1 in 8 advanced prostate cancers may be linked to faulty genes

“Nearly one in eight men who develop [advanced] prostate cancer carry mutations in genes which repair damage to DNA,” The Daily Telegraph reports.

One of the difficulties in detecting and treating prostate cancer is that some cancers spread rapidly around the body (metastatic cancers) causing illness and death, while others grow very slowly within the prostate (localised cancers) and may never cause problems. There is currently no reliable test for showing which type of prostate cancer a man will get.

This study found that mutations in 16 genes linked to DNA repair were more common among 692 men with metastatic cancer compared to those with localised prostate cancer. This could suggest a way forward for treatment as scientists already know that men with metastatic prostate cancer and DNA repair gene mutations respond well to certain types of cancer therapy.

Research we discussed in 2015 suggests that a type of drug called olaparib, licensed for the use of ovarian cancer, may also help slow the progress of these types of gene-associated prostate cancers.

The researchers further suggest that, because DNA repair genes tend to run in families, causing breast, ovarian and pancreatic cancers as well as prostate cancer, a test might also enable men’s relatives to know their own risk.

However, screening is another issue that would warrant careful consideration of the possible benefits and harms.        

Where did the story come from?

The study was carried out by researchers from the University of Washington, Fred Hutchinson Cancer Research Center, Institute of Cancer Research and Royal Marsden Hospital, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, Prostate Cancer Clinical Trials Consortium, University of Michigan, Howard Hughes Medical Institute and Dana–Farber Cancer Institute.

Funding was provided by grants from institutions including Stand Up To Cancer, US National Institutes for Health and Department of Defense and Prostate Cancer UK.

Some of the authors reported commercial relationships with a number of pharmaceutical companies which manufacture prostate cancer drugs.

The study was published in the peer-reviewed New England Medical Journal. 

Much of the UK media seemed to miss the point of the story – that mutated DNA repair genes, including BRCA1 and BRCA2, are more common among men with advanced (metastatic) prostate cancer than localised prostate cancer.

The Daily Telegraph said that “nearly one in eight men who develop prostate cancer” carry mutations to DNA repair genes, which is not correct. The figure refers only to men in the study with metastatic cancer – men with localised cancer had a much lower rate of DNA repair gene mutation, at 4.6%. The Daily Mail made the same error, saying the “faulty BRCA2 gene is linked to 1 in 20 cases of the disease in men,” without explaining that this referred only to metastatic cancer.

BBC News correctly identified the figures as relating only to metastatic prostate cancer and explained the significance of the study.

The distinction is important as sometimes localised prostate cancer is slow-growing so it does not pose an immediate threat to health (in some cases, no threat at all). This means the treatment plan is entirely different than for metastatic prostate cancer.

What kind of research was this?

This was a case series study, in which researchers analysed the DNA of 692 men with metastatic prostate cancer (advanced cancer that’s spread to other parts of the body). They wanted to see how common it was for these men to have mutations in one of the genes known to be important for DNA repair, and then compare this to men with localised forms of the disease.

This type of study is useful to find how common something is within a specific group, but it is not a reliable way of comparing groups, because we don’t know if there are factors affecting the other groups that might skew the results. Also, it can’t tell us whether something (in this case a gene mutation) directly and independently causes something else (prostate cancer); only how many people with prostate cancer have a gene mutation.

What did the research involve?

Researchers analysed DNA from saliva or blood taken from 692 men who had been diagnosed with metastatic prostate cancer, from seven hospitals in the UK and US. Their DNA was analysed to check for the presence of variants among 20 genes known to affect DNA repair.

They compared their results to data from other studies of men with localised prostate cancer, and to databases of people not diagnosed with any cancer, to see whether these mutations were more common in men with metastatic cancer.

The men studied were not selected on any grounds other than their diagnosis – for example, their age, family history or initial prostate cancer risk score – because the researchers wanted to get an overview of how big a role gene mutations played in all metastatic prostate cancer. However, they went on to look at whether these factors affected the likelihood of having a gene mutation. 

