Research teams led by the Wellcome Trust Sanger Institute announce the first comprehensive analyses of cancer genomes. 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 tumor 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.”
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.
Release Date: December 16, 2009
Source: Wellcome Trust Sanger Institute