Patients with prostate cancer exhibit changes in the levels of some urinary molecules compared with people with benign prostate diseases and healthy individuals, a study found, suggesting that these changes could be used to develop a highly sensitive, non-invasive diagnostic test for the condition.
The study, “Integrated RNA and metabolite profiling of urine liquid biopsies for prostate cancer biomarker discovery,” was published in the journal Scientific Reports.
Measuring the levels of prostate specific antigen (PSA) in blood has been a mainstay in prostate cancer screening and diagnosis for three decades, but the test fails to identify many people with cancer, and incorrectly diagnoses many healthy men with prostate cancer. Moreover, PSA levels are not good at distinguishing slow-growing cancers from aggressive ones.
Cancer cells exhibit an abnormal metabolism that helps them proliferate and survive, the remnants of which (metabolites) are secreted in urine. Scientists believe that measuring metabolites in urine can be a good approach for the early identification of cancer in a non-invasive, accessible manner.
“Tissue biopsies are invasive and notoriously difficult, because they often miss cancer cells, and existing tests, such as PSA elevation, are not very helpful in identifying cancer,” Ranjan Perera, PhD, director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital and the study’s senior author, said in a press release. “A simple and noninvasive urine test for prostate cancer would be a significant step forward in diagnosis.”
The researchers compared the metabolites, as well as the RNA molecules, found in the urine of 64 prostate cancer patients with those of 31 men with benign prostatic disease and 31 healthy individuals. RNA is a molecule that is produced using DNA. While RNAs are often used as templates to make protein, many RNAs are present in blood and secreted in urine.
In particular, they examined RNAs and metabolites that were present at different levels in the urine of prostate cancer patients than in controls.
The researchers were able to examine the RNA levels of 11 prostate cancer samples and 12 normal samples. While RNA levels alone were not enough to distinguish men with prostate cancer from healthy patients, an analysis of RNAs from cancer-specific genes revealed 13 pathways that were highly active in prostate cancer samples.
Similarly, 14 metabolic pathways were significantly different in prostate cancer patients. Those pathways were involved in the metabolism of some amino acids, in energy-producing chemical reactions, and in the metabolism of nucleotides — the building blocks of DNA.
These differences could distinguish men with prostate cancer from normal prostates or from diseased prostates. They could also distinguish men with slow-growing cancers from those with more aggressive cancers.
The metabolites involved in energy production, in particular, seemed to be significantly increased in aggressive prostate cancer samples, suggesting they could be used to identify men with rapidly progressing disease.
An integrated analysis looking at both RNA and metabolite levels confirmed that these energy production pathways — the glutamate pathway and the tricarboxylic acid cycle — were aberrant in prostate cancer samples, and that this was mainly dependent on the GOT-1 and GOT-2 genes, known to be involved in glutamate metabolism.
Researchers further validated the role of GOT-1 after discovering it is significantly higher in prostate cancer samples across several clinical datasets. GOT-2, however, had no significant differences.
“In this study, we discovered cancer-specific changes in urinary RNAs and metabolites, paving the way for the development of sensitive and specific urinary PCa diagnostic biomarkers either alone or in combination,” the researchers wrote.
They emphasized that theirs was a proof-of-principle study for the urine test, and must be validated in larger studies before it is incorporated into clinical use.
“We discovered cancer-specific changes in urinary RNAs and metabolites that — if confirmed in a larger, separate group of patients — will allow us to develop a urinary test for prostate cancer in the future,” said Bongyong Lee, PhD, first author of the study and a senior scientist at the Cancer & Blood Disorders Institute.