The ‘mystery’ culprit causing kidney cancer worldwide

Behind every cancer is a pattern of mutations.  

Mutations are small changes to the DNA in our cells. Not all mutations will lead to cancer, but if a cell accumulates enough of them, under certain conditions it may begin to divide and multiply uncontrollably, which is how cancer starts.   

Some mutations occur randomly, caused by things like mistakes that our cells make when trying to repair damage to our DNA. These mistakes will cause mutations that differ each time. 

But others, like those caused by chemicals in tobacco or UV radiation, leave a distinct mark. 

These marks are what we call mutational signatures. They’re unique to the carcinogen that caused them, meaning we can recognise them. For example, if we were to look at the DNA of someone who smokes, we would be able to tell which mutations had been caused by tobacco. 

Think of it like this: if a cancer cell was a crime scene, mutational signatures would be the fingerprints left by the culprit. 

Studying mutational signatures can also give us insight into why certain types of cancer are more common in certain countries, as specific carcinogens may be more prevalent in certain areas. 

When we find fingerprints we recognise, we can follow them back to their origin to identify what might have caused that cancer. But in cases when we don’t recognise them, we’ve got even more work to do.  

Matching an unknown fingerprint to its culprit is like detective work, but if we can crack the case, we might be able to use the results to prevent more cases of cancer in the future.  

Take smoking. It may seem obvious now that it causes cancer, but we didn’t know it until scientists found it’s fingerprints in cases of lung cancer. 

So, to give us the best chance of finding new culprits, we need a detective. Or, in this case, a team of them.  

Ambition on an epic scale

Mutographs is one of the teams of international researchers funded by Cancer Grand Challenges, the funding initiative we co-founded with the National Cancer Insitute in the US. 

Led by Professor Sir Mike Stratton and including researchers in the UK, US and France, Mutographs were funded by Cancer Grand Challenges in 2017 to identify unknown causes of cancer to help prevent more people from developing the disease. 

And in the spirit of a grand challenge, they’re not working on a small scale.  

They’ve collected samples from more than 5,000 people with bowel, kidney, oesophageal, bladder or pancreatic cancer across 5 continents. 

Importantly, these people are from countries with either high or low levels of these cancers. The driving factors behind these sometimes-huge differences in cancer incidence between countries are currently unknown, and Mutographs want to change that.  

The team hope to uncover the mutational signatures that are more common in countries with high incidence, and less common in those with low incidence.  

From there, they can work to link the signatures with what might be causing them and determine if those causes can be avoided in future to prevent more cancers. 

And new research from the team, published today in Nature, is taking us three steps closer. 

Around the world 

In the research, the team focussed on kidney cancer. 

We know that smoking, hypertension and obesity are all risk factors for kidney cancer, but these factors alone aren’t enough to explain the variation we see in incidence globally. There must be an additional cause, or causes, that we aren’t aware of. 

To dig deeper into that, Mutographs collected 962 samples from cases of clear cell renal cell carcinomas, the most common type of kidney cancer, across 11 countries.  

These countries included Lithuania and Czech Republic, which have some of the highest incidences of kidney cancer in the world, and Brazil and Thailand, which have a relatively low incidence. 

They extracted the mutational signatures from the genome of each person’s cancer and compared them to those found in the Catalogue of Somatic Mutations in Cancer (COSMIC) database, the world’s largest database of cancer mutations.    

That allowed them to see which mutational signatures each person’s cancer has in its DNA, what might have caused each one, and crucially, how that differed in kidney cancers between countries. 

From there, the detective work could begin. 

“These signatures are present in most Romanian cases, and quite a lot of Serbian cases, but rare elsewhere,” Senkin says.  

“We found out that the exposure to this specific carcinogen, which is known to cause kidney disease, is widespread. Potentially tens of millions of people in the Balkans are exposed to it.” 

So, in Romania and Serbia, the team were able to follow the fingerprints to find their culprit from an existing list of suspects. But over in Japan, there was something else going on. 

An unexpected offender

When the team analysed the DNA from the cases of kidney cancers in Japan, they found something unusual.  

There was a mutational signature that appeared in over 70% of Japanese cases but was almost entirely absent elsewhere. 

“Japan doesn’t have a particularly high incidence rate of kidney cancer, it’s very middle ground,” says Dr Sarah Moody, at the Wellcome Sanger Institute, the other co-lead of the study. “And we weren’t expecting to find anything unique in Japan.” 

If that weren’t enough, after looking over some old data, they found that this unknown carcinogen wasn’t just leaving its fingerprints in kidney cancers. Its signature had already been found in liver cancers. 

“When we reviewed the old data, it turned out that a majority of liver cancers in that cohort were from Japan, but nobody had really looked at the difference in the signature between the Japanese and the non-Japanese,” says Moody. 

“And when I went back and did that, I saw the exact same pattern. 

“So, we now know it’s affecting the kidneys, and we know it’s affecting the liver. But we don’t know what other tissues it might be affecting.” 

In both the European and Japanese cases, the signatures the team were finding were localised: visible in high numbers in specific areas, but rare across the rest of the world.  

But it was only when they began to zoom out that the true scope of their findings became clear.