Published online 16 December 2009 | Nature | doi:10.1038/news.2009.1143

Corrected online:

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Sequencing of skin and lung cancers show that many mutations could be prevented.

Sun and smoke leave their fingerprints on cancer genomes. MOREDUN ANIMAL HEALTH LTD / SCIENCE PHOTO LIBRARY

Researchers have completed the genetic sequences of two types of cancer — skin cancer and small-cell lung cancer — revealing that the genomes bear the hallmarks of their respective carcinogens: sun and smoke. Worldwide, the two diseases kill a total of nearly 250,000 people each year, despite the fact that they are largely preventable.

Tumours develop when a normal cell's DNA is damaged, allowing that cell to proliferate unchecked. By sequencing and cataloguing all the mutations in a single tumour type from multiple individuals, scientists aim to identify the genes that are most susceptible to damage, to understand the processes underlying DNA repair, and to develop drugs that counteract certain types of damage.

Scientists from the Cancer Genome Project at the Wellcome Trust Sanger Institute in Hinxton, near Cambridge, UK, and their collaborators at partner institutions describe the genetic sequences of cell lines derived from patients with small-cell lung cancer1 or malignant melanoma2. The studies are published online today in Nature.

“Every pack of cigarettes is like a game of Russian roulette.” Peter Campbell

Wellcome Trust Sanger Institute, Hinxton

These papers mark the completion of the fourth and fifth cancer-cell genomes to be sequenced, and come just one year after a team from Washington University School of Medicine in St Louis published the first cancer genome, from a patient with leukaemia3. The breast-cancer genome was published by a Canadian-led consortium in October this year4, and dozens more sequences are expected to come out of The Cancer Genome Atlas Program of the US National Cancer Institute in Bethesda, Maryland — a project that is slated to receive US$275 million over the next two years from the National Institutes of Health.

"We are in the middle of an explosive development in cancer-genome sequencing," says Matthew Meyerson, a cancer-genomics expert at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was not involved in the research. "Whole-genome sequencing is the wave of the future for both cancer-gene discovery and, eventually, for cancer diagnosis."

Fifteen cigarettes, another mutation

Peter Campbell, a haemotologist and cancer-genomics expert at the Sanger Institute who worked on the latest studies, says that the number of genetic mutations they identified — 33,345 for melanoma and 22,910 for lung cancer — was remarkable. The mutations were not distributed evenly throughout the genome — many were present outside of gene-coding regions, suggesting that cells had repaired damaged DNA in those key regions.

Campbell says that the findings help to answer lingering questions about whether carcinogens cause most mutations directly, or if cancer itself contributes to the mutations by disrupting the function of DNA-repair mechanisms. The team found that most mutations were single-base DNA substitutions that could be traced to the carcinogenic effects of chemicals in tobacco smoke (in the case of the small-cell lung cancer genome) or ultraviolet light (in the melanoma genome), supporting the idea that these two cancers are largely preventable. The team estimates that every 15 cigarettes smoked results in a DNA mutation. "Every pack of cigarettes is like a game of Russian roulette," Campbell says. "Most of those mutations will land where nothing happens in the genome and won't do major damage, but every once in a while they'll hit a cancer gene."

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The lung-cancer study also identified one recurrent mutation — a duplication of the chromatin-remodelling gene CHD7, which regulates the activity of other genes. The team had already identified the existence of this mutation in 2008, but the current study1 confirms its presence in three independent cell lines. Such recurrent mutations could point to key cancer genes that may be useful drug targets.

Some scientists, however, are more circumspect about the benefits of cancer-genome sequencing. Steve Elledge, an expert in DNA damage and cancer genetics at Harvard Medical School in Boston, Massachusetts, was impressed with the new analysis but says that the potential impact on cancer diagnosis and treatment will not be fully felt until scientists have hundreds of sequences at hand — a costly prospect. "It's still very expensive, and I think all these efforts should be coupled with an equal amount of effort on studying gene function," he says.

Corrected: This article previously stated that each cigarette smoked could result in an estimated 15 DNA mutations. In fact, the typical smoker would acquire one mutation for every 15 cigarettes smoked.