SCIENTISTS IDENTIFY GENE INVOLVED IN 70 PER CENT OF MELANOMAS
Researchers have identified a major genetic change that leads to malignant melanoma, a potentially lethal form of skin cancer that kills more than 1,600 people per year in the UK. Researchers say that the mutation, which makes skin cells grow out of control, is so clear-cut that drugs are already being designed to block the action of the defective gene.
The discovery is the first fruit of the Cancer Genome Project, the world's largest cancer genome study, at the Wellcome Trust Sanger Institute. The institute is one of the world's leading centres for genome research, renowned worldwide for its pivotal role in the international Human Genome Project. The findings will be published in an online version of 'Nature' on Sunday.
Malignant melanoma, which is mainly caused by undue exposure to sunlight, accounts for just 11 per cent of skin cancers, but almost all of the deaths. The incidence of malignant melanoma has doubled in the past decade. In the UK about 6,000 new cases are diagnosed each year. In 2000, 1,680 people died of the disease (see footnote).
Following the release of the freely available human genome sequence – one third of which was generated at the Wellcome Trust Sanger Institute – the Cancer Genome Project team have embarked on a massive screen to identify which of our 30,000 genes are involved in cancer.
Among the first 20 genes they looked at the researchers (led by Professor Mike Stratton, Dr Andy Futreal and Dr Richard Wooster) found preliminary evidence that a gene called BRAF (pronounced B-RAF) was mutated. They then extended the study of the gene to around 1,000 different cancer samples.
Normally, BRAF acts as a component of a chain of control switches that must all be 'on' for a cell to grow and divide. Collaborators Professor Chris Marshall and Dr Richard Marais, who work at The Institute of Cancer Research in the Cancer Research UK Centre for Cell and Molecular Biology, showed that the mutation renders BRAF active all the time so it is no longer responsive to the signals that should control it, and the affected cells can multiply unchecked, leading to cancer.
BRAF was found to be mutated in about 70 per cent of malignant melanomas, 10 per cent of colon cancers and a smaller proportion of other cancer types. The BRAF gene consists of about 2200 letters of DNA code. Remarkably, most of the mutations in the BRAF gene involve the same single letter of DNA.
Professor Mike Stratton said: "The most exciting thing about this discovery is that it could be a direct lead to new treatments for malignant melanoma. Because mutated BRAF is permanently stuck in the 'on' position, we have already started searching for drugs that will switch it back off. These drugs would be expected to stop the growth of these cancers."
Dr Mike Dexter, Director of the Wellcome Trust, said: "I hope that over the next five years the Cancer Genome Project will identify the vast majority of the genes involved in the most common cancers. In 20 years, I expect that genome information will have spearheaded a revolution in the way we treat cancer."
Dr Richard Wooster of the Cancer Genome Project added: "The combination of knowledge about the specific molecular abnormalities in the cancer coupled with the potential of drugs developed against these abnormal genes offers the prospect of 'tailored' therapies, where a drug is only given to people whose cancers contain the specific molecular change that makes the cancer sensitive to the drug."
Dr Andy Futreal of the Cancer Genome Project said: "This is an important step in the fight against a type of cancer which can be very difficult to treat once it has spread. We know that all cancers are a disease of DNA. With the human DNA sequence now available to us, we have started the lengthy and daunting task of trawling through the vast tracts of genome, gene by gene, to see if we can find the abnormal genes that drive cells to behave as cancers. BRAF was a welcome but unexpectedly early discovery in our search."
Professor Peter Rigby, Chief Executive of the Institute of Cancer Research, said: "We are constantly seeking new treatments for cancers such as malignant melanoma. I am extremely optimistic that this enormously exciting work will bring new therapies for melanoma to the clinic in the near future."
The Cancer Genome Project is a Wellcome Trust-funded programme to identify the genes that are mutated and cause cells to behave as cancers. To do this they intend to use the human genome sequence (of which a third was generated at the Wellcome Trust Sanger Institute) to examine systematically all 30,000 genes in about 50 human cancers. To assess the importance of the genes that are discovered the Cancer Genome Project has collected the world's largest collection of cancer cell lines (approximately 1,500).
The results from these early stages of the project validate the method that the Cancer Genome Project team propose. The search which led to the discovery of BRAF started only 12 months ago and has served as a proof-of principle for the full genome-wide exploration. The project will involve millions of experiments capitalising on the automated, high-throughput systems in place at the Wellcome Trust Sanger Institute.