This research article focused on variances in the levels of different microRNAs (miRNAs) in
both the blood and urine of patients with prostate cancer, some of which
were metastatic. First off, it is necessary to understand what miRNAs
are. They are very short, non-coding, sections of RNA that bind to
complementary mRNAs and alter gene expression. So far, about 1,000
miRNAs have been discovered, and each of these is capable in altering
the gene expression of up to 1,000 genes. The hypothesis of this
research team was that differences in the levels of circulating miRNAs
in blood and urine could be correlated to prostate cancer. Furthermore,
they also believed that they could predict if the cancer was metastatic
In the first case, they found that 12 miRNAs were expressed in significantly higher concentrations in the blood of men with prostate cancer versus those without the disease (1).This indicates that in men with prostate cancer, there is a difference in the transcription rate of these miRNAs which means that genes are being controlled differently since miRNAs are involved with gene transcription regulation. This follows logically from what we know about cancer: there must be a difference in the expression of genes so that the cells proliferate indefinitely and resist apoptosis, among other events.These miRNAs should be able to be measured and determine a patient's likelihood of having prostate cancer.
However, after running statistical analysis software, the team found that this miRNA test did not have significantly greater specificity or sensitivity than the prostate specific antigen, or PSA, test which is the standard of care (1). This means that the levels of the miRNAs are too erratic to accurately test for the presence of prostate cancer in an individual.
On a more positive note, the team did find that this test was able to accurately predict if the cancer was metastatic or not. There were 16 miRNAs associated with metastatic cancer which were highly specific to the metastases. 15 of these miRNAs were expressed in significantly higher concentrations while 1 was expressed in significantly lower concentration in patients with metastatic cancer (1). Many of these miRNAs are at double the concentration in patients with metastatic cancer versus those with localized cancer, showing that large numbers of cells have altered their gene expression. This is very promising because this test is accurate enough to gauge the level of metastases of the cancer, which is something that the PSA test could not accurately do.
Another promising point of this research article was that urinalysis of men with prostate cancer versus those without it was shown to be highly accurate in predicting prostate cancer. There were 2 miRNAs that were significantly decreased in expression in the urine of men with prostate cancer. You can see in the figure at the right that both miRNA 107 and 574-3p had lower expression that was significant. This is shown because their 95% confidence intervals do not overlap very much at all. By using these 2 miRNAs as indicators, it is possible to predict if a patient has prostate cancer. The team also ran statistical analysis software on this test and found that it was more accurate in predicting prostate cancer cases than the PSA test (1).
Conclusion and Final Thoughts
I believe that this research team allowed some miRNA concentration differences to be classified as significantly different when, in fact, they were not. A lot of the p-values that they accepted were higher than the 0.005 value which is generally accepted. Furthermore, the fold change in many of the miRNAs was only about 2. If the fold change in concentration is that low, I believe that the p-value must be smaller in order to imply statistical significance. The research group claimed that their new screening method with blood samples was not better than the PSA test currently used and I believe that this is because they were testing for miRNA expression that had false significance in regards to prostate cancer. The research group should pursue testing and screening with miRNAs that showed a high fold change in concentration with a small p-value.
Based on their data, an appropriate cut-off for significance would be a fold change in concentration of about 5 and a p-value of less than 0.005. I determined these numbers based on the previous three tables in my blog. Since the team's test for metastatic versus non-metastatic was tested as accurate, I used the average p-value obtained in that series of tests. To determine the appropriate fold change in concentration, I analyzed the fold changes in both the blood test and the urine test and determined that a fold change of about 5 was suitable because it would eliminate many of the smaller fold changes while leaving about 5 miRNAs to be tested. I believe that these two changes would increase the specificity and decrease the sensitivity, which would benefit this screening method.
1. RJ Bryant1, T Pawlowski2, JWF Catto3, GMarsden1, RL Vessella4, B Rhees2, C Kuslich2, TVisakorpi5 and FC Hamdy. Changes in circulating microRNA levels associated with prostate cancer. British Journal of Cancer.