DNA strand double helix
One of the best ways to save lives from cancer is preventing tumours from developing in the first place.
But like any new treatment, ways to prevent cancer also have to be tested in clinical trials to make sure they work. Even something as widely used as aspirin, for example, is no exception and is currently being scrutinised in large-scale cancer prevention studies across the world, to make sure its potential benefits as well as harms are understood.
Clinical trials are still tests though, and there’s no guarantee that they will have a positive outcome. While we need trials to be certain that a new way to prevent cancer saves lives, a failure can be costly and potentially harm people.
But there’s an exciting new area of research that may help to better predict if a clinical trial is likely to succeed or not. And researchers can do this by simply by looking at the natural variety in our genes.
In a study published yesterday in the Journal of the National Cancer Institute, led by Professor Richard Martin from the University of Bristol, a team of researchers looked at genetic data from tens of thousands of people and compared it to a clinical trial that wasn’t successful. They wanted to see if their new method – called Mendelian randomisation – could have predicted the trial’s outcome.
The results were almost bang on the mark.
A trial with unintended consequences
Let’s hop back in time to 2001 and take a look at the newly launched Selenium and Vitamin E Cancer Prevention Trial (SELECT). Based on results from population and lab research, doctors set up the trial with the aim of finding out whether taking vitamin E or the chemical selenium as daily diet supplements could lower the risk of prostate cancer.
It was a large trial; more than 35,000 healthy men from the US, Puerto Rico and Canada signed up to take part.
The men were split into 4 groups and given a dummy pill, a vitamin E supplement, a selenium supplement, or both vitamin E and selenium together. Doctors measured levels of vitamin E and selenium in blood samples taken from the men, then kept records of what happened to the men over the next 5 years.
The first results from the trial were released in 2008, and the figures were concerning.
Although it was early days, the results suggested that men taking vitamin E by itself were at increased risk of developing prostate cancer, and suggested those taking selenium were at a higher risk of developing type 2 diabetes. Men taking part were told to stop taking their supplements.
Follow up results in 2011 confirmed the early findings – men taking vitamin E were at 17% increased risk of developing prostate cancer.
There was weaker evidence that while selenium didn’t affect the overall risk of prostate cancer and so didn’t prevent the disease as predicted, men were more likely to develop an aggressive form of the disease. And more men taking selenium developed diabetes, although again this link was less certain.
The trial was abandoned at a cost of $114m (£84.5m) and had led to more cases of prostate cancer. But that’s just science, right?
Was the answer in our genes all along?
According to Martin and his newly-published research published, there may have been a way to predict this result in advance.
The basis of ‘Mendelian randomisation’ is natural variation in our genes, says James Yarmolinsky, a PhD student in Martin’s lab and one of the study authors.
“We’re interested in genetic variation at certain locations in our DNA that we’re born with – called SNPs – that subtly affect differences that exist between individuals in many of their characteristics, like hair colour, body weight, and blood pressure,” Yarmolinsky says.
Even though as individuals we look quite different to each other, our DNA is remarkably similar: 99.5% identical. But SNPs can change the instructions of our DNA code, resulting in slightly different protein molecules being made. Such genetic differences give us variation as a species and are the backbone of evolution.
“We are studying these SNPs because of the way that we randomly inherit them from each of our parents,” Yarmolinsky says.
“This random process mimics how researchers carry out clinical trials to test out potential treatments for diseases, where people are randomly assigned to which treatment group they’re in. That’s why Mendelian randomization is sometimes called ‘Nature’s randomised controlled trial.’”
The researchers think in some cases, SNPs could give us better information than traditional studies of large groups of people, helping us understand things we could do to lower cancer risk, such as behaviour and lifestyle changes.
Starting with selenium
The level of selenium found in the bloodstream is partially down to a person’s genes, says Yarmolinsky.
So seeing if genetics can offer the same information as the SELECT trial found is “a good place to start”, he adds. Instead of the researchers changing the levels of selenium in trial participants’ bloodstreams using supplements, they could just look at how these levels vary naturally thanks to our genetics.
Previously published research had already identified a group of SNPs that are strongly linked to selenium levels in people’s blood.
There are 4 chemical ‘letters’ that make up DNA. Scientists spot SNPs by looking for variations in the sequence of letters throughout our DNA. “If we know what letter different groups of people have at each of these SNPs in their DNA, we can accurately compare differences between their selenium levels,” explains Yarmolinsky. “So the question we wanted to answer was could we use a set of these ‘selenium SNPs’ to replicate the results of the SELECT trial?”
At the end of the trial, the amount of selenium in blood samples from men taking the supplement increased by around 114 micrograms per litre of blood as compared to men not taking it. So the researchers used a set of SNPs that allowed them to estimate the effect of increasing blood selenium to a similar level as that achieved by the trial.
Then they looked at these same combinations of SNPs in more than 70,000 men who had taken part in other studies around the world, allowing them to recreate the groups from the original trial. They analysed how many of these men had actually gone on to develop prostate cancer to see what differences there were between the groups.
“The results were almost exactly the same as the SELECT trial,” says Yarmolinsky. “The overall risk of developing prostate cancer wasn’t increased in men with naturally higher levels of selenium.
“But, exactly the same as the clinical trial, men with high selenium levels who do get prostate cancer were at around 21% higher risk of developing an aggressive form of the disease.”
And there was a similar increase in the number of men developing type 2 diabetes as well.
Preventing more cancers
It’s still early days, but this study indicates that information from our DNA could help to better predict clinical trial results than more conventional population-based studies.
“Of course it depends on having SNPs that reliably tell you about the element of the environment you’re looking at,” says Yarmolinsky. “We couldn’t repeat the study looking at vitamin E, because we don’t have a good enough set of SNPs that can be used to predict people’s vitamin E levels.”
But it’s an intriguing idea and one with big potential.
“The trouble with the way that scientists have typically performed population studies is that there is often a lot of confounding information which makes it very hard to tease apart specific things, like differences in our diet or lifestyle, that influence cancer risk,” Yarmolinsky says.
Because there are so many of these differences, it’s very hard to understand the effects of any one thing in isolation. For example, people who have a poor diet may also be more likely to drink a lot of alcohol and be physically inactive, all of which affect a person’s cancer risk. This means population studies have to include hundreds of thousands of people, and even then this may not be enough to come up with a clear answer.
“Using information from SNPs is much less prone to bias, because the processes governing the inheritance of these DNA variations are random. So it’s generally easier to look at something in isolation without the results being confused by other aspects of people’s environments and lifestyles,” says Yarmolinsky.
Having more accurate information about things in our surroundings and lifestyle that affect cancer risk might help researchers to spot new ways to reduce the risk of the disease, and help better inform clinical prevention trials like SELECT.
“Who knows, if we’d have been able to do this kind of analysis before the SELECT trial was set up, maybe it wouldn’t have gone ahead,” says Yarmolinsky.
Decreasing the risk of these big clinical trials failing could save precious time, money, and not put people in harm’s way.
We’re constantly striving through the research we fund to find better, kinder treatments for cancer. But, as the saying goes, an ounce of prevention is worth a pound of cure. Research like this could help to find ways to reduce the burden of cancer in the UK.
And fewer people getting cancer would be a great thing.
Yarmolinksy, et al. (2018) Circulating Selenium and Prostate Cancer Risk: A Mendelian Randomization Analysis. JNCI. DOI: 10.1093/jnci/djy081