The catalogue of somatic mutations in a small-cell lung cancer genome (top) and the COLO-829 (malignant melanoma) genome (bottom).
All cancers are caused by mutations in the DNA of cancer cells which are acquired during a person’s lifetime. The studies, of a malignant melanoma and a lung cancer, reveal for the first time essentially all the mutations in the genomes of two cancers.
Lung cancer causes around one million deaths worldwide each year: almost all are associated with smoking. The number of mutations found suggest that a typical smoker would acquire one mutation for every 15 cigarettes smoked.
Although malignant melanoma comprises only 3% of skin cancer cases, it is the cause of three out of four skin cancer deaths. The melanoma genome contained more than 30,000 mutations that carried a record of how and when they occurred during the patient’s life.
“These are the two main cancers in the developed world for which we know the primary exposure,” explains Professor Mike Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute. “For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight. With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent.
“We can also see the desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation. Our cells fight back furiously to repair the damage, but frequently lose that fight.”
The studies used powerful new DNA sequencing technologies to decode completely the genome of both tumour tissue and normal tissue from a lung cancer and a malignant melanoma patient. By comparing the genome sequence from the cancer to the genome from healthy tissue they could pick up the changes specific to the cancer. The studies are the first to produce comprehensive genome-wide descriptions of all classes of mutation, producing rich accounts of the genetic changes in the development of the two cancers.
“In the melanoma sample, we can see sunlight’s signature writ large in the genome,” says Dr Andy Futreal, from the Wellcome Trust Sanger Institute. “However, with both samples, because we have produced essentially complete catalogues, we can see other, more mysterious processes acting on the DNA. Indeed, somewhere amongst the mutations we have found lurk those that drive the cells to become cancerous. Tracking them down will be our major challenge for the next few years.”
” With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent. “
Professor Mike Stratton
The lung cancer genome contained more than 23,000 mutations, the melanoma more than 33,000. Identifying the causative mutations among the large number found poses a challenge, but the complete genome sequences mean, that for the first time, that challenge can be met.
“Nearly ten years on, we are still reaping the benefit from the first human genome sequence and we have much still to do to get to grips with these new disrupted landscapes of cancer genomes,” explains Dr Peter Campbell from the Wellcome Trust Sanger Institute. “But the knowledge we extract over the next few years will have major implications for treatment. By identifying all the cancer genes we will be able to develop new drugs that target the specific mutated genes and work out which patients will benefit from these novel treatments.”
A complete genome catalogue for each patient would be expected to help select between treatments and to direct treatment in the most efficient and cost-effective way. The Sanger Institute is already working with researchers at Massachusetts General Hospital on a large scale project to tie genetic changes in cancers to their responses to anticancer treatments.
“We want to drive healthcare through better understanding of the biology of disease,” says Sir Mark Walport, Director of the Wellcome Trust. “Previous outcomes from our Cancer Genome Project are already being fed into clinical trials, and these remarkable new studies further emphasise the extraordinary scientific insights and benefits for patients that accrue from studying the genome of cancer cells.
“This is the first glimpse of the future of cancer medicine, not only in the laboratory, but eventually in the clinic. The findings from today will feed into knowledge, methods and practice in patient care.”
The human genome is large. Moreover, there are more than one hundred different types of cancer and sequencing genomes is expensive. To ensure that thousands of cancers ultimately are sequenced in the same way as these two, the International Cancer Genome Consortium has been established, on the model of the Human Genome project itself to coordinate cancer genome sequencing across the globe.
These catalogues of mutations across the broad diversity of cancer types will provide powerful insights into the biology of cancer and will be the foundation for understanding cancer causation and improving prevention, detection and treatment.
Cancer is a leading cause of death worldwide. The disease accounted for 7.4 million deaths (or around 13% of all deaths worldwide) in 2004. The main types of cancer leading to overall cancer mortality each year are:
- lung (1.3 million deaths/year)
- stomach (803,000 deaths)
- colorectal (639,000 deaths)
- liver (610,000 deaths)
- breast (519,000 deaths)
Notes to Editors
- Pleasance ED et al. (2009) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature
Available online at doi: 10.1038/nature08629
- Pleasance ED, Cheetham RK et al. (2009) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature
Available online at doi: 10.1038/nature08658
This work was supported by the Wellcome Trust.
Support for individual researchers was from the Kay Kendall Leukaemia Fund, Human Frontiers Science Program and the National Cancer Institute.
The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the focus for UK sequencing efforts. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by the Wellcome Trust to enable the Institute to build on its world-class scientific achievements and exploit the wealth of genome data now available to answer important questions about health and disease. These programmes are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, UK.