Multiple Genetic Mutational Signatures Associated With Smoking

Key Points

  • The authors found that, on average, smoking a pack of cigarettes a day led to 150 mutations in each lung cell every year.
  • Other organs were also affected, with the study showing that a pack a day led to an estimated average 97 mutations in each cell in the larynx, 39 mutations for the pharynx, 23 mutations in the mouth, 18 mutations for the bladder, and 6 mutations in every cell of the liver each year.
  • The study revealed at least five distinct processes of DNA damage due to cigarette smoking, the most widespread of which is a mutational signature already found in all cancers. In this case, tobacco smoking seems to accelerate the speed of a cellular clock that mutates DNA prematurely.

Scientists have measured the genetic damage caused by smoking in different organs of the body and identified several different mechanisms by which tobacco smoking causes mutations in DNA. Researchers at the Wellcome Trust Sanger Institute, the Los Alamos National Laboratory, and their collaborators found smokers accumulated an average of 150 extra mutations in every lung cell for each year of smoking 1 packet of cigarettes a day.

Reported by Alexandrov et al in the journal Science, the study provides a direct link between the number of cigarettes smoked in a lifetime and the number of mutations in the tumor DNA. The highest mutation rates were seen in the lung cancers, but tumors in other parts of the body also contained these smoking-associated mutations, explaining how smoking causes many types of human cancer.

Smoking has been epidemiologically associated with at least 17 types of human cancer, but until now, no one has seen the mechanisms by which smoking causes many of these cancer types. In the first comprehensive analysis of the DNA of cancers linked to smoking, researchers studied over 5,000 tumors, comparing cancers from smokers with cancers from people who had never smoked. They found particular molecular fingerprints of DNA damage—called mutational signatures—in the smokers' DNA and counted how many of these particular mutations were found in the different tumors.

Mutational Signatures Found

The authors found that, on average, smoking a pack of cigarettes a day led to 150 mutations in each lung cell every year. These mutations represent individual potential start points for a cascade of genetic damage that can eventually lead to cancer. The numbers of mutations within any cancer cell will vary between individuals, but this study shows the additional mutational load caused by tobacco.

First author Ludmil Alexandrov, PhD, of Los Alamos National Laboratory, said, “Before now, we had a large body of epidemiologic evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking. 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.”

Other organs were also affected, with the study showing that a pack a day led to an estimated average 97 mutations in each cell in the larynx, 39 mutations for the pharynx, 23 mutations in the mouth, 18 mutations for the bladder, and 6 mutations in every cell of the liver each year.

Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that don't come into direct contact with smoke. However, the study revealed different mechanisms by which tobacco smoking causes these mutations, depending on the area of the body affected.

Coauthor David Phillips, PhD, Professor of Environmental Carcinogenesis at King's College London, said, “The results are a mixture of the expected and unexpected, revealing a picture of direct and indirect effects. 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.”

The study revealed at least five distinct processes of DNA damage due to cigarette smoking. The most widespread of these is a mutational signature already found in all cancers. In this case, tobacco smoking seems to accelerate the speed of a cellular clock that mutates DNA prematurely.

Joint lead author Sir Mike Stratton, FMedSci, FRS, of the Wellcome Trust Sanger Institute, said, “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. 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.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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