Discovered: a new genetic route to skin cancer

UK - A complex chain of molecular triggers involved in the development of malignant melanoma has been unravelled

A complex chain of molecular triggers involved in the development of malignant melanoma, the deadliest form of skin cancer, has been unravelled, according to a study carried out by scientists at the Institute of Cancer Research (ICR) and published in Cancer Research*.

Most skin cancers are caused by damage to genes from UV (ultraviolet) rays in sunlight. Melanoma occurs when melanocytes, the cells in the skin that protect us from UV light, grow uncontrollably. Knowing the way in which the sun-damaged genes cause skin cancer could lead to the development of drugs to target people whose cancer developed in this way. The research team discovered how a damaged version of a gene called RAS stimulates the growth of about 15–20 % of malignant melanomas. The growth and behaviour of melanocytes are controlled by many different factors. Crucially, faults in the RAF genes are important because they send signals to the cell telling it to grow. Scientists already know that faults in the B-RAF gene are associated with around 50–70% of melanomas.

However, until now it was not known how a growth signal was generated in the melanomas in which B-RAF is not mutated. This new research reveals that faults in the RAS gene activate another form of RAF, C-RAF, which then substitutes for B-RAF and so contributes to the development of melanoma.

Lead researcher Professor Richard Marais (left), at the ICR, said: ‘We knew that RAS is mutated in up to a fifth of melanoma cases, but did not know how it was able to drive the growth of cancer cells. This research found that RAS activates one of the RAF proteins and from our previous work, we knew that a different RAF protein was implicated in the development of most other melanomas. Knowing more about the behaviour of all the different pathways involved in the development of melanoma could have implications for drug targeting. This discovery has the potential to enable us to develop targeted treatments to repair this particular fault and reverse the effects of the disease.’
Professor John Toy, Cancer Research UK’s medical director, said: ‘These findings will help improve our general understanding of how melanomas develop and grow out of control. Finding new treatments to effectively target melanoma is of critical importance because cases of the disease are set to treble over the next thirty years.’

* In melanoma RAS mutations are accompanied by switching signalling from B-RAF to C-RAF and disrupted cAMP signalling. Dumaz et al. (2006). Cancer Research Vol 66 Issue 19.

Malignant melanoma
About 8,000 cases of malignant melanoma are diagnosed in the UK annually, and it causes almost 1,800 deaths each year there. The disease usually develops in cells in the skin’s outer layer, with first visible signs possibly a change in the normal look or feel of a mole.
Although the risk of this disease increases with age, it is one of the few cancers to affect young adults and is the third most common cancer amongst 15–39 year olds.
More women than men develop malignant melanoma. Melanomas in women are most common on the legs and in men they are more common on the back.
When melanoma is caught early it can be treated successfully. However, if a malignant melanoma is left it can spread to other parts of the body and may prove fatal.

Non-malignant melanoma
Over nine in 10 skin cancers are non-malignant and these are a more easily treatable and less likely to spread. These cancers are most common on areas of skin frequently exposed to the sun such as the head, neck, hands and forearms. Those most at risk have, for example, fair skin, red or fair hair, many moles or freckles, a personal or family history of skin cancer, and experience of sunburn. Over 65,000 new cases are reported annually in
the UK.