One in five people in the developed world will die of the diseases we call cancer

One in five people in the developed world will die of the diseases we call cancer. What they die of is not one disease, but a bewildering array of cancers, each of which behaves differently, grows differently and - crucially - responds to treatment differently.

One of the goals of the Cancer Genome Project at The Wellcome Trust Sanger Institute is to bring order to our understanding of the differences between cancers. By cataloguing the changes within the genomes of cancer cells and identifying the mutant genes responsible for the development of the disease, we will better be able to choose the best treatments for each patient and search for new treatments.

As reported in Nature on Thursday 30 September 2004, the team and their colleagues have identified a gene (ERBB2) involved in 4% of non-small-cell lung cancers (NSCLCs), a type of lung cancer. Most significantly, they propose that an existing drug might work in individuals that carry mutations in the ERBB2 gene.

Dr Andy Futreal, Co-Leader of the Cancer Genome Project, said: "ERBB2 is one of a series of biological 'switches' in our cells that plays a vital role in controlling whether cells survive and proliferate. When the ERBB2 protein is switched on, it talks to other molecules in the cell to initiate a cascade of changes that alter how cells grow."

"Some mutations in the ERBB2 protein make it appear to the other molecules as if it were switched on all the time. The consequence is uncontrolled cell division - cancer."

"What we found is that the ERBB2 activating mutation occurs in 4% of lung cancers (non-small-cell lung cancers, NSCLC) and in 10% of a particular type called adenocarcinoma."

Perhaps 40% of all lung cancers are adenocarcinomas and the number appears to be increasing. A role for ERBB2 has been suggested in other cancers, including breast cancer, and a drug called trastuzumab (Herceptin), which dampens the activity of ERBB2, has been developed to help treat these.

The Cancer Genome Project results are the first time a mutation within the ERBB2 gene has been found in tumour cases. The Project team suggest that trastuzumab and other anti-ERBB2 agents should be tried in patients who carry mutations of the type they have discovered.

"We have an existing drug that works against the overactive ERBB2 protein," continues Dr Futreal, "And can now identify patients with NSCLC who have mutations in this gene. Our understanding from other studies suggests that these patients may benefit from treatment with anti-ERBB2 agents."

"With this strategy of searching for the root causes of gene problems we have an opportunity to make progress in the treatment of other cancers. I have to stress, however, we are still a long, long way from cures."

"Picking apart the biology that underlies cell behaviour in cancer will help us define what has gone wrong and how it has gone wrong. In many cases we will need to seek new treatments but in some - such as this - we will be able to see which patients might be helped by carefully chosen existing medicines."

The role of ERBB2 in cancer has been suspected for more than 15 years. It is only with strategies such as those used by the Cancer Genome Project that it is becoming possible to identify cancer patients who may have a mutations in particular target genes.

"Understanding cancer genetics is beginning to transform our treatment of these diseases," said Professor Stan Kaye, Cancer Research UK Professor of Medical Oncology at the Institute of Cancer Research and Royal Marsden Hospital. "When we understand specific aberrations in cancer cells, we can begin to find ways to target them and to prevent them from dividing and spreading."

"Using genomic sequences we can begin to develop new treatments, based on the subtle differences in the diseases we call cancer. We may also find that treatments developed for one type may also have considerable benefit in other types of cancer. That is one of the most exciting aspects of this report."

"We are still some way from unravelling the relevant genomic sequences in all forms of cancer and further still from finding treatments. But we have turned a corner and the bringing together of DNA sequence, patient samples and basic research provides renewed hope that we know where we should go."

"While advances such as these hold out considerable hope for lung cancer patients, we must remember that the greatest impact in this disease relates to persuading people to stop smoking."

Cells that contain mutations leading to overactivity of proteins like ERBB2 appear to become 'addicted' to the mutant protein: its overactivity becomes important for continued survival of the cell. One consequence is that drugs that inhibit the overactive protein have a greater effect on mutant cells than on cells without the mutation.

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