Hide and seek: tracing prostate cancer’s origins

In the well-known ‘Where’s Wally’ kids books, you had to try and pick out Wally from a sea of characters who were all wearing red-and-white striped outfits.

Somehow, you had to find Wally hiding among all these people who look just like him. He was only a little bit different from everyone else. Sometimes it was really hard to find that tiny little difference that made Wally, Wally.

And it can be just as hard to spot early changes that could develop into cancer.

But new research from our scientists suggests that, much like the sea of stripy tops Wally hides among, so seemingly ‘normal’ cells in a man’s prostate may also carry important genetic faults commonly found in tumours.

And this could have important implications for how the disease is treated when it’s caught early. Although it should be remembered that treatments for early-stage disease are very effective – survival is at an all-time high.

Finding Wally

Prostate cancer, the most common cancer in men, often occurs as many smaller tumours in the same prostate, all with different genetic fingerprints – something called ‘multi-focal’ disease.

Quite how often is still a matter of debate – some studies suggest six out of ten men with prostate cancer have multifocal disease. Others suggest it’s more like nine out of ten.

And just as the degree of this variation is still unknown, scientists are also trying to work out how it arises. Cracking this puzzle could open up new opportunities to work out how much of a man’s prostate is affected by the disease, giving doctors a better idea of how to treat it.

The leading theory is that the entire prostate is affected by a process, or processes, that cause it to slowly develop more and more cancer-like characteristics, and that different areas eventually tip over the edge into cancer.

And new research published in the journal Nature Genetics earlier this week – goes a long way to confirm this idea.

What’s normal?

The collaborative research team included scientists from The Institute of Cancer Research (ICR) in London, the Wellcome Trust Sanger Institute, and the University of Cambridge, who were working as part of a global project called the International Cancer Genome Consortium. This project is tasked with mapping the vast number of genetic changes found in lots of different types of cancer, and Cancer Research UK is supporting two teams – one looking at oesophageal cancer, another looking at prostate cancer.

And the prostate cancer team have found that what appears to be ‘normal’ prostate tissue might not be that normal after all.

Lead author Professor Ros Eeles, at the ICR, explains: “When we examine the cells that lie close to prostate cancer under the microscope, we look at their shape, size and relationship to surrounding cells. If everything appears normal then we may assume that we’re looking at healthy tissue.”

But advances in technology mean researchers no longer need to use the naked eye to ‘find Wally’ – Eeles and her colleagues went looking for his DNA fingerprint instead. The team took samples or biopsies from distinct areas of prostate tumours, as well as ‘normal’ tissue, from the prostates of three men. They then used advanced genome sequencing technology to read the complete DNA code inside the cells present in all these biopsy samples.

Crucially, the team found that normal-looking prostate cells surrounding the tumours were actually harbouring early genetic faults in their DNA that could develop into cancer.

The findings suggest that prostate cells that look normal under a microscope, actually carry a variety of genetic faults. Genetic mutations were found in almost half (48 per cent) of the ‘normal’ samples.

This strongly supports the idea that the processes that lead to prostate cancer are actually at work across the whole prostate, rather than being focused on one single area.

“It’s an important finding,” says Professor Malcolm Mason, a Cancer Research UK prostate cancer expert at the Velindre Cancer Centre in Cardiff. “This study adds further weight – and new detail – to previous findings that areas of the prostate around a tumour already contain some of the mutations which are found in the tumour itself.”

Refining treatment

But as well as shedding light on the way prostate cancer develops, it also could lead to improvements in how it’s treated. The past decade of prostate cancer treatment has seen a rise in new localised treatment techniques – for example, cryotherapy and high-intensity focused ultrasound – that aim to destroy or remove particular portions of the prostate, rather than surgically removing the whole gland, called a prostatectomy.

The thinking was to minimise the complications and side effects associated with prostatectomy.

But while these new procedures effectively got rid of the localised tumour, patients would still sometimes relapse.

This study provides one explanation for why this might happen, but also raises the question of whether doctors should treat the tumour cells and the precancerous cells at the same time.

Professor Mason explains: “Any treatment which does not destroy these abnormal cells would leave a risk that a tumour could recur, or a new one could form.”

“So future treatment plans would need to include an adequate margin around the tumour, which might mean a bigger part of the prostate, or possibly removal of the whole gland. How big an area, would be something that would need to be worked out in further studies.”

This is just one of many studies that will emerge from the International Cancer Genome Consortium, as researchers find out more and more about tumours’ genetic make-up. The key challenge, of course, is to translate these fascinating insights in biology, into new ways to improve things for people affected by the disease.

Misha

Reference

• Cooper, C., et al. (2015). Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue Nature Genetics DOI: 10.1038/ng.3221

Image

• Where’s Wally image by William Murphy under CC BY-SA 2.0, via Wikimedia Commons