mutations and genetic patterns that showed how DNA is sometimes rearranged in these tumours. The researchers suggest that these patterns may be unique to prostate cancer and may have a role in initiating it.

Such research helps further our understanding of the complex genetic reasons why some men may develop prostate cancer while others do not. However, it will be some time before this knowledge can be used in diagnosis or treatment as several thousand mutations were identified in each tumour and it is unclear what effect each mutation has. The study also looked at only seven tumours, so further research must verify the presence of these mutations in more samples.

 

Where did the story come from?

Numerous researchers from several research institutions across the US contributed to this research. The study was funded by several US organisations, including the Prostate Cancer Foundation Movember campaign, the Howard Hughes Medical Institute, the National Human Genome Research Institute, the Kohlberg Foundation, the National Cancer Institute and the National Institutes of Health. It was published in the peer-reviewed scientific journal Nature.

The newspapers generally reported the study clearly, although the Daily Mail did not highlight that this study has limitations due to the small number of samples tested. Given that the research only studied samples from seven men, it needs to be repeated on a larger scale.

 

What kind of research was this?

This genetic study set out to sequence the entire DNA code of prostate cancer cells. Prostate cancer is a major disease and the second most common cause of cancer deaths in men in the UK. Previous research, through genome-wide association studies, has identified that certain single-letter variants within the DNA code are associated with an increased risk of cancer. In fact, nine such variants were identified by four studies covered by Behind the Headlines in September 2009. These studies concluded that many regions in the DNA appear to contribute to the risk of prostate cancer and that further variants are likely to be discovered.

The methods of this research differed from those employed in genome-wide association studies, which look at associations that may exist between specific DNA variations and the risk of developing a particular disease. In this current study, researchers “read” (sequenced) the entire genetic code of a person’s prostate cancer cells and compared it with the genetic sequence of that person’s healthy prostate cells. Using this method, the researchers could see what genetic changes and mutations occurred in these cells as they became cancerous.

 

What did the research involve?

The researchers used DNA extracted from prostate tumour samples from seven men given a radical prostatectomy (removal of the prostate and related tissue). They also had blood samples from these men. DNA extracted from the blood was used as a control in the experiments, to show what the men’s DNA was like in non-cancerous cells.

The researchers sequenced the entire genome of the prostate cancer cells, looking for mutations and variations that did not exist in normal cells from the same patient. They looked for small differences in the sequence of the DNA, larger-scale changes in the chromosome arrangements and instances where part of one chromosome had broken off and attached to another chromosome to form a hybrid. The DNA was sequenced using established methods in this field and the information was processed by complex software that could identify the presence of mutations in the DNA.

A portion of the mutations detected were checked using different methods to validate the original process. The researchers reported how many mutations they detected in the tumour cells and their observations on the common types of genetic rearrangements. They then discussed how certain variations may increase the risk of prostate cancer developing.

 

What were the basic results?

The researchers found about 3,866 single-letter mutations of the genetic code in each tumour, a rate of mutation that they say is similar to that seen with acute myeloid leukemic and breast cancer but lower than that seen in small cell lung cancer and skin cancer.

Two of the seven tumours tested had mutations within two genes called SPTA1 and SPOP. In three of seven tumours, there were mutations in three genes called CHD1, CHD5 and HDAC9, which are responsible for producing chromatin modifier proteins. These proteins are known to play a role in suppressing tumours, regulating how genes are switched on and off, and stem cells’ capacity to develop into different body cells. Three of seven tumours also had mutations in HSPA2, HSPA5 and HSP90AB1, a set of genes linked to cells’ response to environmental stress and damage. Other genes were mutated in only one of the seven tumours.

The researchers identified 90 chromosome rearrangements in each tumour and noted that this number was similar to that seen in breast cancer cells. The rearrangements showed a distinctive pattern that had reportedly not been seen in other solid tumours before.

Some of the rearrangements involved genes that were affected by single-letter mutations in other tumours, including the chromatin modifier gene CHD1. A number of rearrangements also occurred near multiple known cancer genes.

Overall, sixteen genes affected by a rearrangement mutation were found in at least two tumours.

 

How did the researchers interpret the results?

The discovery of many mutations in the genetic code of prostate cancers, some of which are associated with known genes, led the researchers to conclude that these mutations may contribute to the development of tumours in the prostate.

They also say that the high number of “recurrent gene fusions” suggests that rearrangements in the DNA may be critical events in initiating prostate cancer. These are complex rearrangements and the researchers note that a “whole-genome approach”, looking at the whole of a tumour cell’s genetic code, is necessary to profile them.

 

Conclusion

This important study looked at the entire genetic sequence in a sample of prostate tumour cells and compared this with that of normal tissue. It has revealed that there are many mutations and rearrangements of DNA, which the researchers suggest could increase the risk of this cancer type. Importantly, only seven tumour samples were used in this analysis, and the mutations identified were not present in all tumour samples. This confirms what is already suspected about the disease, that factors affecting prostate cancer are complex, particularly the genetic elements.

The methods of this study will need to be replicated in a larger sample of individuals, a process which is likely to be extensive and time consuming. Such research will also need to confirm the extent to which each mutation or DNA rearrangement increases the risk of the disease and the normal function of the genes around the mutation sites. Such information could be critical in the development of screening or treatment approaches in the future.

While this study has importantly applied a whole genome approach to understanding the genetics of prostate cancer, this now needs to be applied to more samples. Only then can the full implications of the genetic changes found through this research be appreciated.

Links to the headlines

Genetic map of prostate cancer cracked. The Daily Telegraph, February 10 2011

Prostate cancer's genetic code cracked by U.S. scientists in breakthrough set to transform treatment of the disease. Daily Mail, February 10 2011

Links to the science

Berger MF, Lawrence MS, Demichelis F et al. The genomic complexity of primary human prostate cancer. Nature: 470, 214–220 February 10 2011

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Edited by NHS Choices