Scientists find major gene defect involved in deadly skin cancer

Monday, June 10th 2002, 12:00 am

By: News On 6

LONDON (AP) _ Scientists have determined that a spontaneous change in a certain gene is involved in 70 percent of cases of melanoma, the deadliest form of skin cancer, which kills nearly 40,000 people a year worldwide.

Experts say the finding might lead to more effective drugs for melanoma, which accounts for just 11 percent of skin cancer, but is hard to treat once it has spread and accounts for almost all deaths from skin cancer.

Dr. Paul Meltzer, a senior cancer genetics investigator at the U.S. National Human Genome Research Institute called the finding the biggest breakthrough in melanoma research for many years.

The discovery, published Sunday in the online version of the journal Nature, is the first fruit of the Cancer Genome Project, a spin-off of the international Human Genome Project being run by researchers at the Wellcome Trust Sanger Institute in Cambridge, England.

Cancer is the disease that lends itself best to an analysis of the human genome because all cancers are a disease of DNA, said Mike Stratton, head of the Cancer Genome Project, which aims to identify which of the 30,000 human genes are involved in cancer and how.

Genes are made up of a DNA code, represented by a sequence of letters. A mutation occurs when the order of the letters changes.

Mutations can be acquired in two ways: either when DNA is damaged by such toxins as radiation, chemicals or viruses, or when mistakes are made before cell division.

Each cell in the body contains a copy of the genome, and duplicates it before it divides into two. The copy isn't always perfect.

Most of the mutations are harmless. However, sometimes a mutation will occur in a particular cell in a key gene and the result will be that the gene will be either switched on or switched off.

That cell will then start to behave abnormally. It will divide when it should stop dividing. It will move out of its usual position in a tissue and may even float off into the bloodstream and deposit in another organ.

That is how cancer evolves. Experts estimate it takes about 25 years from the first gene mutation for a tumor to appear in an adult.

``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,'' said Dr. Andy Futreal, a leader of the Cancer Genome Project.

Meltzer, who was not involved with the research, said the melanoma finding raises great hopes that the ambitious Cancer Genome Project will pan out.

The scientists start by looking at the genes in 48 tumor samples comprising six common cancers. They take each one of the 30,000 genes of the human genome in each sample and look for abnormalities.

After that, they look at the suspect genes in a further 1,000 samples of cancerous tissue, derived from nearly every type of human cancer, to see how important a role the gene mutation plays.

The first abnormality they have found is in the gene called B-RAF, which is one of a chain of genes that must all be switched to the ``on'' position for a cell to grow and divide.

Normally, it switches on and off, but the scientists found that the mutation makes the gene stay switched on all the time and ignore prompts to turn itself off. The cells with the mutation keep multiplying unchecked, leading to cancer.

The researchers found that the code letters in the B-RAF gene were shuffled in 70 percent of melanoma cases, making it the most frequently messed up gene in melanoma.

The scientists also found that about 10 percent of colon cancers had mutations in the B-RAF gene and less frequently in a variety of other cancer types.

Stratton said that because the B-RAF mutation was found in 70 percent of melanoma cases and because the fault in the gene is so specific, it is a promising target for a new melanoma drug, which would be designed to switch off the gene only in cells with a mutated version.

``We're very excited, but we have to temper that with a certain amount of caution. Cancers are devious beasts, they are unpredictable beasts. They don't always respond in the way we would like them to,'' Stratton said. ``We should be optimistic but we should recognize that the path will take several years.''