A project that aims to identify all of the cancer genes in the human genome has hit its first jackpot. Researchers have pinpointed the genetic mutation responsible for most cases of malignant melanoma, the lethal form of skin cancer.
The discovery was made during the early phase of the Cancer Genome Project, a 6-year, $54 million effort funded by the Wellcome Trust. It is the only project that aims to search systematically through the entire genome for cancer genes. The team, based at the Sanger Institute near Cambridge, U.K., chose 20 genes that regulate cell growth to test-run their new robotics and bioinformatics systems. While gearing up, the researchers screened DNA from 378 samples of human cancers.
The first mutation they found was in a gene called BRAF. BRAF was mutated in six of nine malignant melanomas and in a smaller proportion of other cancer types, they report 10 June on the online version of Nature. And the mutations are surprisingly uniform: 80% of the mutations in the BRAF gene involve the same single letter of DNA. "We were very fortunate that during the development phase we actually made a discovery," says cancer geneticist Richard Wooster, a group leader in the Cancer Genome Project.
With additional experiments, collaborators Chris Marshall and Richard Marais, molecular biologists at the Institute of Cancer Research in London, showed that the mutation renders BRAF deaf to control signals. Normally, BRAF is part of a chain of genetic switches that must be "on" for a cell to grow and divide. Mutated BRAF is stuck in the "on" position, creating a short circuit that allows cells to multiply unchecked, leading to cancer.
The discovery is an important clue to the disease, says cancer geneticist Paul Meltzer of the National Human Genome Research Institute. "Finding this high mutation frequency is a breakthrough in the field of melanoma research," he says. Cancer geneticist Mike Stratton, who heads the Cancer Genome Project, says the group has already started searching for drugs that will switch BRAF back off.