Smoking leaves 'signatures' far from lungs

While it's not surprising that hot, noxious and carcinogenic tobacco smoke can cause cancer in the throat and mouth, it's something of a puzzle how other parts of the body - such as the liver and bladder - are also at risk.

Researchers have gleaned a greater insight by looking at "fingerprints" left behind in the DNA of tumors from smokers. Their study, reported in the journal "Science," found that genetic damage could be cause by a number of different mechanisms.

Scientists from the Britain's Wellcome Trust Sanger Institute and the Los Alamos National Laboratory in the US looked at 5,000 tumors and compared the cancers of smokers with those who had never smoked. The researchers found certain molecular fingerprints, also known as "signatures," that were prevalent in the DNA of smokers.

Direct damage only half the story

While mutations can cause cancer directly, they're also potential starting points for indirect mechanisms - cascade effects that change the cellular environment and lead to genetic damage.

"The results are a mixture of the expected and unexpected, and reveal a picture of direct and indirect effects," says co-author Dave Phillips, Professor of Carcinogenesis at King's College, London.

The cells that came into direct contact with inhaled smoke were the ones where there was most damage from carcinogens that directly cause misreplication of DNA. This was true not only in the lungs but also the oral cavity, pharynx and esophagus.

The mutational signature that was apparent in those organs was not present in tumors from other parts of the body, such as the stomach or ovary.

Elsewhere it was different. "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," says Phillips.

In fact, the study showed there were at least five different processes of DNA damage due to cigarette smoking. The most widespread was a process that appeared to speed the cellular clock, aging and mutating the DNA prematurely.

Another of the signatures was linked to overactive editing of DNA enzymes.

Fingerprints representing other mutations were found consistently in the study, even if it was not always possible to work out how the damage occurred.  

A tumor's 'archeological record'

Tumors contain genetic clues about the pathways that lead to their becoming cancerous. Scientists now hope to delve further into this field.

"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," says Professor Mike Stratton, joint lead author of the study. "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 can provide provocative new clues to how cancers develop and thus, potentially, how they can be prevented," Stratton says.

A closer understanding of risk

The researchers found that smokers accumulated 150 additional mutations per lung cell for each year that they smoked, providing a direct link between the number of cigarettes smoked during a lifetime and the number of mutations in tumor DNA.

"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," says Dr Ludmil Alexandrov from the Los Alamos National Laboratory, and another lead author. 

While the effects on the lungs are particularly pronounced, the increased risk of mutations in other organs are considered clear from the study. There were an estimated average 97 extra mutations in each larynx cell, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver for each year of smoking a packet of cigarettes a day.

A survey published in September showed that smoking could leave its marks on an individual's DNA as many as 30 years after they quit.

That study, which looked at blood samples from 16,000 patients showed "epigenetic" damage caused by DNA "methylation" associated with smoking. While some of the affected genes were linked with cancer and cardiovascular diseases, scientists found many more parts of the genome showed the signatures of mutation caused by smoking.