Even long stretches of DNA that contain no genes at all can affect the risk of breast cancer, by physically interacting with genes elsewhere, a new study reports.
Scientists led by a team at The Institute of Cancer Research, London, found that single letter variations deep within ‘gene deserts’ - long stretches of non-coding DNA - raised the risk of breast cancer by affecting the activity of key genes.
The study, published in the journal Genome Research, helps to explain how DNA that does not code for genes - once dismissed as ‘junk DNA’ - can actually play an important role in human health and disease.
The research was funded by Breakthrough Breast Cancer, Cancer Research UK, Breast Cancer Campaign and the Medical Research Council.
The researchers found that single letter changes within gene deserts affect the way in which DNA loops together, allowing non-coding sequences to regulate the activity of distant genes.
Around 70 single letter variations have previously been linked to breast cancer. Women with an unusual DNA code letter at each variation point - a G, instead of a T, for example - are more likely to develop the disease, although almost all of these variations each cause only a very small increase in risk. The vast majority occur in regions of non-coding DNA - which makes it much harder to understand how they might affect cancer risk.
In the study, researchers used an innovative technology, called Capture HiC, to focus in on three gene deserts, each of which harbours one of these variations.
The technology, which ‘fishes’ for physical interactions with other areas of DNA, was able to identify where gene desert DNA was most likely to bind with DNA elsewhere - including with known breast cancer genes.
For one region, the researchers were able to show that a specific single letter variation was directly involved in a looping interaction that made contact with DNA sequences that regulate the function of a gene with multiple cellular effects.
This so-called polymorphism disrupted the physical joining between a section of DNA in a gene desert and another section near a gene called IGFBP5, which researchers believe may play a role in breast cancer.
The physical interactions between DNA sequences could occur across comparatively enormous distances within the genome - up to around 2.6 million letters of DNA code away, and even across different chromosomes.
Study leader Dr Olivia Fletcher, Group Leader in Genetic Epidemiology at The Institute of Cancer Research, London, said: “Around 70 single letter variations in DNA code have been linked with breast cancer. Most have only a small effect on risk, and how they cause their effect has been a mystery - particularly as many lie in stretches of DNA that contain no genes at all.
“Our research suggests that some of these variations may be raising the risk of breast cancer by physically interacting with genes in distant parts of the genome, in order to turn their activity up or down. Our study provides important clues about the causes of breast cancer, as well as shining a light on the roles played by gene deserts - fascinating, gene-less regions of DNA, the mystery of which we are only just beginning to understand.”
Dr Matthew Lam, Senior Research Officer at Breakthrough Breast Cancer, said: “Understanding how changes to DNA associated with breast cancer actually impact on the risk and development of the disease is crucial if we are to develop effective preventative strategies. A lot of research has gone in to identifying these changes but, because they tend to fall outside of the coding regions of DNA, it’s not been clear what the functional significance of these changes could be.
“The innovative technique used in this research by Dr Fletcher and her team has now revealed some insight into how these changes may affect genes important in breast cancer located elsewhere within DNA.”
Dr Kat Arney, science communications manager at Cancer Research UK, said: “It’s becoming increasingly clear that the DNA in-between our genes is full of important control switches that turn genes on and off, yet relatively little is known about this ‘dark matter’ within our genome. Studies like this are vital if we’re to understand how DNA changes - whether within or outside genes - affect cancer risk and tumour growth, and to develop more effective treatments based on that knowledge.”