Mutant gene boosts melanoma risk

Researchers have known that the gene MITF controls the growth of melanocytes, which make the skin turn brown after exposure to the sun. The newly discovered mutation causes MITF to work abnormally and increase the chance that sunlight or other causes will lead the melanocyte to become a malignant melanoma.

The mutant gene is more commonly found in people who have many moles and a family history of melanoma. About 4% of Australians develop melanoma at some point in their life, and the MITF mutation boosts this personal risk to about 10%.

The researchers' findings are published in the prestigious international science journal Nature today.

Professor Mann has been working for nearly 20 years on the project at the Westmead Millennium Institute for Medical Research, University of Sydney and the Melanoma Institute Australia. Professor Mann said: "We found 1% of people are carrying this mutation. In Australia, that means there are 200,000 people carrying this mutation, and their risk of melanoma is nearly 2.5 times higher than your average Australian, just for this reason.

"This work helps to explain why some people are more vulnerable to melanoma than others. It will help determine how often people need to be screened and how they can best protect themselves from melanoma," he added.

The research was part of a concerted effort with the Queensland Institute for Medical Research, the University of Sydney School of Public Health, University of Melbourne, Queensland Cancer Fund, Harvard Medical School, and the Translational Genomics Institute, Phoenix.

The discovery comes from combining the results of two studies, using cutting-edge gene sequencing. The first, an ongoing study of DNA from families with melanoma, started in the 1980s. Researchers discovered in 1993 that a gene called p16 contributes to melanoma in such families.

Professor Mann commented: "But that only accounted for a quarter of the families. We've been trying since then to find the mutations contributing to the rest of the families' melanomas.

"The key step was to sequence the DNA of every gene of one person from each of these large families, using technology that's only become available in the last few years. The mutation in MITF stood out, but we were puzzled that it did not seem to cause melanoma in most people who carried it."

Because the team had also been comparing the DNA of thousands of people with and without melanoma across Australia, they were able to solve this mystery, showing that the extra risk from the mutation was only moderate - about 2.5 times the Australian average.

"This is much less than the effect of p16 mutation, but MITF mutation is much more common," Professor Mann said.

"Most importantly, we have been able to show how the mutation works - it makes the MITF more active, and this gives us a handle on how to counteract it."

The same researchers are now hoping to identify all the common gene mutations that lead to the deadly cancer melanoma so they can tailor each patient's treatment.

"We are beginning to see the fruits of decades of work on melanoma genetics," said Professor Mann. "The next important stage is the Melanoma Genome Project, which will allow us to build on these discoveries so that new diagnostic tests and new targeted drugs can be developed to combat the mutations that drive melanoma and make it often so dangerous."

The two-year Melanoma Genome Project, which researchers are about to commence, will cost $5 million to complete, and seeks to identify all of the genetic mutations in melanoma.

Melanoma kills more than 1200 people in Australia each year. It is the most common cancer among people aged 15 to 44 and the numbers are rising.