Discovering how Down’s syndrome can protect against cancer

People with Down's syndrome have an extra dose of cancer-protective genes

Although it may not seem obvious at first, there are important links between Down’s syndrome and cancer.  Down’s syndrome affects one in every 1,000 babies born in the UK. Named after the British doctor who first described the disease in 1866, it happens when a baby gets an extra copy of (or part of) chromosome 21 – meaning that the child has three copies instead of the usual two.

As well as having learning difficulties and other health problems, people with Down’s syndrome are at increased risk of certain types of cancer, including some types of leukaemia as well as testicular cancer. But, intriguingly, they actually have a lower risk of many other types of solid cancer – such as bowel cancer – although the reasons for this aren’t clear.

In research published this month, Cancer Research UK-funded scientist Professor Kairbaan Hodivala-Dilke and her European colleagues have made a significant step forward in understanding why Down’s syndrome is linked to lower risk of these cancers, according to research published in this week’s Nature.  And their work points towards new avenues for preventing and treating cancer in the wider population.

Hunting for cancer-protective genes

Because people with Down’s syndrome have an extra copy of chromosome 21, they effectively carry an extra ‘dose’ of the genes on that chromosome – including any genes that protect against cancer. Working together with colleagues in the UK, France, Switzerland, Spain and Italy, Professor Hodivala-Dilke set out to track down some of these genes, and understand how they cut the risk of tumours.

To hunt for these genes, the researchers studied specially bred mice that carry most of human chromosome 21, and so have a condition very similar to Down’s syndrome. Because mouse and human genes are very similar, these mice are a reasonably good ‘model’ of Down’s syndrome and also have an unusually low risk of many types of cancer.

The researchers found that melanoma and lung cancer cells grew at a much slower rate in the Down’s syndrome mice, compared to genetically normal mice. When they looked closely, the scientists discovered that there were far fewer blood vessels growing into the tumours in the Down’s syndrome mice. This was an important clue, as we already know that the growth of blood vessels into tumours – a process called angiogenesis – is vital for cancers to grow and spread.

Normally, tumours produce a number of chemical signals that ‘trick’ the body into growing new blood vessels, including a molecule called VEGF. But the researchers found that the Down’s syndrome mice didn’t respond to VEGF, failing to produce new blood vessels in response to the signal – another clue.

The next step was to track down the genes involved. To do this, the team used a technique called RNA interference to ‘knock out’ individual genes found in the extra copy of human chromosome 21 carried by the mice.

They discovered that knocking out any of four genes – going by the rather clunky names of ADAMTS1, ERG, JAM-B and PTTG11P – switched blood vessel formation back on in response to VEGF.  This tells us that these genes normally help to prevent the growth of blood vessels. Researchers have previously known that ADAMTS1 and ERG are linked to angiogenesis, but the other two are new additions to the process.

What next?

These results suggest that having an extra ‘dose’ of any of these four genes can slow down the growth of blood vessels into tumours, in turn slowing down cancer growth. For a start, this explains why people with Down’s syndrome are at a lower risk of certain types of cancer, because they carry an extra copy of all of these genes.

But as Professor Hodivala-Dilke says, “The next stage is to think about how we might be able to exploit this and use it to develop cancer treatments in the future to block tumour growth.”

As we’ve written about on the blog before, angiogenesis research is a hot topic, and one that Cancer Research UK is actively funding.  Many scientists around the world are working on treatments that affect how tumours’ blood vessels grow, which could prevent the disease from growing and spreading, or improve the effectiveness of chemotherapy and other treatments.

This research provides us with four new ‘doors’ to walk through in the quest to beat cancer, and builds on results from other groups investigating the genes that underlie the reduced cancer risk in people with Down’s syndrome.  Although much more work needs to be done, perhaps in the future we’ll see treatments for cancer based on adding extra amounts of these genes, or the proteins they produce.

Finding out more about Down’s syndrome and cancer

Professor Hodivala-Dilke says that “It’s incredibly inspiring to know that by studying the genetic makeup of people with Down’s syndrome we have been able to make important discoveries that help us understand far more about the intricate processes involved in tumour growth.” But for Cancer Research UK, the story doesn’t stop there.

Since 2007, we’ve been funding the Children with Down’s syndrome Study (CDSS), which we also supported as a pilot trial back in 2005. The CDSS is the first systematic study of Down’s syndrome and cancer, collecting samples and information from more than 300 children with Down’s syndrome across the north of England, for five years from birth.

As we mentioned earlier, as well as having a lower risk of many types of cancer, people with Down’s syndrome are at higher risk of developing leukaemia, especially in childhood. The CDSS team are investigating certain genes on chromosome 21 known to be linked to leukaemia, as well as searching for new candidates.

Not only will the results from the study shed light on the genes involved in leukaemia, but they could also help doctors to pinpoint Down’s syndrome children who are at greatest risk of the disease.

Kat

Reference:

Reynolds, L. et al (2010). Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome Nature, 465 (7299), 813-817 DOI: 10.1038/nature09106