Researchers have quantified the damage smoking does in different organs of the body for the first time and have also identified several different mechanisms by which tobacco smoke causes mutations to appear in DNA. The new study published by the Wellcome Trust Sanger Institute, the Los Alamos National Laboratory, and contributors, found that smokers show an average of 150 extra mutations per cell in their lungs for each year of smoking one pack a day.
The study provides a clear and solid link between the number of cigarettes smoked over a person's lifetime and the number of mutations in tumor DNA. The highest rates were seen in the organs and body parts which come into contact with smoke -- particularly lungs -- but other areas also showed damage from smoking. Tumors in these areas also contained smoking-associated mutations even if they don't come into contact with smoke -- helping to explain why smoking can cause multiple types of cancer in humans.
Cancer appears when a cell's DNA becomes too different from its original state by accumulating mutations. The study provides the first comprehensive analysis of the genetic make-up of cancerous cells linked to smoking. The team studied over 5,000 tumors, comparing cancer cells from smokers to those of non-smokers (people who had never smoked were selected). They found that smoking left molecular "fingerprints" on DNA, called mutational signatures, and counted how many of these particular variations existed in different tumors. On average, they found, one-pack-a-day smokers developed 150 new mutations in each lung cell per year. And each one of these mutations could lead to cancer.
"Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking," said Dr Ludmil Alexandrov, first author from Los Alamos National Laboratory.
"With this study, we have found that people who smoke a pack a day develop an average of 150 extra mutations in their lungs every year, which explains why smokers have such a higher risk of developing lung cancer."
While the exact number of mutations per lung cell will obviously vary from individual to individual, the study found it's not only lung cancer smokers have to worry about. Larynx cells, for example, rake in an average of 97 mutations per year; for pharynx cells, an average of 39 mutations was recorded. Mouth cells, 23. Bladder, 18 mutations, and liver cells 6 mutations per year. While it was known that smoking increases the overall risk of cancer in other parts of the body than the respiratory system, we didn't really understand why. The team revealed that different mechanisms determine mutations from tobacco smoke in different parts of the body.
"The results are a mixture of the expected and unexpected, and reveal a picture of direct and indirect effects," said Prof David Phillips, co-author of the paper and Professor of Environmental Carcinogenesis at King's College London.
"Mutations caused by direct DNA damage from carcinogens in tobacco were seen mainly in organs that come into direct contact with inhaled smoke. In contrast, other cells of the body suffered only indirect damage, as tobacco smoking seems to affect key mechanisms in these cells that in turn mutate DNA."
Five distinct mechanisms of DNA damage were identified. The most widespread is a mutational signature found in all cancers -- here, tobacco seems to accelerate a kind of cellular clock that mutates DNA prematurely.
"The genome of every cancer provides a kind of "archaeological record," written in the DNA code itself, of the exposures that caused the mutations that lead to the cancer," said Professor Sir Mike Stratton, joint lead author from the Wellcome Trust Sanger Institute."
"Our research indicates that the way tobacco smoking causes cancer is more complex than we thought. Indeed, we do not fully understand the underlying causes of many types of cancer and there are other known causes, such as obesity, about which we understand little of the underlying mechanism. This study of smoking tells us that looking in the DNA of cancers can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented."
Smoking has been epidemiologically linked with at least 17 different types of human cancer. There are roughly six million tobacco-associated fatalities every year, worldwide. The WHO predicts that, if current trends continue, we'll see more than 1 billion tobacco-related deaths by the end of the century.
The full paper, "Mutational signatures associated with tobacco smoking in human cancer" has been published in the journal BioRxiv.