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Prostate Cancer Grades Can Be Distinguished Using MicroRNA Signature, Study Finds

NEW YORK (GenomeWeb) – A set of circulating microRNAs appears to be able to distinguish patients with very high-risk prostate cancer, according to a team of researchers from Northwestern University.

Northwestern's Chad Mirkin and his colleagues measured the expression level of miRNAs in serum from patients with low- and high-risk prostate cancer. As the researchers reported in the Proceedings of the National Academy of Sciences this week, the expression of five miRNAs — some of which had been linked previously to prostate cancer pathogenesis — differed between the two groups.

Currently, serum prostate-specific antigen is used as a prostate cancer screening tool, but, the researchers noted in their paper, there is no way to differentiate between aggressive and indolent forms of the disease, which may lead to overtreatment.

"This molecular signature will assist in differentiating patients who may benefit from therapy from those who can be closely monitored on active surveillance," Mirkin and his colleagues added in their paper.

Using an assay platform that they previously developed called Scanometric MicroRNA, or Scano-miR, the researchers profiled the exosomal miRNA of patients with very high-risk prostate cancer as determined by their Gleason score, and compared them to profiles from healthy controls and patients with low-risk prostate cancer. In the Scano-miR assay, exosomes are first isolated before undergoing miRNA extraction and ligation. Those ligated miRNAs are then hybridized onto miRNA microarrays, and spherical nucleic acid probes are added along with a gold enhancement solution. The probe signals are then read to determine miRNA expression levels.

From their discovery set of 16 samples, the investigators identified five exclusively expressed miRNAs. For instance, miR-200c was expressed in all samples with a high Gleason score and was below the limits of detection in the other samples. At the same time, the assay identified 58 miRNAs that were co-expressed in all samples.

Mirkin and his colleagues then validated this signature in a cohort of nine people with very high-risk prostate cancer, nine with low-risk prostate cancer and 10 healthy people using qRT-PCR. Among the nine very high-risk prostate cancer samples were samples from four patients who were initially diagnosed with low-risk prostate cancer but who were then found to have more aggressive disease.

In this set, the researchers also identified the five miRNAs. Four of these — miR-605, miR-135a*, miR-433, and miR-106a — were differentially expressed between the very high-risk prostate cancer samples, including those that had been initially undergraded, and the low-risk prostate cancer samples. Again, miR-200c was only expressed in samples from very high-risk prostate cancer patients. This suggested to Mirkin and his colleagues that the panel could be used to distinguish very high- and low-risk prostate cancer. They added that it appeared to do better than needle biopsy-based Gleason scoring at telling the subtypes apart.

The five miRNAs of this panel were mapped to 42 candidate pathways and five common pathways, including ones like the PI3K-Akt signaling pathway that have already been linked to cancer progression. This, the investigators noted, indicates that the miRNAs of their signature might target genes in pathways involved in the transition from local to metastatic prostate cancer.

"This work serves as an initial proof-of-principle study that circulating miRNA biomarkers can identify specific grades of [prostate cancer]," the researchers wrote, "and further investigations with larger numbers of patient samples are currently underway to validate the utility of using these biomarkers and scoring signature to unambiguously diagnose the disease."

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