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. 2012;7(8):e43470.
doi: 10.1371/journal.pone.0043470. Epub 2012 Aug 20.

Cell-free circulating plasma hTERT mRNA is a useful marker for prostate cancer diagnosis and is associated with poor prognosis tumor characteristics

José A March-Villalba  1 , José M Martínez-Jabaloyas, María J Herrero, Jose Santamaria, Salvador F Aliño, Francisco Dasí
Affiliations

Cell-free circulating plasma hTERT mRNA is a useful marker for prostate cancer diagnosis and is associated with poor prognosis tumor characteristics

José A March-Villalba et al. PLoS One. 2012.

Abstract

Background: Serum prostate-specific antigen (PSA) is the most widely used marker for diagnosing prostate cancer (PCa). It lacks specificity and predictive value, resulting in inaccurate diagnoses and overtreatment of the disease. The aim of this study was to assess the usefulness of plasma telomerase reverse transcriptase (hTERT) mRNA as a diagnostic and prognostic tool for PCa and its association with clinicopathological parameters of tumors.

Principal findings: Plasma hTERT mRNA levels were determined by qRT-PCR in 105 consecutive patients with elevated PSA levels and in 68 healthy volunteers. The diagnostic accuracy, the efficacy as a prognostic factor of biochemical recurrence and the association with tumor clinicopathological parameters of plasma hTERT mRNA and serum PSA tests were determined using univariate and multivariate analyses. The results show that plasma hTERT mRNA is a non-invasive biomarker for PCa diagnosis that shows higher sensitivity (85% vs. 83%), specificity (90% vs. 47%), positive predictive value (83% vs. 56%), and negative predictive value (92% vs. 77%) than serum PSA. Plasma hTERT mRNA is significantly associated with poor prognosis tumor clinicopathological parameters and is a significant independent predictor of PCa (p<0.0001). Univariate analysis identified plasma hTERT mRNA (but not serum PSA) as a significant prognostic factor of biochemical recurrence. Plasma hTERT mRNA Kaplan-Meier curves confirmed the significant differences between groups and patients with higher levels than the cut-off value showed diminished recurrence-free survival (p=0.004), whereas no differences were observed with serum PSA (p=0.38). Multivariate analysis indicated that plasma hTERT mRNA (but not serum PSA) and stage were significantly associated with biochemical recurrence.

Conclusions: Overall, these findings indicate that hTERT mRNA is a useful non-invasive tumor marker for the molecular diagnosis of PCa, affording a greater diagnostic and prognostic accuracy than the PSA assay and may be of relevance in the follow-up of the disease.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Flow diagram showing that PSA screening results in a high percentage of unnecessary biopsies.
One hundred and five consecutive patients with elevated PSA levels underwent prostate biopsy. Forty-six of the 105 patients (44%) were diagnosed with PCa, and fifty-nine patients (56%) showed no evidence of cancer. PCa: Prostate Cancer BPH: Benign Prostatic Hyperplasia.
Figure 2
Figure 2. Boxplot diagram showing hTERT mRNA, serum PSA levels and histopathological findings.
Data are expressed as median and interquartile range. A) Quantification of plasma hTERT mRNA levels discriminates between PCa patients and healthy individuals (p<0.001). B) Although PSA levels were significantly higher in PCa patients than in controls (p<0.001), quantification of serum PSA was unable to discriminate between PCa, BPH and prostatitis patients. BPH = Benign Prostatic Hyperplasia.
Figure 3
Figure 3. hTERT mRNA diagnostic accuracy. Comparison with serum PSA.
ROC curves show that plasma hTERT mRNA, but not serum PSA, discriminates between PCa patients and healthy individuals or patients with prostatitis or BPH. Plasma hTERT mRNA shows higher sensitivity (85% vs 83%), specificity (90% vs 47%), PPV (83% vs 56%), NPV (92% vs 77%) and AUC ROC (0.932 vs 0.651) than PSA with respect to PCa diagnosis. Pairwise comparison of hTERT mRNA and PSA ROC curves showed significant differences (p<0.001).
Figure 4
Figure 4. Efficacy of plasma hTERT mRNA and serum PSA as predictors of biochemical recurrence.
ROC curves show that plasma hTERT mRNA, but not serum PSA, is a significant predictor of biochemical recurrence. Plasma hTERT mRNA shows higher specificity (91.8% vs 87.7%) and AUC ROC curve (0.932 vs 0.658) than PSA with respect to biochemical recurrence. The PSA assay shows higher sensitivity (71.4% vs 100%) than hTERT mRNA in predicting biochemical recurrence. Pairwise comparison of hTERT mRNA and PSA ROC curves showed significant differences (p<0.001).
Figure 5
Figure 5. Kaplan-Meier analysis of time to biochemical recurrence.
Kaplan-Meier curves indicate that there are significant differences in recurrence-free survival between high and low hTERT groups (A) but not between high and low serum PSA groups (B).
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