Gene Signature Identifies Five Risk Subtypes of Prostate Cancer

Dr Helen Ross-Adams Cancer Research UK, Interview with:
Dr Helen Ross-Adams
Cancer Research UK, London

Medical Research: What is the background for this study? What are the main findings?

Dr. Ross-Adams: Prostate cancer is the most common non-skin cancer in men in both the UK and US. At the moment, prostate cancer is diagnosed and monitored mainly on the basis of blood tests for prostate specific antigen (PSA), a protein in the blood. MRI scans and examination of biopsy tissue samples under a microscope are also used to decide on the best course of action for each patient.

Despite all this, as a community, we still struggle to reliably predict which men with an initial diagnosis of prostate cancer will go on to have a fast-growing, aggressive form of the disease (a ‘tiger’) from men who will have a much slower-growing form of the disease that won’t really cause problems in the man’s lifetime (a ‘pussycat’). This means some men may get treatment they don’t need, while others could benefit from earlier, more intensive treatment.

With this in mind, we studied a total of 250 men with prostate cancer and tested their tumour and healthy tissues at the molecular level. The idea was two-fold:

  • Could we identify different sub-types of prostate cancer using this genetic information, and
  • Could we link any of the sub-types we did find with other patient characteristics that clinicians would normally have, like histological staging information or PSA test results?

We looked at their DNA, to see whether any regions were deleted or repeated (copy number alterations), and we also measured the activity levels of thousands of genes in the tumour and healthy prostate tissues (gene expression). Each of these approaches on their own can be used to stratify patients, but we decided to combine this information and hopefully find genes that had a big impact on prostate cancer.

Using this approach, we identified five different subtypes of prostate cancer, each with their own ‘molecular profile’:

  • One group had lots of DNA deletions and only low levels of certain genes
  • Another had lots of repeated DNA with high levels of associated genes
  • Two more groups had very ‘quiet’ genomes, with very few changes at the DNA level, and not much disruption at the gene expression level
  • The fifth and final group had an intermediate amount of copy number changes (DNA level), but no major changes at the gene expression level (mRNA level)

When we correlated these different molecular subtypes with the patients’ standard post-surgery follow-up data (the results of 6-monthly PSA tests), we found that these subtypes predicted how well a patient would do after surgery. We ultimately identified 100 key genes (a gene signature) that were most useful in classifying men into one of the 5 cancer subtypes we identified.

This was derived from 150 men in Cambridge, UK. To check our findings, we repeated the same work in a group of 100 men from Stockholm, Sweden who had also had prostate surgery, and found that the 100 gene signature worked just as well – it subdivided the men into 5 different groups, each with different rates of relapse. In both cases, men with the most genetic alterations had the greatest chance of relapsing after surgery.  

Medical Research: What should clinicians and patients take away from your report?

Dr. Ross-Adams: The idea is that this gene signature would be used alongside current clinical tests like the Gleason score and PSA test, to give doctors a better idea of how patients will do after surgery to remove their prostate – which men are most at risk of relapse?   This extra molecular information would give doctors a more accurate idea of what’s happening in a specific patient’s tumour, so the patient could be provided with more appropriate (’personalised’) treatment advice.

We’re obviously very excited with these results, but as with most research, there are some caveats; we still need to do more research before doctors in the hospital could use this technique routinely.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Ross-Adams: So, these findings are based on patients who’d already had surgery for their prostate cancer, and have given us some important insights into which types of cancers are more likely to come back after treatment. But because these weren’t samples taken at the time they were initially diagnosed, there’s work to do to see whether this gene signature can be used to divide prostate cancer patients into different groups based on diagnostic biopsies, and whether it should be used to determine treatment early on. One key thing here is whether we can get enough genetic material from a diagnostic biopsy to be able to do this analysis. Also, we need to be sure that the sample taken at biopsy is representative of the cancer cells in the tumour; targeted biopsies (using MRI) may help with this.

An essential next step is to confirm these findings in much larger studies, and in other ethnic groups, and really examine each molecular subtype in depth. This information would be invaluable in identifying more effective ways to treat prostate cancer patients, and develop new treatments for each subtype.

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Dr Helen Ross-Adams (2015). Gene Signature Identifies Five Risk Subtypes of Prostate Cancer