Melanoma and the BRAF gene

9/6/02. By Giles Newton

Professor Mike Stratton, Richard Wooster, Andy Futreal and their team of researchers working on the Cancer Genome Project at the Wellcome Trust Sanger Institute have identified a major genetic change that is involved in 70 per cent of cases of malignant melanoma, a potentially lethal form of skin cancer.

The Cancer Genome Project is a Wellcome Trust-funded programme to identify the genetic changes that cause cells to become cancerous. Researchers at the Sanger Institute are using human genome sequence data to examine systematically all 30 000 genes in about 50 human cancers.

The BRAF gene 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. Remarkably, most of the mutations in the BRAF gene involve the same single letter of DNA.

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 the BRAF protein 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.

The mutation is so clear cut that drugs are already being designed to block the action of the defective protein. The findings were published in Nature in June 2002.

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 6000 new cases are diagnosed each year, and more than 1600 people die of the disease.

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 the BRAF mutations 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.

The Wellcome Trust announced a £300 million grant in October 2001 to take the Sanger Institute into the postgenomic era. As part of this funding programme, the Cancer Genome Project will receive up to £36 million over five years to search for the genetic changes that cause the most common cancers, including breast, lung, colorectal, ovary and prostate.

Photo credit: Paul J.Smith and Rachel Errington