Value Of MicroRNA-182 And Prostate Health Index In The Diagnosis Of Prostate Cancer Patients With PSA Gray Zone

Background and objectiveProstate cancer(PCa)is one of the most common malignancies in males worldwide and one of the principal causes of death from cancer in the male population.Although there currently are FDA-approved biomarkers and other useful supplementary tests,effective biomarkers supporting diagnosis and prognostic of PCa are still lacking.The clinical use of serum prostate-specific antigen(PSA),the first FDA approved test,has facilitated the detection of PCa at early disease stages but owing to the lack of cancer-specificity,its use is associated with high false-positive rate and detection of non-life threatening PCa(overdiagnosis)and consequent overtreatment.Especially in patients with PSA levels between 4.0 and 10.0 ng/ml(gray zone),results in a high rate of unnecessary traumatic biopsies.Prostate health index(PHI)is the FDA-approved blood test.This test integrates the values of p2PSA(precursor PSA isoform),free PSA(fPSA),and total PSA(tPSA)in an algorithm that tries to distinguish PCa from benign forms among patients with PSA levels between 4.0 and 10.0 ng/mL(gray zone)and normal digital rectal examination(DRE).Previous studies have shown that this test might play a role as a tool able to diminish overdiagnosis and overtreatment in a PCa clinical scenario.MicroRNAs(miRNAs)are small non-coding RNA molecules,with about 22 nucleotides,which act as modulators of gene expression in human cells and tissue.MiRNA expression signatures have been shown to differ between cancer and normal tissues and also among cancer subtypes.MiR-182,of the miR-183 cluster family,is consistently expressed at high levels in many human cancer types.Previous research has shown that miR-182-5p is one of the most significantly up-regulated miRNAs in prostate cancer compared with para-cancer tissues and may be a potential diagnostic indicator of prostate cancer.In this study,the expression levels of miR-182 and the value of PHI in PCa and BPH patients with PSA gray zone were detected to evaluate their diagnostic value and the predictive value for aggressive PCa with Gleason score? 7,and compare them with the traditional indicators.Materials and methods1.Patients and controls:100 cases of PCa patients and 50 cases of PBH patients confirmed by the department of Urology Surgery of the First Affiliated Hospital of Zhengzhou University were selected.All the 150 cases were DRE(-),had the serum PSA levels between 4.0 and 10.0 ng/mL(gray zone)and underwent transrectal ultrasonography guided biopsy(TRUSP)of the prostate.2.Detection of plasma miR-182:The expression level of miR-182 in plasma samples of the PCa and BPH patients was detected by real-time quantitative polymerase chain reaction(qRT-PCR).3.The serum levels of tPSA and fPSA were detected before biopsy.The detection of tPSA and fPSA was completed by the Clinical Lab of First Affiliated Hospital of Zhengzhou University,the level of p2PSA was detected by using human p2PSA ELISA Kit(Beckman Coulter).The PHI was calculated using the formula:PHI=(p2PSA/fPSA)×?tPSA.4.Statistical analysis:The SPSS 21.0 and Prism 7.0 software were used for data analysis of the indicators and graph drawing.Using the receiver operating characteristic curve(ROC)and area under curve(AUC)to analyze the diagnostic value of the indicators separate or in combination,the MedCalc was used to compare the difference of AUC values.All the analyses in this study were two-tailed and the P vales less than 0.05 were deemed statistically significant.Results1.Compared with the BPH group,the expression level of miR-182 in PCa patients was significantly up-regulated(0.084±0.031 vs 0.057±0.029,P<0.001).The AUC of miR-182 in the diagnosis of PCa was 0.728(95%CI:0.649-0.797),with a sensitivity of 84.0%and a specificity of 52.7%.2.The level of PHI in PCa patients with PSA gray zone was significantly higher than that in the control group(50.78±21.82 vs 35.37±15.12,P<0.001).The AUC of PHI in differentiating of PCa group from BPH group was 0.741(95%CI:0.653-0.830),with sensitivity of 73.0%and specificity of 68.0%.3.miR-182 and PHI had higher diagnostic eficacy(AUC)compared with the traditional diagnostic marker tPSA(P<0.05).At prespecified sensitivity of 85%,the PHI and miR-182 had a better specificity compared with traditional markers.Take the value of miR-182 or PHI as a reference,40(26.7%)or 37(24.7%)patients could have avoided undergoing a biopsy,respectively.There was no significant difference in AUC between the two indicators(0.728 vs 0.741,P=0.821).4.The PCa patients were divided into two groups according to the tumor aggressiveness(Gleason score),the levels of PHI and p2PSA in high score group(GS?7)were higher than those in patients with GS?6(P<0.05).PHI was also the strongest predictor of PCa with GS?7.There was no statistical significance in miR-182 between the two groups(P=0.154).5.The AUC of miR-182 combined with PHI in the identification of PCa and BPH patients with PSA gray zone was 0.802(95%CI:0.729-0.862),higher than that of the miR-182 or PHI separately.The results showed that the value of combined diagnosis was better than that of single indicator.Conclusions1.The relative expression level of plasma miR-182 in PCa patients with PSA gray zone was significantly up-regulated.This suggests that miR-182 has a potential diagnostic value for PCa.2.The value of PHI was significantly increased in PCa group compared with the BPH group and higher PHI was also associated with more aggressive PCa.3.Compared with the traditional indicators,PHI and miR-182 had a better diagnostic value and can reduce the proportion of unnecessary prostate biopsies.4.miR-182 combined with PHI is superior to single indicators in the diagnosis of PCa,and might contribute to the early noninvasive diagnosis of PCa patients with PSA gray zone.