Scientists Identify Gene Involved In 70 Percent 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 1600 people per year in the UK.

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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 are published in an advanced online version of Nature on Sunday 9th June and in the paper version on 27 June 2002 Nature 417, 949 – 954 (2002).

Malignant melanoma, which is mainly caused by undue exposure to sunlight, accounts for just 11 percent 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. In 2000, 1680 people died of the disease (Figures from Cancer Research UK).

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.

Amongst the first 20 genes they looked at, the researchers, led by Professor Mike Stratton, and Drs Andy Futreal and 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 1000 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 percent of malignant melanomas, 10 percent 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.

“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.”

Professor Mike Stratton of the Cancer Genome Project

“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 Mike Dexter, Director of the Wellcome Trust

“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 Richard Wooster of the Cancer Genome Project

“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.”

Dr Andy Futreal of the Cancer Genome Project

“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.”

Professor Peter Rigby Chief Executive of the Institute of Cancer Research

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 1500).

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 capitalizing on the automated, high-throughput systems in place at the Wellcome Trust Sanger Institute.

More information

  1. The electronic version of the Nature paper can be referenced using the following unique identifier: 10.1038/nature00766
  2. The Wellcome Trust announced a £300 million grant in October 2001 to take the Wellcome Trust Sanger Institute into the post-genomic era, an additional £65 million was also awarded for IT infrastructure to support the Institute’s strategic plan.
  3. As part of this funding programme, the Cancer Genome Project will receive up to £36 million over five years to search for genetic mutations that cause the most common cancers, including breast, lung, colorectal, ovary and prostate.
    At the time, Professor Stratton, said: “Our goal is to identify large numbers of new genes that are mutated in cancer and to measure the frequency of mutations every major cancer. There are more than 100 different types of cancer, but we need to understand what makes them all different. This information will then be used to develop new, more specific drugs for improved treatment. The scale of the Cancer Genome Project is without match anywhere in the world.”
    The first phase of the Cancer Genome Project is also looking at other genome abnormalities–ie. deletions or gaps in genetic information–in cancer cells than all previous studies combined. More than 100 of these genomic ‘addresses’ have so far been found and the study team are currently identifying the relevant cancer genes that would be located in these deletions. This research is expected to lead to the identification or many new tumour suppressor genes (ie. those genes which normally suppress tumour growth).
    A new project aims to identify genes on the X chromosome (one of two sex chromosomes, of which women have two copies and men one) that give rise to the wide variety of disorders, using techniques employed for the Cancer Genome Project. The X-linked disease project will initially be used to search for genes involved in primary or nonspecific X-linked mental retardation, one of the most common disorders presenting at genetic clinics. Affected individuals have cognitive impairment but do not have any distinctive clinical or biochemical features in common.
  4. The Institute of Cancer Research is a centre of excellence with some of the world’s leading scientists working on cutting-edge research. It was founded in 1909 to carry out research into the causes of cancer and to develop new strategies for its prevention, diagnosis, treatment and care. The Institute works in a unique partnership with The Royal Marsden Hospital, which enables scientific discoveries to be translated quickly into patient care.
  5. Cancer Research UK is the world’s leading charity dedicated to research on the causes, treatment and prevention of cancer. We support research throughout the UK in universities, hospitals and institutes and in our own research centres. We rely almost entirely on voluntary donations to fund this work.