Study of DNA and datasets gives fresh insight into cancer

Published On Wed 7 May 2014 by Grant Hill

Researchers from the University of Dundee have used knowledge of an ancient evolutionary leap to reveal new patterns of DNA mutations in thousands of cancer patients and raise the possibility of developing new treatments.

A team led by Carol MacKintosh, Professor of Molecular Signalling and Associate Dean of Research at the University’s College of Life Sciences, has examined the issue through the prism of knowledge of man’s evolution and, in particular, a leap made 500 million years ago.

At that time, our ancestor was a simple animal with cells controlled by linear command pathways. Via dramatic evolutionary events these pathways were quadrupled, creating complex networks that transmit multiple control signals. Such complexity enabled the backboned animals, including humans, to evolve.

The paper by Professor MacKintosh and her colleagues, published today in the Open Biology journal, shows that mutations in many cancers block certain routes through these communication networks, forcing information flow through a restricted number of non-mutated pathways. This raises the possibility of developing drugs to block the non-mutated components as a new approach to anti-cancer therapy.

It has long been known that mutations in a person’s DNA play a role in many diseases, including cancer, but the more scientists have learned about them, the more complexities have been discovered. People with the same disease may have different mutations, or people with the same mutations may experience different outcomes, making it more difficult to identify the common denominators that give rise to disease.

Professor MacKintosh said, “There has been a tremendous push to identify mutations that cause cancer and one of the big surprises is that cancers in different patients have different patterns of mutations so it’s become difficult to understand how all these explain why the disease develops.

“Our ancient ancestors were simple animals with cells controlled by simple, linear control pathways then, for unknown reasons, there was a major evolutionary event and these pathways quadrupled. These pathways then evolved into complex communication networks in modern day humans. These networks control cells in a very sophisticated manner, meaning they can respond to all sorts of different stimuli and integrate them and make subtle responses.

“What we decided to do was investigate how cancer mutations map onto these communication networks. Essentially what we’ve discovered is that there are many different mutations that effectively shut off part of these networks. What that means, we think, is that in cancer cells communication flow is very restricted to selected pathways though the networks so this is telling cancer cells to grow and divide in a way that is inappropriate.

“This can help to explain how different patterns of mutations can give rise to the same effect. If you imagine a roads network, there are lots of different places you can put bollards and in the end have the same result of closing down part of that road network.

“We also think that we’ve been able to identify proteins whose lack of mutations is important for the cancer.  We propose that these mutation-free genes and proteins are needed by the cancer to keep parts of these networks open for it to receive commands to grow.”

Professor MacKintosh and her colleagues looked at a recently published dataset of the DNA from 7000 patients with 30 different types of cancer to try and work out how these cellular networks actually operate. The team already had some limited scientific understanding of how they work, which suggested that there might be some selection of pathways operating in cancer and this acted as a starting point for the research.

“The ancient leap gave us the complexity to evolve into humans, and if our ancestors hadn’t gone through that we’d still be like little filter-feeders living at the bottom of the ocean,” she continued. “This also brought certain vulnerabilities because if the complex networks are deregulated it can give rise to cancer.

“It should be noted that the networks themselves are very robust. To use a digital analogy, if one node on the internet breaks down you can message through another path and this is how our cellular system works and is one of the reasons why we relatively rarely get cancer. Most cancer diagnoses occur late in life because it can take quite some time for networks to go wrong.”

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