British scientists have developed “the first reliable test of whether men are at high risk of prostate cancer”, reported the Daily Mail. It said the test has so far proven to be twice as precise as the existing PSA test, and is of urine rather than blood, which would make it cheaper to perform.

Prostate cancer is the most common cancer in men, affecting 35,000 men in the UK a year, with 10,000 of those dying from the disease. This research shows that men with the disease have reduced levels of a protein called MSMB.

This is very early laboratory research, and it is too early to suggest that the test “offers hope to thousands”. It is still not known whether a test based on this research could improve prediction of prostate cancer risk, prostate cancer diagnosis or disease monitoring. Larger studies within the community are needed before we have a better idea of whether this test could be a useful addition to the existing tests for prostate cancer.

Where did the story come from?

The study was carried out by researchers from the Cancer Research UK (CRUK) Cambridge Research Institute and other research centres in the UK, US and Australia. It was funded by the University of Cambridge, CRUK, The Institute of Cancer Research, The Everyman Campaign, the EU, Hutchison Whampoa Limited and The Prostate Cancer Research Foundation. The study was published in the peer-reviewed open-access journal PLoS ONE.

The Daily Mail, The Guardian, BBC News and The Daily Telegraph covered this story. They suggest that the test may be able to identify people at greater risk of prostate cancer and could be part of a screening programme.

However, some of the reports may give the wrong impression of how developed this test is. The research is still at an early stage, and it is not known whether this protein can be used to detect those at greater risk of prostate cancer, or how long it will take to become commercially available. There is much more work to be done on this test.

What kind of research was this?

The researchers say that previous genetic studies have identified a particular single letter genetic variation within a gene called MSMB that is more common in people with prostate cancer.

Which form of this single letter (nucleotide) variation, called rs10993994, a person carries has been found to affect how active their MSMB gene is. The form of the variation that is linked with prostate cancer (called the ‘high risk allele’) causes the MSMB gene to be less active than it normally would be. The MSMB gene produces a protein called microseminoprotein-beta (MSMB), which is the second most abundant protein in semen after prostate serum antigen (PSA).

About 30 to 40% of men of European descent carry the high-risk allele, and 70 to 80% of men of African descent. However, not all men carrying the high-risk allele will develop prostate cancer. Previous studies have suggested that men who carry one copy of the high-risk allele are 1.3 times more likely to develop prostate cancer than those with no copies of the high-risk allele.

The researchers were interested in further investigating the role that MSMB might play in prostate cancer, and whether the high-risk allele influenced this role. They were also interested in seeing whether MSMB could be used to differentiate between men with and without prostate cancer. In this study, they looked at levels of MSMB protein in prostate tissue and in urine samples from men with or without prostate cancer.

This sort of research is an appropriate way to start investigating whether a variation identified in genetic studies has an

effect on the disease in question. The diagnostic portion of this study should be considered to be preliminary, as much more research would be needed to support its usefulness as a diagnostic test.

What did the research involve?

The researchers first looked at the MSMB protein in benign and malignant prostate cancer tissue samples, and whether this varied in people with the high-risk form of rs10993994. As each person carries two copies of rs10993994, they also looked at whether having one or two copies of the high-risk allele affected levels of MSMB protein in the prostate. They then
looked at levels of the MSMB protein in urine samples, and whether this was related to levels of prostate serum antigen (PSA) in the urine, the presence or absence of prostate cancer, rs10993994 allele, and age at onset of prostate cancer.

The researchers also looked at whether levels of the MSMB protein was more accurate than PSA in telling apart urine samples from men with prostate cancer and men without prostate cancer.

The researchers used tissue, blood and urine samples collected from about 336 men with prostate cancer who had biopsies taken or their prostates removed at two UK hospitals between 1995 and 2008. They also used samples obtained from about 215 men taking part in another research study, who did not have prostate cancer or only had benign prostate lesions.

Varying numbers of men could be included in the different analyses, depending on what samples had been collected and the quality of these samples. For example, the tissue samples of 168 prostate cancer patients were examined under the microscope, while samples from 145 prostate cancer patients could be assessed to see which form of the rs10993994 variation they carried. Eighty-nine prostate cancer patients provided tissue, DNA and a urine sample.

What were the basic results?

Levels of MSMB protein were much lower in cancerous prostate tissue than normal prostate tissue. They were also reduced in a type of early pre-cancerous prostate lesion called prostatic intra-epithelial neoplasia (PIN) compared with normal prostate tissue.

Men who carried two copies of the high-risk rs10993994 allele had the lowest levels of MSMB protein in their prostate tissue. Those who carried no copies of the high-risk rs10993994 allele had the highest levels of MSMB protein in their prostate tissue.

The researchers then compared the levels of MSMB in urine samples from 89 men with prostate cancer and 215 men without prostate cancer. Men with prostate cancer had higher levels of MSMB protein in the urine than men without cancer.

Assessing levels of the MSMB protein in the urine was better at differentiating between men with and without cancer in this sample than assessing PSA levels. This was true for tumours of all different levels of aggressiveness (as measured by the Gleason score).

How did the researchers interpret the results?

The researchers concluded that the rs10993994 high-risk allele, which was identified by using genome-wide association methods, does have an effect on the prostate and prostate cancer. They say that they have provided “the first link” between such a genetic variation for prostate cancer and a potential test for use in human tissue and bodily fluids.
The researchers also say, “there is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring”.

Conclusion

This early research has found that MSMB protein levels in the urine vary between men with and without prostate cancer. Much more research will be needed to determine whether these findings can be used as the basis for improved detection of prostate cancer risk, prostate cancer diagnosis or disease monitoring.

When developing a diagnostic test, many factors have to be considered and tested. These include:

•Is the test accurate?

•How well does the test differentiate between those with and without the disease, or those at higher risk of the disease from those at lower risk?

•If the test is for predicting the likelihood of developing a disease, what can be done for those at higher risk? If there are no known ways of reducing a person’s risk, knowing that they were at higher risk might not be helpful.

•When used in practice, does the test improve people’s outcomes, e.g. reducing the likelihood of developing the disease or dying from the disease?

Better ways of detecting and monitoring prostate cancer are needed, and this research may well contribute to the development of these. However, it is too early to suggest that this study has already solved these problems and “offers hope to thousands”.

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