Engrailed-2 (EN2): a new tumour-specific biomarker on the horizon for prostate cancer screening

Prashanthi Ratnakumar, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP

Prostate cancer is the second commonest cause of death in men, and although curable, advanced and metastatic disease continues to be associated with poor prognosis. Currently, screening for prostatic cancer is carried out by testing for Prostate Specific Antigen (PSA) in serum samples. However, there has been some controversy about the specificity of this test, as PSA is a prostate-specific and not a prostate-cancer-specific biomarker; it is possible to have high levels of PSA in non-malignant conditions such as benign hypertrophy or prostatitis. Various trials looking at sensitivity and specificity of serum PSA as a marker for cancer (such as the Prostate Cancer Prevention Trial) have shown that there are significant limitations in use of the test for screening, and therefore there is significant value in finding a more specific biomarker for increased accuracy in screening.

A group in Surrey headed by Morgan et al looked at Engrailed-2 (EN2), a transcription factor belonging to the HOX family of genes. Based on previous research suggesting that EN2 was expressed and secreted in prostate cancer, but not in healthy prostate tissue, the group evaluated the diagnostic potential of EN2 as a biomarker in urine. The study was carried out in a single centre, recruiting 194 participants from asymptomatic patients with family history, with lower urinary tract symptoms, or with abnormal PSA readings. These were then compared against control groups, and presence of EN2 in first-pass urine samples was investigated using Western blotting, ELISAs, immunohistochemistry and semi-quantitative RT-PCR. Looking at the key results comparing sensitivity and specificity between the two, the current serum PSA test (using the clinical cut-off of 4ng/ml) shows sensitivity of 24% and specificity of 93%. In comparison, the cut-off chosen for EN2 of 42.5ng/ml showed sensitivity of 66% and specificity of almost 90%, suggesting that this may be a more discriminate biomarker for use at least in conjunction with serum PSA in screening tests. (1)

The study concluded that EN2 was of significant potential as a biomarker of prostate cancer using a simple ELISA test. Similar results were also found in a study conducted by an independent group in Cambridge, which used the same ELISA protocol for a separate population. This is promising: at present, our screening protocols for prostate cancer are still completely dependent on the serum PSA test, and so there is great scope for a marker such as EN2, which may bring increased sensitivity and specificity in primary screening, at least alongside serum PSA. Overall, there is a growing base of evidence for design of a multicentre trial to further investigate and refine a potentially vital screening test for one of our commonest, and most curable, cancers.

References: 

1. Morgan R, Boxall A, Bhatt A, Bailey M, Hindley R, Langley S, Whitaker HC, Neal DE, Ismail M, Whitaker H, Annels N, Michael A, Pandha H. Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer. Clinical Cancer Research 2011 Mar;17(5):1090 -1098.
doi: 10.1158/1078-0432.CCR-10-2410