Scientists complete genome analysis of lung cancer, malignant melanoma
Findings set to change way cancer is viewed

In a major breakthrough which is likely to change the way cancer is viewed from here on in, research teams led by the Wellcome Trust Sanger Institute have completed the first comprehensive genome analysis of malignant melanoma and lung cancer.

The studies reveal for the first time almost all of the mutations in the genomes of the two cancers – more than 23,000 for lung cancer and more than 33,000 for malignant melanoma.

“This is the first glimpse of the future of cancer medicine, not only in the laboratory, but eventually in the clinic. The findings will feed into knowledge, methods and practice in patient care,” said Sir Mark Walport, Director of the Wellcome Trust.

Professor Mike Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute, explained: “These are the two main cancers in the developed world for which we know the primary exposure. 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. The genomes – cancer cell and normal cell – were sequenced more than 70 times over to produce accurate data. 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. Identifying the causative mutations among the large number of mutations found poses a challenge, but the complete genome sequences mean, that for the first time, that challenge can be met.

“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.”

“Cancers occur when control of cell behaviour is lost – cells grow how, when and where they shouldn’t,” Dr Futreal explained. “Mutations in DNA caused by, for example, cigarette smoke are passed on to every subsequent generation of daughter cells, a permanent record of the damage done. Like an archaeologist, we can begin to reconstruct the history of the cancer clone – revealing a record of past exposure and accumulated damage in the genome.”

Dr Peter Campbell from the Wellcome Trust Sanger Institute, commented: “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. 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.

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.

● Citation: Pleasance ED et al. (2009) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature doi:10.1038/nature08629

● Pleasance ED, Cheetham RK et al. (2009) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature doi:10.1038/nature08658  

ate of upload: 26th Jan 2010

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