Prostate cancer genetics

“Every man could have his risk of developing prostate cancer determined with a new screening test within four years,” said The Daily Telegraph today. The newspaper went on to add that researchers have found seven genetic variations that increase a man’s risk of developing prostate cancer by 60%. Although the variations are common individually, it was reported that having a combination of them significantly increases risk.

The report said that the researchers are now going to produce a test based on these genetic variations, so that men with the highest level of risk can be offered regular prostate screening.

Numerous news sources covered this well-conducted genetic study. Although the genetic variants that were identified may not themselves cause prostate cancer, they may be useful as part of a screening programme. However, as with all proposals that offer services to healthy people, more research is needed to show that such a screening programme will not only reduce mortality, but will also be simple to deliver, convenient for patients and will not cause harm, such as incorrect diagnosis.

The newspapers give differing information about the increased risk of prostate cancer if a man had all or some of these variants. For most of the variants identified, having two copies of a risk variant increased the risk of prostate cancer by between 19% and 61%, while having two copies of the least common variant doubled risk of prostate cancer. The study reported the increase in risk for each variant individually, and did not calculate the overall risk if a person had a combination of the risk variants.

Where did the story come from?

Dr Rosalind Eeles from the Institute of Cancer Research and colleagues at universities in the UK and Australia carried out the research. The study was published in the peer-reviewed scientific journal: Nature Genetics.

What kind of scientific study was this?

This was a genome wide association study (a type of case control study) that aimed to identify variations within the DNA that could be associated with susceptibility to prostate cancer.

The researchers took blood samples from 1,854 white men in the UK who had prostate cancer showing clinical symptoms. All the men had either been diagnosed by 60 or had a family history of prostate cancer as this meant that they were more likely to have a genetic component to their cancer than men diagnosed later or who had no family history.

The researchers also obtained blood samples from 1,894 white men aged 50 or over from the UK who did not have prostate cancer. All the men in this control group had low levels of prostate-specific antigen (PSA) and these men were chosen as men with low PSA levels are unlikely to develop prostate cancer.

The DNA was extracted from these blood samples and the researchers looked at 541,129 points in the DNA that were known to have variations to see whether they could find genetic variants that were more or less common in cases than in controls. To confirm these results the researchers repeated the tests on DNA from another 3,268 men with prostate cancer and 3,366 controls from the UK and Australia.

The researchers then looked at the genes near the identified variants and suggested some effects the variants might have.

What were the results of the study?

In the first stage of the study, the researchers found that variants in regions on chromosomes 8 and 17 were associated with risk of prostate cancer, confirming previous findings from other studies. They also found eight other variants associated with an increased risk of developing prostate cancer, and three variants associated with a reduced risk. Eight of these variants, located in seven different areas, were confirmed by the tests on the second set of cases and controls.

The researchers compared their results to those of another similar genome wide association study, and found that five of the eight variants had showed some association with prostate cancer in the other study.

Men who carried two copies of the risk variant on chromosome 3 were about twice as likely to develop prostate cancer as those who carried no copies of this rare risk variant. However, it is possible that this result might not be very accurate (the estimate had wide confidence intervals). When they looked at the other risk variants individually, having two copies increased the risk of prostate cancer by between 19% and 61% compared to men who had no copies of the risk variant.

When the genes located near these variants were examined, it was found that the variant with the strongest association with prostate cancer lay near the MSMB gene, a gene that encodes a protein that is made by cells in the prostate gland. It is possible that the newly-discovered variant could affect how active the MSMB gene is.

Another of the variants was located in a part of the LMTK2 gene that does not contain code that is translated into protein, and another lay between the genes KLK2 and KLK3.

What interpretations did the researchers draw from these results?

The researchers concluded that they have identified genetic variants in seven areas that are associated with prostate cancer. They say that their results show that prostate cancer is “genetically complex”, and may help in prostate cancer screening or in finding new therapeutic targets.

What does the NHS Knowledge Service make of this study?

This is a well-conducted genetic study, which increases confidence in its results by replicating its findings in a separate sample of individuals. However, there are some important points to note when interpreting this study:

• As the authors themselves report, the contribution of each of these genetic variants is “modest”, and together they explain only about 6% of the familial risk of prostate cancer. This means that there are probably many other genetic factors playing a role.
• As is the case with this type of study, even though a variant may be associated with a disease, this does not mean that it is causing the disease. Although some of the variants lie close to genes that could be involved in the development of prostate cancer, none of the variants have been proven to affect how these genes function. Until this can be done, it  cannot be assumed that they are “causing” prostate cancer.
• In order to improve the likelihood of detecting genetic variants that contribute to prostate cancer risk, the first part of this study included only men whose prostate cancer was likely to have had a genetic component: those whose cancer occurred at a younger age and those who had a family history of the disease. For men without these features, these genetic variants may contribute less to their susceptibility.
• This study included white men from the UK and Australia only. The variants identified may not play a role in risk of prostate cancer in men from other countries and with different ethnic backgrounds.

As the authors say, the genetics of prostate cancer is complex, and there will be many genetic and environmental factors playing a role. Further studies are needed before large-scale genetic screening programmes for susceptibility to prostate cancer become a reality.

Sir Muir Gray adds...

The decision not to introduce prostate cancer screening for all men was partly based on the knowledge that research was taking place that could identify men at higher risk; this is it and it does indicate that there may be a place for a focussed screening programme. Research to assess the effectiveness of a screening programme is now needed.