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How Sun and Smoke Trigger Cancer

Sequencing tumor genomes reveals the origins of some cancer-causing mutations.
December 21, 2009

Smokers may develop a mutation for every 15 cigarettes smoked, according to new analysis of the genome of a tumor from a lung cancer patient. By comparing the patient’s normal genome sequence to the sequence of the tumor, scientists at the Wellcome Trust Sanger Institute, in London, found that the tumor cells had acquired more than 23,000 mutations, according to research published in Nature on Thursday.

Researchers at the, also sequenced the tumor of a patient with melanoma, which contained more than 30 000 mutations, many of which can be linked to exposure to ultraviolet light. They say the findings will shed light on how environmental factors trigger the genetic changes that ultimately lead to cancer.

“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, in a statement from the Wellcome Trust. “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.”

According to a release from UT Southwestern Medical Center.

When the researchers analyzed the 23,000 mutations, they found distinctive patterns associated with the cocktail of carcinogens present in cigarette smoke. The DNA sequence of the cancer cells also revealed that the cells had attempted to repair their smoke-damaged DNA using two mechanisms, but the cells were only partially successful.

“By applying the same approach to other cancers not associated with cigarette smoking, including the very large group of people who develop lung cancer but have never smoked, it may be possible to discern which carcinogens play a role in those other cancers as well,” said [Dr. Adi Gazdar, a professor of pathology in the Hamon Center at UT Southwestern, who provided the lung cancer cells and normal cells for the research.]

According to an article in the London Times,

“It’s like doing an archaeological excavation,” said Professor Mike Stratton, of the Cancer Genome Project at the Sanger Institute. “We can see traces and imprints of all these processes that have been operating for decades before the cancer became symptomatic. This will be fundamental to understanding the causes of cancers and how we treat and prevent them.”

The next challenge for scientists is to determine which of these thousands of mutations are harmless “passengers”, and which are the critical drivers of the disease. This will involve sequencing DNA from hundreds more tumours to identify mutations that occur again and again.

When such driver mutations are found, they will immediately become attractive targets for the development of new drugs that can shut them down, without harming healthy tissue and causing the distressing side-effects of present chemotherapy and radiotherapy.

To map the mutations, the scientists sequenced the genetic code of tumour cells and healthy cells from the same patients, then compared them to find DNA changes that were present only in the cancerous tissue.

This approach was made possible by new technology that has significantly increased the speed of genome sequencing while reducing its cost. Each pair of genomes took several months to read, at a cost of about £60,000. Similar studies are now taking about six weeks and costing half as much, Professor Stratton said, and capacity is improving all the time.

As the costs fall, it will become practical to sequence every cancer patient’s tumour before he or she is treated, so that doctors can use the results to choose the best therapeutic strategy.

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