Moderate smokers can expect to inflict a new mutation on their DNA every day, the first catalogue of the genetic changes found in lung cancer has suggested.
The genetic map of a 55-year-old man?s tumour has revealed 22,910 different mutations, most of which were caused by the carcinogenic agents found in cigarette smoke.
While the patient?s past smoking behaviour was unknown, lung cancer typically develops among those who have smoked an average of 365,000 cigarettes, the equivalent of a pack a day for 50 years.
This means that the patient probably acquired a new mutation for every 15 cigarettes he smoked.
?It?s a little like Russian roulette,? said Peter Campbell, of the Wellcome Trust Sanger Institute, who led the research. ?Every time you smoke a cigarette you are firing mutagens into the lung. Most do nothing, but every so often they cause a mutation that can contribute to cancer.?
This detailed view of the genetic havoc wreaked by smoking is among several important insights into cancer that have emerged from the first two projects to sequence the entire genome of a patient?s tumour.
Over the next decade scientists expect similar research to produce even more dramatic results, which will transform understanding of the genetic origins of cancer and deliver ?smart? drugs that target the mutations which drive the disease.
Genome sequencing has tremendous power to unlock the secrets of cancer because it is always at root a disease of the genes. Though cancer is often thought of as an environmentally induced condition, carcinogens such as cigarette smoke are harmful because they damage DNA.
The two studies, published in the journal Nature, are the first to catalogue this damage in full ? for a lung cancer and a malignant melanoma skin tumour.
Each has revealed a staggering level of genetic chaos in cancer cells ? the melanoma genome, from a 43-year-old man, is even more scrambled than the lung cancer sequence, with 33,345 mutations. These range from single-letter DNA spelling mistakes to larger errors in which hundreds of thousands of letters have been rearranged, deleted altogether, or swapped between chromosomes.
In each case, the precise patterns of damage betray how they were inflicted. Most of the melanoma mutations carry the signature of ultraviolet radiation, while the lung cancer cells show more varied defects caused by the dozens of different carcinogens in cigarette smoke.
?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.
?We?ll be able to generate these catalogues of mutations within the six-week time frame that it takes for a patient to be seen, biopsied and reviewed in the clinic,? Dr Campbell said.
Professor Carlos Caldas, of Cancer Research UK?s Cambridge Research Institute, said: ?This is ground-breaking research. Like molecular archaeologists, these researchers have dug through layers of genetic information to uncover the history of these patients? diseases.
?What?s so new in this study is the researchers have been able to link particular mutations to their cause.
?By repeating and refining this technique with other forms of cancer, and comparing the results to data from the Human Genome Project, the hope and excitement for the future is that we?ll eventually have a detailed picture of how different cancers develop, and ultimately how better to treat and prevent them.?
The genetic map of a 55-year-old man?s tumour has revealed 22,910 different mutations, most of which were caused by the carcinogenic agents found in cigarette smoke.
While the patient?s past smoking behaviour was unknown, lung cancer typically develops among those who have smoked an average of 365,000 cigarettes, the equivalent of a pack a day for 50 years.
This means that the patient probably acquired a new mutation for every 15 cigarettes he smoked.
?It?s a little like Russian roulette,? said Peter Campbell, of the Wellcome Trust Sanger Institute, who led the research. ?Every time you smoke a cigarette you are firing mutagens into the lung. Most do nothing, but every so often they cause a mutation that can contribute to cancer.?
This detailed view of the genetic havoc wreaked by smoking is among several important insights into cancer that have emerged from the first two projects to sequence the entire genome of a patient?s tumour.
Over the next decade scientists expect similar research to produce even more dramatic results, which will transform understanding of the genetic origins of cancer and deliver ?smart? drugs that target the mutations which drive the disease.
Genome sequencing has tremendous power to unlock the secrets of cancer because it is always at root a disease of the genes. Though cancer is often thought of as an environmentally induced condition, carcinogens such as cigarette smoke are harmful because they damage DNA.
The two studies, published in the journal Nature, are the first to catalogue this damage in full ? for a lung cancer and a malignant melanoma skin tumour.
Each has revealed a staggering level of genetic chaos in cancer cells ? the melanoma genome, from a 43-year-old man, is even more scrambled than the lung cancer sequence, with 33,345 mutations. These range from single-letter DNA spelling mistakes to larger errors in which hundreds of thousands of letters have been rearranged, deleted altogether, or swapped between chromosomes.
In each case, the precise patterns of damage betray how they were inflicted. Most of the melanoma mutations carry the signature of ultraviolet radiation, while the lung cancer cells show more varied defects caused by the dozens of different carcinogens in cigarette smoke.
?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.
?We?ll be able to generate these catalogues of mutations within the six-week time frame that it takes for a patient to be seen, biopsied and reviewed in the clinic,? Dr Campbell said.
Professor Carlos Caldas, of Cancer Research UK?s Cambridge Research Institute, said: ?This is ground-breaking research. Like molecular archaeologists, these researchers have dug through layers of genetic information to uncover the history of these patients? diseases.
?What?s so new in this study is the researchers have been able to link particular mutations to their cause.
?By repeating and refining this technique with other forms of cancer, and comparing the results to data from the Human Genome Project, the hope and excitement for the future is that we?ll eventually have a detailed picture of how different cancers develop, and ultimately how better to treat and prevent them.?
