Scientists have uncovered the genomic mutations and DNA methylation patterns likely caused by tobacco smoke in 17 types of cancerous tumors. DNA methylation is a mechanism used by cells to control gene expression.

In their comprehensive analysis, a research team from England’s Wellcome Trust Sanger Institute and the Los Alamos National Laboratory in New Mexico found that those who smoke have on average 150 additional mutations in every cell of their lungs for each year of smoking one pack of cigarettes per day.

The study reporting the findings, “Mutational signatures associated with tobacco smoking in human cancer,” is published in the journal Science.

For more than 60 years, it’s been common knowledge that smoking tobacco is one of the most avoidable risk factors for cancer. Tobacco smoking has been associated with at least 17 types of human cancer, and more than 6 million people die every year because of cigarette smoking, according to the World Health Organization.

Tobacco smoke is a complex mixture of chemicals, including at least 60 carcinogens. Many of these are thought to cause cancer by inducing DNA damage that, if misreplicated, lead to an increased burden of mutations and an elevated chance of acquiring trigger mutations in cancer genes.

But exactly how tobacco smoke damages the genome and creates the mutations that ultimately cause cancer were still not fully understood.

Now, Ludmil Alexandrov and his colleagues examined mutational signatures and DNA methylation changes in 17 different types of cancer from 5,243 tumors.

The team discovered a complex pattern of mutational signatures in the smokers’ DNA and determined how many of these mutations were found in the different tumors. On average, smoking one pack of cigarettes every day caused 150 extra mutations in each lung cell every year, the researchers found.

These mutations can be considered starting points for a cascade of DNA damage that may eventually 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,” Alexandrov said in a news release.

“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,” he said.

Apart from the lungs, the study also showed an average of 97 cigarette-causing mutations in each cell in the larynx, 39 in the pharynx, 23 in the mouth, 18 in the bladder, and six in the liver.

Prof. David Phillips, an author of the study and professor of environmental carcinogenesis at King’s College London, said the study’s results “are a mixture of the expected and unexpected, and reveal 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,” he said.

The researchers were able to identify at least five different mechanisms of DNA damage caused by tobacco smoking. The most widespread of these processes is a mutational signature, found in all cancer types, that appears to speed up a cellular regulation process 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 Prof. 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,” Stratton said. “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.”