BioWorld International Correspondent

LONDON - A project to trawl through all 30,000 genes in the human genome looking for those that cause cancer already has borne fruit after its first year, with the discovery of a gene that causes two-thirds of malignant melanomas among the first 400 genes examined.

Within a decade, those diagnosed with malignant melanoma could be offered tailored drug therapy following a test to find out the precise genetic defect causing their tumors.

Researchers who made the discovery are at the Cancer Genome Project, based at the Wellcome Trust Sanger Institute in Hinxton. They are confident that before long they will have uncovered many other mutations that cause cancer, and that drugs to combat those abnormalities can be found. They have commissioned a company, Biofocus, of Cambridge, to carry out small-molecule screening with the aim of identifying candidate drugs that will interfere with the metabolic abnormality present in cells that carry the newly identified genetic defect.

Richard Wooster, senior team leader with the Cancer Genome Project, told BioWorld International: "Our objective is to discover genes that are frequently mutated in all common cancers. Because there are an estimated 30,000 genes in the human genome, our strategy is to give priority to those that we think are likely candidates - those that are known to have some association with cancer or have some similarities to known cancer genes."

Wooster, together with colleagues in Hinxton and at the Institute of Cancer Research in London and collaborators in the UK, Australia, the U.S., Italy and Hong Kong, reports the team's findings in a paper published by Nature online June 9, 2002, titled "Mutations of the BRAF gene in human cancer."

The Wellcome Trust, which is funding the Cancer Genome Project, has patented applications of the finding. 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."

Malignant melanoma kills 1,600 people a year in the UK, and 7,400 people a year in the U.S.

The Cancer Genome Project was the brainchild of Andrew Futreal, Mike Stratton and Wooster, all at Hinxton, who realized that the availability of the human genome sequence offered scientists a way to track down genes responsible for cancer, which were becoming increasingly difficult to find using traditional methods. Furthermore, there was already one example where identification of a genetic fault - the BCR-ABL translocation that causes chronic myelogenous leukemia - had been successfully translated into effective drug treatment.

Stratton, Futreal and Wooster decided to begin with the five common cancers of the breast, lung, colon, prostate and ovary. They obtained tumor cell lines from nine people in each type, along with normal cell lines from the same 45 people.

"It is thought that most people have a germline polymorphism every thousand base pairs or so, so if we just compared the tumor genome sequence to the reference human genome sequence, we would be misled by all these germline polymorphisms," Wooster said. "By comparing the tumor DNA to the normal DNA from the same person, we can specifically identify the somatic mutations that have occurred in the tumor." The Cancer Genome Project is screening the entire coding region of the genome in each group.

A discovery of a mutation in a gene in any of the initial 45 tumors triggered follow-up experiments initially in another 200 cell lines and eventually in 500 primary tumors. "We wanted to be able to confirm that any gene mutated in a cell line was also mutated in primary tumors," Wooster said.

In the experiments reported in Nature online, the first mutation they discovered in the panel of 45 cell lines occurred in cells derived from lung cancer. The mutation was in a gene called BRAF. The group found a few such mutations in lung cancer samples, but discovered that the same mutation was present in 66 percent of malignant melanomas. BRAF also is mutated in about 10 percent of colon cancers.

Surprisingly, the mutation found was always the same: a valine to glutamic acid substitution at position 599 of the BRAF protein.

"This is a well-studied gene that has never been previously implicated in cancer. We know that it is a member of a signaling pathway in the cell, and just from looking at the mutation, it is possible to predict that this would have the effect of activating the BRAF gene," Wooster said.

Tests carried out by Chris Marshall and Richard Marais at the Institute of Cancer Research in London confirmed that was indeed the case.

The search is now on to identify a drug that can switch the gene off or at least disable the BRAF protein.

"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," Wooster said.

This would, he told BioWorld International, mean savings on the cost of the drugs because they would be given only to those who would benefit; furthermore, patients who would not benefit from the drug would not suffer any potential side effects.