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Tobacco Smoke Mutation Signatures Refined Through Sequencing Studies

NEW YORK (GenomeWeb) – The collection of mutation signatures present in tobacco smoke-related tumors appears to differ depending on whether they occur in tissues that are directly exposed to carcinogens in tobacco smoke, according to a new study published in Science.

Researchers from the Wellcome Trust Sanger Institute, the Los Alamos National Laboratory, and elsewhere analyzed exome or whole-genome sequences coinciding with more than 5,200 tumors from smoking-related cancer types, including lung or larynx cancers and cancers affecting the bladder, kidney, or liver. With the genetic information in these samples and array-based methylation profiles, they uncovered dozens of mutational signatures, though representation of signatures associated with smoking varied depending on the tissue where a tumor originated.

"Our research indicates that the way tobacco smoking causes cancer is more complex than we thought," senior author Michael Stratton, the Sanger Institute's director, said in a statement. "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."

Tobacco smoking is believed to influence the risk of some 17 cancer types, Stratton and his colleagues noted. But while patterns for some of the rampant mutations associated with tobacco smoke have been untangled over the years, the researchers suspected smoking might lead to more complicated combinations of mutational signatures, both in tissues exposed to the thousands of chemicals in tobacco smoke and downstream sites in the body affected by other biological processes altered by smoking.

Indeed, the new study suggests that "[t]obacco smoking damages DNA in organs directly exposed to smoke as well as speeds up a mutational cellular clock in organs that are both directly and indirectly exposed to smoke," Los Alamos National Laboratory researcher Ludmil Alexandrov, a co-lead author on the study, explained in a statement.

For example, the team described a mutational signature known as signature 4 — largely found in tumors from lung, larynx, and oral cancers in smokers — that appears to be the result of DNA damage introduced by carcinogens in cigarette smoke and subsequently misreplicated.

So-called signature 5 mutations involving base substitutions spanning 96 subtypes that seem to pop up with clock-like regularity were more widespread, on the other hand. Although that signature turned up across tumor types, regardless of individuals' smoking history, it was enriched in tumors from smokers.

Stratton, Alexandrov, and colleagues tallied up these and other mutation signatures using an analytical framework that members of the same team first described in a paper in Cell Reports in 2013. With this approach, they scrutinized genetic data for 5,243 tumors, including 4,633 exome sequences and 610 genome sequences, along with array-based methylation patterns. At least 2,490 tumors came from individuals who were reported smokers and 1,063 or more individuals who were never-smokers.

Generally speaking, they found that smoking-related tumors did not display dramatically different methylation patterns compared with tumors from never-smokers. Based on substitutions, small insertions and deletions, rearrangements, and other genetic changes detected across all of the cancer types, though, the team defined 26 different mutational signatures. Just five were significantly over-represented in tumors from smokers, with representation of the various signatures depending on the tissue in question. 

"The extent to which these distinct mutational processes operate differs between tissue types (at least partially depending on the degree of direct exposure to tobacco smoke), and their mechanisms range from misreplication of DNA damage caused by tobacco smoke constituents to activation of more generally operative mutational processes," the authors wrote.