Biomarker discovery: PCA3 for prostate cancer as an example

Biomarker discovery

A biomarker is defined as a measurable indicator of a particular disease or physiological state. With improving technological advances, such as genome-wide gene expression profiling and advanced bioinformatics, there has been an explosion of discovery and research in disease biomarkers that can improve our ability to diagnose, prognosticate, or predict patient outcomes. Theoretically, an ideal biomarker is a simple, cost-efficient, minimally invasive, consistent and measurable test with high sensitivity (few false-negatives) and high specificity (few false-positives). Here, we would like to take PCA3 as an example to illustrate how a biomarker is discovered, validated and developed.

PSA in prostate cancer screening

Prostate cancer is the most common visceral cancer in men worldwide and an important health problem. Currently, the most frequently used diagnostic biomarker for prostate cancer is the serum level of prostate-specific antigen (PSA) or its derived measurements. However, the specificity of PSA testing is quite limited. Elevations in serum PSA levels could be found in numerous benign conditions, leading to unnecessary biopsies and over-treatment.

Discovery and application of PCA3

Prostate cancer antigen 3 (PCA3, also referred to as differential display code 3; DD3) is a long non-coding RNA specifically produced by prostate gland.

In 1999, PCA3 was reported to be overexpressed in prostate cancer by differential display analysis comparing RNA expression patterns between normal and cancerous prostate tissues. In addition, no PCA3 RNA have been detected in non-prostate tissues (benign and cancerous), revealing that PCA3 is the most specific biomarker for prostate cancer to date. Since then, a quantitative urinary assay for PCA3 RNA has been developed. Compared to serum PSA, testing the urinary level of PCA3 is not affected by age, prostate volume or other prostatic diseases. Moreover, it shows greater sensitivity, specificity, and malignancy prediction than serum PSA.

In 2012, a commercially available assay, Progensa PCA3 (Gen-Probe), was approved as a diagnostic test by the FDA in the US. Now, the PCA3 assay serves to complement PSA testing and help clinicians make more informed decisions about a repeat biopsy.

Future biomarkers for prostate cancer

Because prostate cancer is a heterogeneous disease, several novel biomarkers are being investigated to improve the diagnosis. The use of a panel of more cancer-specific biomarkers will further improve diagnostic accuracy. It is expected that a combination of numerous urinary biomarkers will eventually replace PSA in the future.