Cancer quest

"The human genome sequence is utterly essential to the Cancer Genome Project," says Professor Mike Stratton. "All cancers arise as a result of mutations in DNA, so we’re using the human genome sequence as a reference to find the genes that are mutated in human cancer."

During everyday life, human cells acquire changes to their DNA as a result of exposure to the environment - chemicals, radiation or viruses - or as a result of errors in the cell's machinery that copies DNA during cell division. Most of these changes are corrected by the cells’ repair mechanisms, but if mistakes occur in a subset of genes known as oncogenes or cancer genes, the cell in which those changes occurred can start to behave abnormally.

In October 1999, the Wellcome Trust and the Institute of Cancer Research funded a new initiative, the Cancer Genome Project, to use high-throughput mutation detection systems to find these cancer genes. "One approach would be to take a cancer cell and to sequence the whole genome," says Professor Stratton. "You’d be sure to find all the mutations that were causing it to become cancerous, but you’d incur the time, expense and effort of doing the Human Genome Project all over again. And the cancer genes involved in a single cancer of the bowel, say, may only represent a proportion of those that cause all bowel cancers, or of cancers of other tissues. That is not to say that some years in the future the technology may not develop to the stage that we can sequence a whole genome quickly and simply, but we’re making a start now."

Big deletions...

In the first phase of the project, Professor Stratton and his team have been looking for large homozygous deletions, where the same piece of the genome have been lost from both copies of the genome in a cell. Such deletions are clues to the location of cancer genes in the genome, in particular the so-called tumour suppressor genes, whose loss leads cells to grow and divide uncontrollably.

"We’ve been looking for these deletions in cancer cell lines," says Professor Stratton. "We now have 1500 of these lines from public repositories and private collections; it’s the largest collection in the world." And the search has been remarkably successful: "Previous research had identified about 40-50 key loci in cancer cells," says Professor Stratton, "and I expected, in the first year, to find about ten new loci. In fact, we’ve picked up all of these known loci, and have found about 100 new regions."

All of these deleted regions will require careful investigation, and add to what is known about the cancer cell lines notes Professor Stratton. "These cancer cell lines are used all over the world for research, from fundamental investigation to drug testing," he says. "Everything we find is adding value for researchers."

...and subtle mutations

The next phase of the Cancer Genome Project is looking for smaller, more subtle mutations within genes, such as base-pair substitutions, small insertions or deletions. "These are much harder to spot," says Professor Stratton, "but we’ve developed a new assay which is highly automated and sensitive. So we'll be looking at 48 primary cancers, and in each cancer we'll scan every gene for differences to the normal genome sequence."

"With all these data, we’d hope to find almost all cancer genes," says Professor Stratton. "And we’ll then go on to examine every known cancer gene in 2000 primary tumours, so we’ll be able to assess which mutated cancer genes work in concert and which are mutually exclusive."

This project also has important implications for future studies at the Sanger Institute. "The Cancer Genome Project is bottom-up science in one sense," says Allan Bradley. "Mike is driving it, he really wants to do it. But it’s also top-down as, strategically, it’s very important for us to invest in technology that can find mutations associated with disease, like Mike is doing for cancer, and apply that technology to other human genetics projects."

See also

• The Human Genome Project: Information on the project and the key issues

External links

• Cancer Genome Project at the Sanger Institute
• Institute of Cancer Research