The groups used for comparison of genetic data were:

• a study of 499 men with prostate cancer that had not spread from the prostate
• a database of 53,105 people without a cancer diagnosis

Researchers analysed the data for likelihood of having any mutation among the 20 genes studied, for mutations of specific genes, and for external factors that might have affected the results.

What were the basic results?

Of the 692 men with metastatic prostate cancer:

• 82 (11.8%) had at least one mutation in a DNA repair gene.
• 37 (44% of all mutations, 5.3% of the sample) had a BRCA2 gene mutation (a mutation also linked to breast and ovarian cancer in women).
• 15 other gene mutations were identified, but these were less prevalent (including BRACA1, 6 men, 7% of all mutations, 1% of the sample). 
• There was no difference between the numbers of men with and without DNA repair gene mutations who had a close relative with prostate cancer (22% for both groups). But 71% of men with these mutations had a close relative with another type of cancer, compared to 50% of men without these mutations.
• Age at diagnosis did not affect the chances of having DNA repair gene mutations.
• Men with a DNA repair gene mutation tended to have a higher prostate cancer risk score at diagnosis, but the numbers were too small to be sure of this result.

Comparing with other groups, 4.6% of men in the localised prostate cancer study had a DNA repair gene mutation, and 2.7% of people without a known cancer diagnosis.

The chances of having a DNA repair gene mutation were five times higher among men with metastatic prostate cancer, compared to people without cancer (odds ratio 5.0, 95% confidence interval 3.9 to 6.3).

How did the researchers interpret the results?

The researchers said their findings have “several important clinical implications.” They say that their findings of higher levels of DNA repair mutations among men with metastatic prostate cancer provides a “clear treatment pathway in accordance with precision medicine strategies,” because men with metastatic cancer and these mutations can be treated with specific treatments.

They also say that identifying these gene mutations provides useful information for male and female relatives, who can be counselled about their own cancer risk.

Conclusion

Much of modern cancer treatment is aimed at finding the right treatment for the right person, and this type of genetic research may help doctors to target treatments at the people who are most likely to benefit from them.

It’s not news that mutations in DNA repair genes like BRCA2 are linked to an increased risk of prostate cancer, although we are still some way from understanding how that link works. But the finding that these mutations seem to be much more common in men whose cancer has spread around the body is interesting.

Doctors have long wanted a test that could identify which prostate cancers are more likely to spread, and this genetic test could potentially add to the information that helps pinpoint that risk.

A class of medication known as poly ADP ribose polymerase (PARP) inhibitors has proved useful in treating other types of cancer associated with mutations in DNA repair genes. Further research to explore this avenue of potential treatment would be useful.

The study has important limitations. Different methods of DNA analysis were used in different hospitals, which might have affected the results. More importantly, there was no direct comparison group, so researchers were unable to balance or match men with metastatic cancer with men with localised prostate cancer of the same age or with the same family history, to get an unbiased comparison between the two groups.

The study used to compare rates of gene mutations in men with localised prostate cancer included mainly men with higher risk cancers, which means it may not be representative of all men with localised prostate cancer. This would affect the usefulness of the gene test in spotting men with cancer likely to spread.

The researchers’ call for men with prostate cancer to be tested so their relatives can then be counselled about their risk of cancer raises questions. Not all people with DNA repair gene mutations like BRCA1 and BRCA2 go on to get cancer, although the mutations do raise the risk of cancer.

Wider testing could put people into a position where they had to decide whether to take drastic preventive action (as actress Angelina Jolie famously chose to do by having her breasts and ovaries removed) or live with the risk.

Links To The Headlines

Genes which raise risk of prostate cancer discovered by scientists. The Daily Telegraph, July 6 2016

Prostate cancer: Test for inherited risk. BBC News, July 6 2016

‘Angelina Jolie gene’ may also cause prostate cancer: Faulty BRCA2 is linked to 1 in 20 cases of the disease in men. Daily Mail, July 7 2016

‘Angelina Jolie’ gene which triggers breast cancer may also cause prostate cancer. Daily Mirror, June 6 2016

DNA test to identify best prostate cancer treatment. The Times, July 7 2016 (subscription required)

Links To Science

Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. The New England Journal of Medicine. Published online July 6 2016