At this point, there’s little doubt that smoking is bad for your health. There’s a reason they call them cancer sticks: Smoking cigarettes is now known to cause 87 percent of lung cancers and one out of three cancers total, adding up to around 6 million deaths per year worldwide according to the Centers for Disease Control. What’s more obscure is how exactly the 60+ carcinogens in tobacco smoke work to do their insidious damage to the lungs, livers and kidneys of smokers and those exposed to secondhand smoke.
To answer that question, researchers from the Wellcome Trust Sanger Institute and the Los Alamos National Laboratory recently examined the DNA of more than 3,000 tumors from the bodies of smokers and nonsmokers. The results, published this week in the journal Science, were sobering: Researchers found deep molecular “signatures” etched in tumor cells, even in organs that were never exposed to cigarette smoke directly. Each of the signatures, showing how DNA has been damaged, is a potential start point for a future cancer.
“Different carcinogens can leave fingerprints on the genome,” explains Ludmil B. Alexandrov, a biophysicist and Oppenheimer Fellow at Los Alamos National Laboratory, and co-lead author of the study. “So what we do is we just perform a bit of molecular CSI, and we lift the fingerprints off the genome of cancers. So we are able to say based on that, what are the processes of this mutation.”
Researchers first identified more than 20 “mutational signatures”—places in the cell’s DNA where genes have been substituted, added or deleted in a predictable, replicable way. In smokers’ cancer cells, five of those 20 were elevated that were not elevated in nonsmokers’ cells. One of these signatures is associated with lung and larynx cancers in smokers.
The study also shed light on how smoking can lead to cancer in organs that lie far from the smoke-exposed lungs, throat and mouth. “Some of them reflect direct damage to DNA,” Alexandrov says, “where you inhale the smoke and the smoke’s constituents bind to the DNA and they mutate it. We also found in organs not directly exposed to inhaled smoke, tobacco smoking is disregulating key cellular processes.”
Cells tend to accumulate more mutations as they divide and age. So, by increasing the number of mutations, smoking is basically aging your cells. In smoking-related bladder, liver and stomach cancers—as well as other cancers where the organ isn’t exposed to smoke—smoking still accelerates a “molecular clock” that normally would “tick” regularly with age, adds Alexandrov.
The researchers were then able to quantify exactly how fast smoking mutates cells by correlating the number of mutations with self-reported smoking habits. For a pack-a-day smoker, they found, each year of smoking causes 150 extra mutations in every lung cell. These were all copies of the same mutation; the more mutations, the more likely that the cell would become cancerous.
“That is 5-10 times higher than the background mutation rate,” Alexandrov says, noting that background rate depends on age, ethnicity and other factors.
Lung cancer is a relatively new disease that came into prominence with the ubiquity of cigarettes in the 20th century. Until 1900, one paper notes, only about 140 cases were known in medical literature. When professors diagnosed lung cancer in a patient, they told their students they might never see another lung cancer patient in their careers. But just a few years later, lung cancer was on the rise. Doctors put forth numerous explanations—asphalt dust, air pollution, the flu of 1918 or exposure to poison gas in WWI—though smoking was also blamed.
It wasn’t until 1964, with the release of the U.S. Surgeon General’s landmark report about the health dangers of cigarettes, that most (though not all) Americans recognized the dangers of cigarette smoking. Today, thanks to media campaigns as well as policy changes like indoor smoking bans and cigarette taxes, smoking rates in America are half what they were in the 60s, but the Surgeon General still calls smoking “an enormous, avoidable public health catastrophe.”
This new study could help researchers establish “not only the complex relationship between tobacco and cancer" but also "the pathogenesis of the disease from its earliest points,” says Dr. Steven Dubinett, director of UCLA's lung cancer research program and a professor of pulmonary and critical care medicine. “This [study] may be an investigation in terms of the nature of mutations, but our hope is we begin to use … the information about mutational load as advantages for therapy,” adds Dubinett, who was not involved in the study.
But don’t rely on the possibility of a future treatment for lung cancer to reverse the consequences of your smoking habit, the researchers caution. “Even if you stop smoking, these mutations are there—they are not reversible,” Alexandrov says. “Even if you just start smoking for a bit you will be scarred, the genetic material of your cells will be scarred for your lifetime.”