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Melanoma genome reveals UV damage and treatment targets

Posted Aug 22 2012 12:00am

We all need a bit of sunshine in our lives – something that’s often lacking in the Great British Summer.

But while UV light (radiation) from the sun helps our bodies to make vitamin D , which is vital for building healthy bones, there’s a dark side to UV. It damages our DNA – the genetic ‘instruction manual’ in all our cells – which increases the risk of skin cancer.

Researchers have shown that eight out of 10 cases of malignant melanoma – the most dangerous form of skin cancer – are caused by getting too much UV, either from the sun or sunbeds. There’s also good evidence from population studies to show that getting sunburned at any age doubles the risk of developing melanoma later in life, and people who have the highest levels of UV exposure also have a higher skin cancer risk.

But up until now, there’s been an inconvenient problem for researchers studying precisely how UV-induced DNA damage leads to skin cancer: the major gene faults known to be involved in melanoma don’t actually show the hallmarks of UV damage. And because UV can cause such widespread damage throughout our genome, it’s been hard to pin down exactly which other genes might be involved in the disease.

Thanks to the advent of high-tech genome sequencing technology, this conundrum may have now been solved by two research teams in the US. Their results prove beyond doubt that UV-induced genetic damage can drive the development of melanoma, and highlight important new targets for future treatments for the disease.

Let’s take a closer look at what they found.


The sun produces two types of ultraviolet radiation – UVA and UVB – and they have different effects on our cells. When it comes to directly causing DNA damage , UVB is the main culprit (although UVA can indirectly cause damage by creating DNA-damaging molecules called free radicals inside cells).

UVB damages DNA by causing neighbouring pairs of ‘letters’ in the DNA code (usually TT or CC – see diagram on the right) to stick together, creating what are known as pyrimidine dimers . This makes the familiar double helix DNA strand distort out of shape.

If cells get a huge dose of UV, the resulting damage usually kills them outright – something you can witness in action if you’re ever unfortunate to get sunburned enough for your skin to peel.  But even amidst this destruction, some cells will survive. And while these cells can often spot internal UV damage and repair it,  sometimes the fused ‘letters’ get copied incorrectly as a cell duplicates its DNA when it gets ready to divide.

This means that incorrect instructions are passed on to the new ‘daughter’ cells, leading to errors in our DNA code – mutations – building up over time in the cells that make up our skin.

Over the years, scientists have discovered several crucial gene faults that are implicated in melanoma.  For example, our researchers discovered that a specific fault in the BRAF gene is a key driver in around half of all melanomas. This research led to the new drug vemurafenib , which targets cancer cells driven by a faulty BRAF gene.

But while a great deal of evidence from studies in large populations of people has shown beyond doubt that UV radiation from the sun and sunbeds causes skin cancer, there’s been a bit of a problem on the molecular side of things. When researchers have looked in detail at the known melanoma genes (including faults in BRAF and another melanoma gene called NRAS ) they’ve found that none of them actually bears the classic hallmarks of UV damage.

At the same time, the effects of UV damage are so widespread in the DNA of melanoma cells that it’s very difficult to separate the ‘drivers’ – gene faults that play a fundamental role in cancer growth – from the ‘passengers’ – mutations that are just along for the ride and aren’t playing a role in the disease.

Both research teams took similar approaches, decoding the DNA sequence of more than a hundred samples of melanoma tumours, along with samples from the patients’ healthy tissue. Chin’s team looked at 121 pairs of samples while Halaban’s group tackled 147, generating vast quantities of data.

Between them, the research teams found more than 100,000 specific mutations in the cancers, which weren’t present in the corresponding healthy tissue. As might be expected, more than 80 per cent of these were the result of pyrimidine dimers caused by UV exposure.

But just knowing about all these mutations isn’t enough – the next task was to sort the drivers from the passengers. To do this, Chin’s team used a cunning computer technique based on the evolutionary principle of selection.

It works on the assumption that growing tumours from different patients will tend to contain driver genes with specific, related faults, because these are essential for driving the cancer. By contrast, faults in the same passenger genes from different patients’ tumours won’t show this selective pressure, and will have an equal number of different faults spread along their length.

Using this technique, Chin’s team turned up a number of the usual suspects already known to be involved in melanoma including BRAF and NRAS, proving that the technique was working. But they also homed in on five new genes – RAC1, PP6C, STK19, SNX31, and TACC1 – which all had characteristic UV-related mutations. Their results were published in the journal Cell .

In a separate study, published in Nature Genetics , Dr Halaban’s team also unearthed faults in 15 genes in samples from melanomas caused by sunlight (sun-exposed) and also from melanomas from the palms, soles, lips and eyes, which aren’t usually caused by UV. As well as turning up faulty versions of BRAF and NRAS, they also pulled out faults in PP6C and RAC1 – genes that were also identified by the Chin team.

One key observation was that  nearly one in ten sun-exposed melanomas had the same specific UV-induced fault in RAC1, compared with none of the non-UV induced cancers, making it the third most commonly mutated gene in all their samples after BRAF and NRAS.

This is where things get exciting.

Regular readers of this blog may remember a post we wrote almost a year ago , describing how RAC1 helps immature healthy pigment cells (called melanoblasts) to move around within the skin to get into the right place.

Back then we speculated that RAC1 might be involved in melanoma – a disease caused by rogue pigment cells growing out of control and spreading through the body – but there wasn’t enough evidence to nail down the link. But the faulty version of RAC1 found by both teams suddenly shines a light on this problem.

The RAC1 gene tells cells how to make RAC1 protein by assembling molecular ‘building blocks’ (called amino acids ) in the correct order. Both the Chin and Halaban labs found a specific fault in RAC1, known as P29S, where one amino acid in the RAC1 protein is substituted for another.

Although it seems like a tiny change, the researchers discovered it has a massive impact on the finished protein. Normally, RAC1 proteins exist in one of two states within cells – active and inactive. The active form helps cells to move and grow, but it’s switched to the inactive state when it’s not needed. The Halaban team found that faulty RAC1 is locked into a permanently active state, sending endless signals that can drive melanoma cells to grow and spread.

Thanks to these two new papers, there’s now strong evidence to show that faulty RAC1 is a ‘driver’ gene in melanoma, and that these faults can be induced by UV radiation. Along with the hatful of other UV-related gene faults found by the scientists, this research neatly answers the question of how UV light can cause melanoma. And it also points towards a potential way to treat melanoma in the future.

Many of today’s targeted cancer treatments are designed to hit overactive proteins and stop them working. Although there are problems with cancers developing resistance to treatment over time , they’re still remarkably effective in the short term in many cases.

One example is vemurafenib , which shuts down the hyperactive, faulty version of BRAF found in around half of all melanomas. The development of vemurafenib was only possible thanks to our researchers, who tracked down the BRAF gene fault responsible back in 2002.

Now drug developers can aim their sights at overactive RAC1, as well as some of the other potential targets identified by the researchers. And there’s good reason to think that drugs targeting RAC1 might be effective in more types of cancer than just melanoma.  The same P29S mutation in RAC1 has turned up in head and neck cancer as well as breast cancer .

Studies like these are only possible thanks to recent leaps in DNA sequencing and analysis technology . We can only guess at what else might lie hidden within cancer’s genetic code , and how smart scientists will turn these discoveries into cancer treatments of the future.



Hodis, E. et al (2012). A Landscape of Driver Mutations in Melanoma, Cell, 150 (2) 263. DOI: 10.1016/j.cell.2012.06.024

Krauthammer, M. et al (2012). Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma, Nature Genetics, DOI: 10.1038/ng.2359

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