Cigarettes and sunlight leave their mark on cancer genomes
Details of the first ever cancer genome sequences are released in two papers published online by the journal Nature. The studies reveal that the genetic sequence of the lung cancer cell line bears all the hallmarks of DNA damage caused by tobacco smoke, while many of the mutations in the melanoma tumour are characteristic of the kind of damage inflicted on DNA by exposure to ultraviolet (UV) light. The sequences also contain traces of the cells' efforts to repair the damaged DNA.
The researchers behind the papers, from the Netherlands, the UK and the US, hope that their work will eventually lead to tailored treatments for cancer in which drugs are chosen on the basis of the mutations identified in their cancer.
"This is the first glimpse of the future of cancer medicine, not only in the laboratory, but eventually in the clinic," commented Sir Mark Walport, Director of the Wellcome Trust Sanger Institute in the UK. "The findings from today will feed into knowledge, methods and practice in patient care."
Cancer cells contain genetic mutations that have built up over a person's lifetime. In these studies, the scientists used the latest DNA sequencing technology to map the genomes of a malignant melanoma and a small-cell lung cancer (SCLC). The team also decoded the genome of healthy cells taken from two patients. By comparing the two, the team could pick out the genetic mutations specific to the cancer.
"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" explained Dr Andy Futreal of the Wellcome Trust Sanger Institute. "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."
Lung cancer causes around 1 million deaths worldwide every year, making it the leading cause of cancer-related deaths. SCLC in particular accounts for around 15% of lung cancer cases. It is notoriously hard to treat, and most patients die within two years of diagnosis.
The majority of lung cancer cases are caused by smoking. Tobacco smoke contains over 60 chemicals that attack DNA, causing mutations. The team recorded over 20,000 mutations in the lung cancer cells. While most of these mutations are harmless, some cause the cell to become cancerous.
"For the first time, we have a comprehensive map of all mutations in a cancer cell," commented Dr Peter Campbell of the Wellcome Trust Sanger Institute. "The profile of mutations we observed is exactly that expected from tobacco, suggesting that the majority of the 23,000 we found are caused by the cocktail of chemicals found in cigarettes. On the basis of average estimates, we can say that 1 mutation is fixed in the genome for every 15 cigarettes smoked."
The analysis also revealed the efforts the cells' repair systems had made to fix the damaged DNA, and even uncovered evidence of an undiscovered system of DNA repair that tackled mutations in highly active genes. This implies that the cell seeks to protect these parts of the genome above many others.
The second study focused its efforts on a sample taken from a patient with malignant melanoma. Although it only accounts for 3% of skin cancer cases, malignant melanoma is responsible for three quarters of skin cancer deaths.
The melanoma genome turned out to harbour over 33,000 mutations, many of which are precisely the kinds of mutations associated with exposure to UV light. "It is amazing what you can see in these genomes. UV-light-induced mutations leave a typical signature, forming the vast majority of the mutations," said Dr Campbell. "Indeed, because of the clarity of the genome data, we can distinguish some of the early, UV-induced mutations from the later mutations that do not have this signature." The researchers suspect that these later mutations arose after the cancer cells had spread from the skin to tissues deeper inside the body.
The next step for the researchers is to study the new sequences in greater detail to determine which mutations caused the cells to become cancerous.
"Cancer is driven by acquired mutations in genes, and we are at a point where it soon will be possible to actually know every mutation in the tumours of each of our patients," commented Dr John Minna of the University of Texas (UT) Southwestern Medical Center in the US. "The key will be to use this information to find new ways to help prevent cancers, diagnose them earlier and to select treatments that might be specific for each patient's tumour. While these findings are the first step, they have lighted our path to clearly point us in the right direction."
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