Inherited gene faults could play greater role in advanced prostate cancer than previously thought

Inherited gene faults are more common among men with advanced prostate cancer than in those with localised disease, UK and US researchers have found.

The faults were discovered in genes that control how cells repair their DNA. And experts believe that patients carrying these faults may benefit from new drugs that target weaknesses in cells’ DNA repair machinery.  

Scientists from the Institute of Cancer Research (ICR), the Royal Marsden NHS Foundation Trust and seven US-based cancer centres used saliva samples to study patients’ inherited genetic profile – so-called ‘germline DNA’.

Around one in eight advanced prostate cancer patients (12%) were found to have at least one inherited fault in a DNA repair gene. This compared to around 5% in patients with localised disease.

Dr Imran Ahmad, a clinician scientist at Cancer Research UK – which part-funded the study – said the prevalence of inherited faults exceeded previous estimations in these patients.

“This new research shows that there are more inherited mutations affecting the DNA-repair machinery in some men with advanced prostate cancer than was previously thought,” he said. 

The analysis, published in the New England Journal of Medicine, was based on almost 700 men with advanced disease and publicly available data from almost 500 men with localised prostate cancer. Saliva samples were tested for faults in 20 genes known to be involved in DNA repair.

Among the genes that were tested was the breast cancer gene BRCA2, which was found to be faulty in 5% of men in the study.

Other faults indicated that some men with advanced disease may benefit from drugs called PARP inhibitors, which exploit weaknesses in the cells’ DNA repair machinery. But the researchers stressed that these were still being tested in clinical trials.

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“We could offer these men drugs such as PARP inhibitors, which are effective in patients with certain DNA repair mutations and are showing important anti-tumour activity in ongoing clinical trials,” said the ICR’s Professor Johann de Bono, who led the study.

Professor Paul Workman, the ICR’s chief executive, said the study’s findings suggest genetic testing for DNA repair faults could play a vital role in the treatment of men with advanced prostate cancer. 

“There is huge diversity in prostate cancers from patient to patient – some men live for decades with localised tumours, while in others cancers develop rapidly and spread round the body,” he said. 

“Genetic markers that can detect the patients at high risk are desperately needed to improve men’s survival chances.”

Cancer Research UK’s Dr Kahn added that the falling costs of this type of genetic analysis could one day make this possible.

“As the cost falls, the cancer sequencing approach used in this study will become more and more relevant, making it possible to routinely examine all men with advanced prostate cancer for inherited mutations,” he said.