Scientists Identify Unexpected Mutations That Might Trigger Cancer

Researchers have just taken a big step towards discovering how mutations might cause certain types of cancer to form, showing that DNA repair is being blocked in important parts of the genome.

You probably already know that cancer is caused by mutations to our DNA. But what you might not know is that many of the mutations in our genome don’t seem to link to cancer at all, and others can instantly be repaired by our cells. So how do we know which mutations will lead to cancer, and which won’t?

Researchers think they might be closer to answering this question, after finding an unexpected link between certain types of cancer, and mutations in a normally overlooked region of the genome.

A team from the University of New South Wales Faculty of Medicine (UNSW Medicine) in Australia has studied more than 20 million DNA mutations across thousands of tumours, to find that in many types of cancers – particularly skin cancers – DNA repair is being blocked in a specific region of the genome known as ‘gene promoters’, the Science Alert repored.

Although these gene promoter regions don’t actually code for anything – and so are often overlooked when scientists seek out cancer-causing mutations – they are incredibly influential because they control which genes are turned on and off.

This means they influence the amount of proteins created, and in turn, the function and type of cell. So mutations that occur here are particularly damaging. And the team has found that they’re incredibly common in certain types of cancer.

“What this research … tells us is that while the human body is pretty good at repairing itself, there are certain parts of our genome that are poorly repaired when we sustain damage from mutagens such as UV light and cigarette smoke,” said the lead author of the study, Jason Wong.

To understand that, you need to understand how DNA gets mutated – and then fixes itself – in the first place. Our DNA is undergoing potentially harmful mutations on a daily basis – as a result of random, naturally occurring errors, or exposure to things such as UV rays and cigarette smoke.

There are different repair systems to fix these types of mutations – for example, UV damage to DNA is repaired by a system known as nucleotide excision repair (NER), but what the UNSW Medicine researchers found is that when these mutations occur in the promoter region of the genome, NER is being blocked by another protein in the area that controls gene expression.

That means that the promoter region is particularly susceptible to mutations from UV, and when they occur there it’s more likely to lead to cancer.

The team thinks this region could play a significant role in other cancer types, too, and could explain why normal DNA repair systems might be working, but don’t seem to prevent tumours from forming. If they can link common promoter region mutations to cancer types, they might also be able to identify people at risk of developing cancer early.

“Our study highlights the need for further research on the role of gene promoter mutations in cancer development,” Wong said. “This may ultimately help doctors to determine why certain cancers develop, enabling them to diagnose cancer earlier and select more tailored treatment therapies for patients.”

Right now, scientists only know of one promoter mutation- part of the TERT gene, that contributes to cancer. For comparison, there are many genes, including TP53, that scientists know can cause a normal cell to become cancerous if it becomes mutated.

The UNSW researchers hope this will soon change.

“The findings are all the more impressive because they were uncovered using existing and publicly available ‘big data’, simply by asking the right questions,” said study co-author and haematologist John Pimanda. “We didn’t need to spend time and money recruiting patients, investigating their cancers and sequencing their cancer genomes. All of this data was available to researchers on public data sharing platforms.”

Hopefully this is the start of something big.

This research was published in Nature.