Cigarettes cause telltale DNA damage: patterns of cancer mutations differ in smokers and nonsmokers.
"We are doing a sort of molecular archaeology," says Ludmil Alexandrov, a cancer geneticist at Los Alamos National Laboratory in New Mexico who led the analysis. While smoking's link to cancer has been known for decades, "it's always been a bit of a mystery why smoking increases the risk of cancers like bladder or kidney--tissues that aren't exposed to smoke," Alexandrov says.
Mutations in DNA arise naturally in a person's lifetime, but some genetic changes--such as those spurred by smoking--increase the risk of certain cancers. Scientists have identified several patterns of mutations that consistently show up in tissues of some cancers. These patterns, which may appear over and over again in a single stretch of tumor DNA, can serve as a signature of the underlying mechanism that led to the mutations, offering clues to how different cancers strike.
"When someone has a cancer, we only see what is now--we don't know what happened 20 years ago when that cancer was only one cell," says cancer biologist Gerd Pfeifer of the Van Andel Research Institute in Grand Rapids, Mich. "These signatures give us a really good clue of what might have happened," Pfeifer says.
Alexandrov and an international team of researchers found several differences in the number of altered DNA signatures in tumors of smokers compared with those from nonsmokers with the same type of cancer. The research adds dismal specifics to what's already known about smoking: It is really bad for you.
"Tobacco smoking leaves permanent mutations; it erodes the genetic material of most cells in your body," says Alexandrov. "Even if you are just a social smoker who occasionally has one or two or five cigarettes, there is still a cumulative effect."
Alexandrov and colleagues compiled data on DNA extracted from more than 5,000 human samples representing 17 cancers for which smoking is a known risk factor. About half of the samples were from smokers. The team then searched the DNA for various patterns of damage, or "mutational signatures."
One suite of mutations, called signature 4, was consistently found in tissues exposed to tobacco smoke. While this signature also appeared in nonsmokers' tumors, it occurred far less often. Smokers with lung squamous cancer, lung adenocarcinoma and larynx cancers had an especially high number of signature 4 mutations. Signature 4 signals damage to guanine (the structural component of DNA known as "G"). This signature has also been found in the DNA of cells in a lab dish that were exposed to a chemical found in burnt products, including polluted air and the tar in cigarette smoke.
Signature 4 mutations also showed up in cancers of the oral cavity, pharynx and esophagus but much less often. The researchers aren't sure why these tissues, which are also directly exposed to smoke, don't have as heavy a mutational load. Those tissues may metabolize smoke differently, the researchers speculate.
Another suite of mutations, known as signature 5, also differed between smokers and nonsmokers. This signature typically shows up in all cancers and across all tissue types. The cause of signature 5 remains unknown, but scientists do know that the number of signature 5 mutations is "clocklike," increasing with age. The new analysis revealed that the signature 5 "clock" ticks faster in smokers. And the more heavily a person smoked, the more signature 5 mutations were found.
In patients with lung adenocarcinoma, far more mutations associated with two other signatures, 2 and 13, had accumulated in smokers than in nonsmokers. There are hints that these mutations result from overactive DNA-editing machinery. But because these signatures are found in many kinds of cancers, it isn't clear why smoking ups the mutation load. Inflammation from smoke might be activating the cellular machinery that underlies the mutations.
When the researchers took into account the quantity smoked, they discovered that the number of mutations for some cancers was linked to the "pack years" smoked (a pack of cigarettes a day for one year). Breaking these data down allowed the team to calculate the average number of mutations caused by smoking in each cell by tissue type: A pack a day for one year leads to 150 mutations on average in each lung cell, 97 in each larynx cell, 39 in pharynx cells, 23 in oral cavity cells, 18 in bladder cells and six in liver cells.
Caption: Smoke signals Smoking harms tissues in the body to differing degrees. Scientists estimate that smoking a pack of cigarettes a day for a year results in 150 mutations on average in each lung cell. Other cell types rack up fewer changes. SOURCE: L.8. ALEXANDROV ET AL/SCIENCE2016
Please note: Illustration(s) are not available due to copyright restrictions.
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|Title Annotation:||GENES & CELLS|
|Date:||Nov 26, 2016|
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