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miR-19, miR-345, miR-519c-5p serum levels predict adverse pathology in prostate cancer patients eligible for active surveillance.

Wang SY, Shiboski S, Belair CD, Cooperberg MR, Simko JP, Stoppler H, Cowan J, Carroll PR, Blelloch R - PLoS ONE (2014)

Bottom Line: Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease.In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression.It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Serum microRNAs hold great promise as easily accessible and measurable biomarkers of disease. In prostate cancer, serum miRNA signatures have been associated with the presence of disease as well as correlated with previously validated risk models. However, it is unclear whether miRNAs can provide independent prognostic information beyond current risk models. Here, we focus on a group of low-risk prostate cancer patients who were eligible for active surveillance, but chose surgery. A major criteria for the low risk category is a Gleason score of 6 or lower based on pre-surgical biopsy. However, a third of these patients are upgraded to Gleason 7 on post surgical pathological analysis. Both in a discovery and a validation cohort, we find that pre-surgical serum levels of miR-19, miR-345 and miR-519c-5p can help identify these patients independent of their pre-surgical age, PSA, stage, and percent biopsy involvement. A combination of the three miRNAs increased the area under a receiver operator characteristics curve from 0.77 to 0.94 (p<0.01). Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease. In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression. Together, these data show that serum miRNAs can predict relatively small steps in tumor progression improving the capacity to predict disease risk and, therefore, potentially drive clinical decisions in prostate cancer patients. It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.

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Staining for miR-19b in patient tumor samples.Images show in situ hybridization staining for miR-19b (left and center panels) and negative control, miR-295 (right panels). Top panels show area of prostate intraepithelial neoplasia (PIN). Middle panels show area of Gleason 3. Bottom panels show area of Gleason 4. Areas of PIN, Gleason 3, and Gleason 4 all stain strongly for miR-19b probe (blue staining). Note each panel has area of normal-appearing epithelium, most clearly seen on the left of each center panel. These areas show much lower staining. Right and left panels, 100× magnification. Center panels, 400× magnification. Center panels represent boxed areas in left panels.
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pone-0098597-g005: Staining for miR-19b in patient tumor samples.Images show in situ hybridization staining for miR-19b (left and center panels) and negative control, miR-295 (right panels). Top panels show area of prostate intraepithelial neoplasia (PIN). Middle panels show area of Gleason 3. Bottom panels show area of Gleason 4. Areas of PIN, Gleason 3, and Gleason 4 all stain strongly for miR-19b probe (blue staining). Note each panel has area of normal-appearing epithelium, most clearly seen on the left of each center panel. These areas show much lower staining. Right and left panels, 100× magnification. Center panels, 400× magnification. Center panels represent boxed areas in left panels.

Mentions: The uncovered serum miRNAs may arise directly from the tumor or from the body's response to the tumor. In order to determine whether the predictive miRNAs are present in prostate tumors, we performed in situ hybridizations with probes for miR-19b on FFPE tumor samples from patients in our cohort (n = 10). We focused on miR-19b as it reached significance in both the discovery and validation sets. Note that the miR-19b probe is unlikely to discriminate between miR-19a and miR-19b due to their highly similar sequences. Staining for miR-19b was strong in areas of high-grade PIN, Gleason pattern 3, and Gleason pattern 4, but absent in normal appearing epithelium (Figure 5). However, there was no obvious difference in intensity of staining with increasing grade from PIN to Gleason pattern 4. Therefore, while miR-19 cellular levels clearly increased with transformation, it was unclear if there was any further increase within the cells with pathological progression.


miR-19, miR-345, miR-519c-5p serum levels predict adverse pathology in prostate cancer patients eligible for active surveillance.

Wang SY, Shiboski S, Belair CD, Cooperberg MR, Simko JP, Stoppler H, Cowan J, Carroll PR, Blelloch R - PLoS ONE (2014)

Staining for miR-19b in patient tumor samples.Images show in situ hybridization staining for miR-19b (left and center panels) and negative control, miR-295 (right panels). Top panels show area of prostate intraepithelial neoplasia (PIN). Middle panels show area of Gleason 3. Bottom panels show area of Gleason 4. Areas of PIN, Gleason 3, and Gleason 4 all stain strongly for miR-19b probe (blue staining). Note each panel has area of normal-appearing epithelium, most clearly seen on the left of each center panel. These areas show much lower staining. Right and left panels, 100× magnification. Center panels, 400× magnification. Center panels represent boxed areas in left panels.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043973&req=5

pone-0098597-g005: Staining for miR-19b in patient tumor samples.Images show in situ hybridization staining for miR-19b (left and center panels) and negative control, miR-295 (right panels). Top panels show area of prostate intraepithelial neoplasia (PIN). Middle panels show area of Gleason 3. Bottom panels show area of Gleason 4. Areas of PIN, Gleason 3, and Gleason 4 all stain strongly for miR-19b probe (blue staining). Note each panel has area of normal-appearing epithelium, most clearly seen on the left of each center panel. These areas show much lower staining. Right and left panels, 100× magnification. Center panels, 400× magnification. Center panels represent boxed areas in left panels.
Mentions: The uncovered serum miRNAs may arise directly from the tumor or from the body's response to the tumor. In order to determine whether the predictive miRNAs are present in prostate tumors, we performed in situ hybridizations with probes for miR-19b on FFPE tumor samples from patients in our cohort (n = 10). We focused on miR-19b as it reached significance in both the discovery and validation sets. Note that the miR-19b probe is unlikely to discriminate between miR-19a and miR-19b due to their highly similar sequences. Staining for miR-19b was strong in areas of high-grade PIN, Gleason pattern 3, and Gleason pattern 4, but absent in normal appearing epithelium (Figure 5). However, there was no obvious difference in intensity of staining with increasing grade from PIN to Gleason pattern 4. Therefore, while miR-19 cellular levels clearly increased with transformation, it was unclear if there was any further increase within the cells with pathological progression.

Bottom Line: Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease.In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression.It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Serum microRNAs hold great promise as easily accessible and measurable biomarkers of disease. In prostate cancer, serum miRNA signatures have been associated with the presence of disease as well as correlated with previously validated risk models. However, it is unclear whether miRNAs can provide independent prognostic information beyond current risk models. Here, we focus on a group of low-risk prostate cancer patients who were eligible for active surveillance, but chose surgery. A major criteria for the low risk category is a Gleason score of 6 or lower based on pre-surgical biopsy. However, a third of these patients are upgraded to Gleason 7 on post surgical pathological analysis. Both in a discovery and a validation cohort, we find that pre-surgical serum levels of miR-19, miR-345 and miR-519c-5p can help identify these patients independent of their pre-surgical age, PSA, stage, and percent biopsy involvement. A combination of the three miRNAs increased the area under a receiver operator characteristics curve from 0.77 to 0.94 (p<0.01). Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease. In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression. Together, these data show that serum miRNAs can predict relatively small steps in tumor progression improving the capacity to predict disease risk and, therefore, potentially drive clinical decisions in prostate cancer patients. It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.

Show MeSH
Related in: MedlinePlus