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Study identifies marker for high-risk prostate cancers

Tuesday 19 November 2013

"Prostate cancer patients could be screened to detect aggressive tumours after scientists identified a protein linked to severe forms of the disease," reports The Daily Telegraph. The news is based on the results of a complex laboratory study looking at a protein called NAALADL2.

Scientists found that levels of NAALADL2 were high in prostate cancer when compared with healthy tissue, and levels were higher in more aggressive and more extensive prostate tumours.

The level of the protein found in the tumours was also linked to whether men survived without recurrence of the cancer and overall survival after having radical prostatectomies (surgery to remove prostate cancer).

This is exciting news as one of the biggest problems in helping men with prostate cancer is estimating the likely outcome. Some prostate cancers cause no or few symptoms and do not have any impact on life expectancy – doctors may tell you that "many men die with prostate cancer, not of prostate cancer".

Other prostate cancers can be extremely aggressive. Around 10,000 men die of the disease in the UK per year.

A test that could accurately identify high-risk cancers could potentially save lives and spare men with low-risk cancers unnecessary testing and treatment.

So far this is early-stage research. The next hurdle is to see if the results of the lab research can be applied in the real world, and, most importantly, whether it can be used to help improve outcomes for men with prostate cancer.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and the Karolinska Institute in Sweden. It was funded by Prostate Cancer UK. The researchers also acknowledged support from the University of Cambridge, Cancer Research UK, the National Medical Research Council, and Hutchison Whampoa Limited, Singapore.

It was published in the peer-reviewed journal Oncogene.

The media reporting of this story was variable. The Daily Telegraph and the Daily Mail's reporting was fairly accurate, though it is premature to suggest a blood screening test is on the way as the Daily Mail reports.

The research is still at an early stage. The majority of the work done so far has been on tissue samples, not on blood. The diagnostic accuracy of a blood test (probably measuring levels of mRNA, the messenger used to make protein) needs to be investigated.

Even if a blood test were then developed, further research would need to demonstrate that it actually gave additional benefits and improved outcomes before it was ever brought into clinical use. 

What kind of research was this?

This was laboratory-based research using samples from normal, benign (non-cancerous) and cancerous tissue from people, as well as using cell lines grown in the laboratory. The researchers were interested in a protein called NAALADL2.

What did the research involve?

The researchers initially looked to see if the NAALADL2 protein was present in a range of normal and tumour tissues from different parts of the body.

They then looked at whether the presence of NAALADL2 could differentiate between benign and cancerous tissue, and whether it could predict survival. Prostate tissue was taken from men who had radical prostatectomies (surgery to remove the prostate cancer) in Cambridge or Stockholm.

The researchers then investigated the localisation of NAALADL2 within the cell, what cells making NAALADL2 can do, and which other genes are switched on (expressed) in combination with NAALADL2.

What were the basic results?

NAALADL2 was present at high levels in colon and prostate cancers.

By measuring the amount of the protein, researchers were able to distinguish between benign and cancerous prostate tissue with a relatively good level of accuracy.

They found that in a group of samples from men in Cambridge:

  • the level of sensitivity was 86% (sensitivity is the percentage of cancerous samples that were correctly given a positive result)
  • the level of specificity was also 86% (specificity is the percentage of benign samples correctly given a negative result)

Similar findings were seen in samples from a group of men from Stockholm.

Levels of NAALADL2 protein increased with the increasing aggressiveness of the prostate cancer, based on the microscopic appearance of the tissue (Gleason grade).

Levels of NAALADL2 protein also increased with cancer stage (the extent and spread of the tumour), particularly between T2 (cancer confined to the prostate gland) and T3 (cancer that has begun to grow and spread outside the prostate into the seminal vesicles, the glands that produce the fluid component of semen).

Levels of NAALADL2 RNA (the "messenger" needed to make NAALADL2 protein) in the blood were found to be higher in men with biopsy-confirmed prostate cancer, compared with men who had raised prostate specific antigen (another protein associated with prostate cancer) but a negative biopsy.

The researchers then looked at whether levels of NAALADL2 protein could predict survival. One hundred and four men had radical prostatectomies in Cambridge, and 38 had recurrence of the cancer over a median follow-up period of 86 months.

There was a trend that higher levels of NAALADL2 led to poorer outcomes, but this wasn't statistically significant. The researchers suggested that this might be because of the small number of men: the smaller the sample size, the less "statistical power" the results have.

They then looked at data from Stockholm: in this cohort, there were 252 men, and 101 of them had recurrence over a median follow-up of 61 months.

Of men with low levels of NAALADL2, 79.9% had no relapse at five years. Five-year recurrence-free survival was reduced to 72.5% for men with moderate levels of protein, and 65.3% for men with high levels of protein (hazard ratio 1.9). The result was still significant after adjusting for a number of factors, including the Gleason grade and cancer stage.

Levels of NAALADL2 could also predict poor survival in low-risk patients (patients with low Gleason grades and cancer stage). Five-year survival was 93% in men with low levels of NAALADL2 and 45% in men with high levels of NAALADL2.

The researchers found that NAALADL2 protein on the basal (base) cell surface, where it promotes cell adhesion, migration (movement) and invasion (movement into tissue). They suggest that this could allow cells to escape the prostatic capsule and form tumours elsewhere. NAALADL2 was found to be expressed alongside androgen-related genes and prostate cancer biomarkers.

How did the researchers interpret the results?

The researchers conclude that, "NAALADL2 protein is expressed in a number of cancers, and highly expressed in prostate cancer, where it predicts for relapse following radical prostatectomy".

They go on to say that, "These data suggest that changes in expression of NAALADL2 can impact upon a number of pathways [involved in cancer development], making it a useful biomarker for both diagnosis and prognosis."


This interesting early-stage research suggests the future potential of using levels of NAALADL2 as an indicator to predict the likely course of prostate cancer.

However, much further research is required to see whether a test could one day be developed that could be used to distinguish between different types of prostate cancer.

Importantly, if such a test were developed, it would need to be demonstrated (for example, through randomised controlled trials) that this gave any benefit when compared with current diagnostic and staging methods, and ensure that it actually improved outcomes for men with prostate cancer. 

Analysis by Bazian
Edited by NHS Website

Links to the headlines

£2 blood test may end needless prostate cancer treatment by assessing levels of protein and identifying life-threatening tumours

Mail Online, 19 November 2013

Test for aggressive prostate cancer

The Daily Telegraph, 18 November 2013

Links to the science

Whitaker HC, Shiong LL, Kay JD, et al.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype

Oncogene. Published online November 18 2013