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Scientists identify 11 new genes linked to aggressive prostate cancer

DNA double helix (computer visualisation)

Researchers have identified 11 new gene alterations that are linked to more aggressive prostate cancer which can be picked up with a simple blood test.

The findings could allow doctors to better personalise treatments for prostate cancer – by spotting those most at risk of aggressive disease and disease progression so that they can benefit from personalised treatments and more frequent checks.

Researchers hope their findings will be considered for addition to gene testing panels currently used in the clinic.

In the largest study of its kind, the researchers analysed blood samples from around 17,500 patients with prostate cancer.

The international team was led by the Keck School of Medicine of the University of Southern California (USC)USC Norris Comprehensive Cancer Centre, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust.

The study, published in JAMA Oncology, identified 11 new gene alterations that are linked to higher risk, more aggressive prostate cancers that aren't currently included on genetic test panels.

Tailored treatments

Including these new alterations would improve doctors' ability to spot patients most at risk of aggressive disease or disease spread. This could reveal opportunities for patients to receive targeted medicines tailored to the specific biology of their cancer, prompt genetic screening of family members who may carry the same gene alterations, and to receive more frequent testing to help promote early detection.

The study also found that some genes which have previously been thought to be linked to risk of aggressive disease do not show association in this larger dataset. They suggest some of these should be removed from current gene panel tests.

The research was funded by the National Institute of Health (NIH) in the US.

The researchers combined information from 18 studies conducted in the US, Europe and Australia, and analyzed blood samples from prostate cancer patients of European descent – 9,185 of whom had aggressive disease to 8,361 who did not and compared the frequency of mutations among the two groups.

In the first stage of their investigations, researchers sequenced the entire set of protein-coding genes within DNA among almost a third of participants, and to look for genes likely to be associated with cancer.

In the second stage, the researchers used samples from the remaining participants to look at 1,749 genes which had been identified as being linked to cancer in the first phase of the study, and genes which had previously established to raise cancer risk.  

That subset included almost 200 genes involved with DNA repair. When that process is disrupted, it creates an opportunity for cancerous cells to arise and take hold.

Genes which had not previously linked to risk of prostate cancer included XRCC2, a gene involved in DNA repair and POLH a gene which codes for DNA polymerase, a key cellular machine that reads instructions provided in DNA.

The researchers note that mutations found in the study also showed up in some patients who didn't have aggressive disease and the researchers suggests that in these patients, mutations may indicate a greater risk of their cancer becoming advanced in future.

They argue that genetic testing should be extended to men with non-aggressive disease as these men could still be at risk of seeing their cancer become advanced. Men harbouring alterations in these 'at-risk' genes could similarly undergo more frequent tests and scans and could take other steps to help prevent their cancer spreading.

They also note some limitations to their study. Firstly, despite its large size, some mutations that drive risk for aggressive prostate cancer are so rare that even larger studies will be needed to untangle their influence on prostate cancer risk. Secondly, that the findings may differ outside of the population under investigation, people of European descent, and studies involving people from more diverse ancestry are needed.

Largest study of its kind

Dr Zsofia Kote-Jarai, Senior Staff Scientist in the Oncogenetics Team at The Institute of Cancer Research, London, who co-led the research, said:

"This study is an important step towards helping us identify individuals who have a high risk of developing aggressive prostate cancer based on their DNA and tailor their screening and treatment options accordingly.

"It's the largest study published so far to compare the inherited genetic influences which separate aggressive and non-aggressive prostate cancers. However, we believe there are other genes that will be identified in further, larger studies which include people with more diverse ancestry, and these will help to establish if additional genes should be added to germline panel-testing. Black men are around twice as likely as men of European ancestry to develop prostate cancer so it's extremely important we also understand how genetic mutations influence the aggressiveness of their cancers."

Giving patients the best chance of successful treatment

Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research, London, and Honorary Consultant in Cancer Genetics and Clinical Oncology at The Royal Marsden NHS Foundation Trust, said:

"This study helps to explain the genetic factors behind why some patients see their prostate cancer remain stable over many years, while others may experience more aggressive disease that requires intensive treatment, or disease progression. Knowing whose cancer is likely to be aggressive, or become advanced, means we can tailor treatment – honing our prevention efforts, offering more intensive treatments earlier, and providing targeted drugs that work against the specific genetic make-up of their cancer.

"This study provides the first evidence that genetic testing should be extended to men with non-aggressive disease - alterations in certain genes amongst these men can indicate a higher risk of cancer becoming advanced despite their cancer appearing to be slow-growing. I hope our findings will be adopted into gene tests currently used in the clinic. This would greatly improve our ability to tailor their care and give them the best chance of successful treatment, and a longer, healthier life."

Lead author Christopher Haiman, ScD, holder of the AFLAC Chair in Cancer Research and professor of Population and Public Health Sciences at the Keck School of Medicine, and co-leader of the Cancer Epidemiology Program at USC Norris Comprehensive Cancer Center, said:

"Very large studies are needed to inform the creation of gene panels used for testing. Some of the genes in these panels were based on small studies and were not associated with prostate cancer in our study. We also found evidence that other genes perhaps ought to be added. The results aren't completely definitive, but it's clear that more work needs to be done to determine which genes oncologists should focus on in testing.

"While screening is focused on men with advanced disease or a family history, finding patients with less advanced disease who carry these genetic variants may enable them to receive targeted forms of treatment earlier on.

"It will be important for similar efforts to take place in men of African ancestry. That's very important. These genes and perhaps others may be important, so additional work needs to be done in other populations."


Ros Eeles prostate cancer personalised medicine Genetic testing
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