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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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Related in: MedlinePlus

Distribution plots for serum miR-19b, miR-19a, miR-345, and miR-519c-5p delta Ct values in case versus control for a) discovery cohort, b) validation cohort.Delta Ct represents difference between Ct of individual miRNA and median Ct value among detected miRNAs within each patient. Horizontal bars represent mean +/– SEM.
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pone-0098597-g002: Distribution plots for serum miR-19b, miR-19a, miR-345, and miR-519c-5p delta Ct values in case versus control for a) discovery cohort, b) validation cohort.Delta Ct represents difference between Ct of individual miRNA and median Ct value among detected miRNAs within each patient. Horizontal bars represent mean +/– SEM.

Mentions: We next compared the serum levels of the 36 detected miRNAs between the case and control groups of the discovery cohort. Four of the detected miRNAs demonstrated differences in serum levels between the cases and controls. MiR-19a and miR-19b displayed lower ΔCt values in the case group compared to controls (Figure 2a, p = 0.06 and p = 0.07 respectively), consistent with higher serum levels in cases. Conversely, miR-345 and miR-519c-5p had significantly higher ΔCt values in the case group when compared to the controls (Figure 2a, p = 0.04 and p = 0.02 respectively), consistent with lower serum levels in the case group. Logistic regression models for predicting case/control status based on single miRNAs represented as binary indicators (with cut-off values selected using classification trees) showed all four miRNAs as highly significant predictors of outcome status (odds ratio) even when controlling for age, PSA, clinical stage, and degree of biopsy involvement (Table 3). Results were not sensitive to whether miRNAs were included in prediction models as continuous variables or as binary indicators based on median detectable levels (data not shown). A nonparametric random forest classifier including all detectable miRNAs (represented as continuous measures) as well as age, PSA, stage, and biopsy involvement ranked the following predictor variables as the six most important (in descending order): age, miR-519c-5p, miR_19b, miR-345, PSA and miR_19a (Figure 3). None of the other measured miRNAs were significantly associated with outcome status.


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)

Distribution plots for serum miR-19b, miR-19a, miR-345, and miR-519c-5p delta Ct values in case versus control for a) discovery cohort, b) validation cohort.Delta Ct represents difference between Ct of individual miRNA and median Ct value among detected miRNAs within each patient. Horizontal bars represent mean +/– SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098597-g002: Distribution plots for serum miR-19b, miR-19a, miR-345, and miR-519c-5p delta Ct values in case versus control for a) discovery cohort, b) validation cohort.Delta Ct represents difference between Ct of individual miRNA and median Ct value among detected miRNAs within each patient. Horizontal bars represent mean +/– SEM.
Mentions: We next compared the serum levels of the 36 detected miRNAs between the case and control groups of the discovery cohort. Four of the detected miRNAs demonstrated differences in serum levels between the cases and controls. MiR-19a and miR-19b displayed lower ΔCt values in the case group compared to controls (Figure 2a, p = 0.06 and p = 0.07 respectively), consistent with higher serum levels in cases. Conversely, miR-345 and miR-519c-5p had significantly higher ΔCt values in the case group when compared to the controls (Figure 2a, p = 0.04 and p = 0.02 respectively), consistent with lower serum levels in the case group. Logistic regression models for predicting case/control status based on single miRNAs represented as binary indicators (with cut-off values selected using classification trees) showed all four miRNAs as highly significant predictors of outcome status (odds ratio) even when controlling for age, PSA, clinical stage, and degree of biopsy involvement (Table 3). Results were not sensitive to whether miRNAs were included in prediction models as continuous variables or as binary indicators based on median detectable levels (data not shown). A nonparametric random forest classifier including all detectable miRNAs (represented as continuous measures) as well as age, PSA, stage, and biopsy involvement ranked the following predictor variables as the six most important (in descending order): age, miR-519c-5p, miR_19b, miR-345, PSA and miR_19a (Figure 3). None of the other measured miRNAs were significantly associated with outcome status.

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