Emerging biomarkers in the diagnosis of prostate cancer

Abstract

Prostate cancer (PCa) is the second most common cancer in men worldwide. A large proportion of PCa are latent, never destined to progress or affect the patients' life. It is of utmost importance to identify which PCa are destined to progress and which would benefit from an early radical treatment. Prostate-specific antigen (PSA) remains the most used test to detect PCa. Its limited specificity and an elevated rate of overdiagnosis are the main problems associated with PSA testing. New PCa biomarkers have been proposed to improve the accuracy of PSA in the management of early PCa. Commercially available biomarkers such as PCA3 score, Prostate Health Index (PHI), and the four-kallikrein panel are used with the purpose of reducing the number of unnecessary biopsies and providing information related to the aggressiveness of the tumor. The relationship with PCa aggressiveness seems to be confirmed by PHI and the four-kallikrein panel, but not by the PCA3 score. In this review, we also summarize new promising biomarkers, such as PSA glycoforms, TMPRSS2:ERG fusion gene, microRNAs, circulating tumor cells, androgen receptor variants, and PTEN gene. All these emerging biomarkers could change the management of early PCa, offering more accurate results than PSA. Nonetheless, large prospective studies comparing these new biomarkers among them are required to know their real value in PCa detection and prognosis.

Keywords: PCA3; PHI; PSA; four-kallikrein panel; miRNAs; prostate cancer.

Figure 1

Overview of PCa biomarkers according to the test’s clinical utility. Note: *Biomarker in evaluation. Abbreviations: AR-V7, androgen receptor splice variant-7; CTCs, circulating tumor cells; PCa, prostate cancer; PCA3, prostate cancer gene 3; PHI, Prostate Health Index; PSA, prostate-specific antigen.

Figure 2

Molecular forms of PSA. Notes: In serum, PSA (80%–95%) circulates mainly as a complexed form (cPSA) bound to several protease inhibitors (e.g., α1 anti-chymotrypsin and β2 macroglobulin). Free PSA is a small fraction of total PSA, which is also composed by three different subfractions: BPSA, iPSA, and proPSA. The native form of proPSA is [−7] proPSA, which contains a 7-amino acid N-terminal pro-leader peptide. Through the proteolytic cleavage of this peptide, promoted by the kallikrein hK2, the other truncated forms of proPSA, known as [−2], [−4], and [−5] proPSA, are produced. Abbreviations: ACT, alpha 1-antichymotrypsin; BPSA, benign PSA; cPSA, complexed PSA; hK2, human kallikrein 2; iPSA, intact PSA; PSA, prostate-specific antigen.