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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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Prediction models for miRNAs.A) ROC curves for age, PSA, and stage plus/minus individual miRNAs or combination of all 3 miRNAs. B) Percentage of patients with either Gleason 6 (light grey) or Gleason 7 (dark grey) post-surgery relative to pre-surgery CAPRA score. C) Same as B, but with addition of miRNAs. A value of 1 is given for each positive miRNA and added to CAPRA score. CAPRA nomogram combines the following variables: Age at diagnosis, PSA at diagnosis, Gleason score of pre-surgical biopsy, Clinical stage, and Percent of involved biopsies.
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pone-0098597-g004: Prediction models for miRNAs.A) ROC curves for age, PSA, and stage plus/minus individual miRNAs or combination of all 3 miRNAs. B) Percentage of patients with either Gleason 6 (light grey) or Gleason 7 (dark grey) post-surgery relative to pre-surgery CAPRA score. C) Same as B, but with addition of miRNAs. A value of 1 is given for each positive miRNA and added to CAPRA score. CAPRA nomogram combines the following variables: Age at diagnosis, PSA at diagnosis, Gleason score of pre-surgical biopsy, Clinical stage, and Percent of involved biopsies.

Mentions: To evaluate the ability of the confirmed miRNAs to discriminate patients with adverse pathology in the validation set, they were included in logistic regression models also adjusting for age, stage, PSA, and extent of biopsy involvement. When considered individually, all four miRNAs showed strong associations with case status, with odds ratios of 9.22, 12.67, 0.03 and 0.06 (p values < 0.01) (Table 3), although because of the relatively small sample size, confidence intervals for estimated odds ratios showed low precision. These miRNAs individually also showed improved discriminatory ability with AUCs of 0.85, 0.86, 0.84, and 0.83 relative to an AUC of 0.77 for a model including only age, PSA, stage, and biopsy involvement (Table 3). These improvements did not achieve significance at the 5% level (although results for miR-19b and miR-345 were significant at the 10% level). Next we evaluated models using different combinations of the miRNAs (Table 4). Notably, miR-19a and miR-19b appeared to be co-dependent, consistent with the fact that they are expressed from a common transcript, miR-17-92. Models consisting of a combination either miR-19a or miR-19b together with miR-345 and miR-519c-5p showed a AUC of 0.94, reaching high significance (pā€Š=ā€Š0.02 and 0.017 respectively) (Table 4 and Figure 4a).


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)

Prediction models for miRNAs.A) ROC curves for age, PSA, and stage plus/minus individual miRNAs or combination of all 3 miRNAs. B) Percentage of patients with either Gleason 6 (light grey) or Gleason 7 (dark grey) post-surgery relative to pre-surgery CAPRA score. C) Same as B, but with addition of miRNAs. A value of 1 is given for each positive miRNA and added to CAPRA score. CAPRA nomogram combines the following variables: Age at diagnosis, PSA at diagnosis, Gleason score of pre-surgical biopsy, Clinical stage, and Percent of involved biopsies.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098597-g004: Prediction models for miRNAs.A) ROC curves for age, PSA, and stage plus/minus individual miRNAs or combination of all 3 miRNAs. B) Percentage of patients with either Gleason 6 (light grey) or Gleason 7 (dark grey) post-surgery relative to pre-surgery CAPRA score. C) Same as B, but with addition of miRNAs. A value of 1 is given for each positive miRNA and added to CAPRA score. CAPRA nomogram combines the following variables: Age at diagnosis, PSA at diagnosis, Gleason score of pre-surgical biopsy, Clinical stage, and Percent of involved biopsies.
Mentions: To evaluate the ability of the confirmed miRNAs to discriminate patients with adverse pathology in the validation set, they were included in logistic regression models also adjusting for age, stage, PSA, and extent of biopsy involvement. When considered individually, all four miRNAs showed strong associations with case status, with odds ratios of 9.22, 12.67, 0.03 and 0.06 (p values < 0.01) (Table 3), although because of the relatively small sample size, confidence intervals for estimated odds ratios showed low precision. These miRNAs individually also showed improved discriminatory ability with AUCs of 0.85, 0.86, 0.84, and 0.83 relative to an AUC of 0.77 for a model including only age, PSA, stage, and biopsy involvement (Table 3). These improvements did not achieve significance at the 5% level (although results for miR-19b and miR-345 were significant at the 10% level). Next we evaluated models using different combinations of the miRNAs (Table 4). Notably, miR-19a and miR-19b appeared to be co-dependent, consistent with the fact that they are expressed from a common transcript, miR-17-92. Models consisting of a combination either miR-19a or miR-19b together with miR-345 and miR-519c-5p showed a AUC of 0.94, reaching high significance (pā€Š=ā€Š0.02 and 0.017 respectively) (Table 4 and Figure 4a).

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