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Never Smoked. Lived Right. Died of Lung Cancer.

The puzzle of cancer in nonsmokers


Avrum Spira’s aunt died of lung cancer almost 20 years ago. She was a nonsmoking exercise buff in her 40s who hadn’t been exposed to any known toxins; she worked in a government office, not a coal mine. “One of the healthiest people you could imagine, did everything right,” says Spira (ENG’02), who at the time was an internal medicine resident at the University of Toronto.

The one thing she didn’t do right wasn’t her fault: she’d been born to a nonsmoking mother who had died from the same illness. “I’m absolutely convinced she had a genetic predisposition” to lung cancer, says Spira, a School of Medicine professor and chief of computational biomedicine. That conviction set him on a quest for the genetic key to a medical mystery: why some people who have never smoked fall victim to this scourge of cigarette users.

Lung cancer kills more Americans than any other cancer, and twice as many women die from it than from breast cancer, although the latter gets greater public attention, says Spira. In 2008, the last year for which data was available, more than 208,000 Americans were diagnosed with lung cancer and almost 158,600 died from it. Spira says between 10 and 15 percent of these annual victims are nonsmokers (the percentage has been edging up slowly in recent years) with no apparent exposure to other toxins—a crucial caveat. “How do you know someone has been or has not been exposed to something in the environment?” he asks. Some potential toxins, like radon, are invisible, he notes, “so people who we’re seeing now, with higher rates of nonsmoking lung cancer—is it because they were exposed to radon 20 years ago?”

It’s true that worldwide, the rise in the incidence of lung cancer—from the eighth leading cause of death in 1990 to fifth in 2010—is mostly a function, perversely, of good news: as living standards have improved in the developing world, more people survive into adulthood, meaning a decline in childhood deaths from malnutrition and infectious diseases. That has brought an accompanying uptick in the number of people dying from diseases mostly found in wealthier countries, among them cancer. Moreover, air pollution in industrializing countries has resulted in more lung cancer in nonsmokers there, Spira says.

But in the United States, he says, doctors believe there’s a similar spurt in lung cancers in nonsmokers who’ve had no apparent contact with other toxins. The most extensive studies, incorporating detailed questionnaires and visits to peoples’ homes to see their environment, show that “there hasn’t been a clear association among nonsmokers who are getting lung cancer with exposures to other things.”

An ongoing, as-yet-unpublished study by a team that includes Spira is looking at tumor tissue and adjacent, noncancerous tissue from the lungs of 32 subjects with lung cancer: 8 smokers, 11 former smokers, and 13 who never smoked and had no apparent exposure to other toxins. The researchers ran the samples through a gene sequencer at MED, which “can give us unprecedented insight into the genomic changes leading to lung cancer” in nonsmokers, says Rebecca Kusko (MED’14), a graduate student spearheading the study in Spira’s lab.

With the sequencer, “we study the normal cells from each person as a control,” says Spira, “and then what happens in their tumor right next door, and say, what’s changed?” Preliminary results suggest that in the smokers, “a huge number of cancer pathways are activated,” as genes controlling cell growth in the tumors turned on. But those pathways weren’t necessarily activated in the nonsmokers, who showed different gene changes between their healthy lung tissue and their tumorous tissue. The researchers’ hypothesis is that the nonsmokers had a genetic predisposition, a pathway, to cancer that was activated by something in their environment.

That trigger, Spira theorizes, may be a viral infection (cervical, liver, and head and neck cancers are all caused by viruses, he says). The researchers are now sequencing the tumor tissue of the nonsmokers to try and find any viral genes. “Even if there’s one viral gene per million human genes, we might pick it up, we believe,” he says. The work will take a year or two.

Potential therapies—which are many more years away, he warns—might include screening people with the genetic predisposition and then giving those with the predisposition regular lung scans to catch cancers early. Another possibility would be drugs that could turn off uncontrolled growth in cancerous cells. (Spira got attention in 2010 for research suggesting that the natural compound myo-inositol could turn off incipient lung cancer in smokers.)

Those who walk Commonwealth Avenue and have to dodge fumes from smokers on break may wonder about secondhand smoke. Research is mixed, but Spira, who researches the amount of smoke necessary to change gene expression and possibly lead to lung cancer, believes that it takes a big dose—perhaps exposure over months or years.

Almost half a century after the surgeon general first warned of smoking’s dangers, Spira says that even Hollywood is catching on that not all cancer victims heedlessly bring the disease on themselves. In 2011, he was a presenter at the Prism Awards, given for accurate portrayals of illness in entertainment media. He handed an award to an actress whose character on the soap opera The Bold and the Beautiful had lung cancer.

The character was a nonsmoker.

Rich Barlow

Rich Barlow can be reached at barlowr@bu.edu.

14 Comments on Never Smoked. Lived Right. Died of Lung Cancer.

  • Mary on 01.25.2013 at 1:08 pm

    Is it not also possible that had a smoker never smoked, they still could have gotten lung cancer? In other words, doesn’t it sound reasonable that someone genetically predisposed to lung cancer, got said cancer due to genetics and not due to the fact that they smoked?

    • Kathy on 02.09.2015 at 3:00 pm

      You have got to be a smoker. You people build an entire belief system based on a habit. You want to smoke; you don’t care if it will eventually kill you and you sure as hell don’t care who you kill along the way.You don’t base your belief on facts. 90% of the people who die from lung cancer are active smokers (American Lung Association). Just because some people die who are non-smokers doesn’t mean that cigarette smoking does not cause cancer.

      You will be on your deathbed dying of lung cancer still swearing that it wasn’t because you smoked, and begging for cigarettes.

      • Robert on 10.07.2015 at 5:09 pm

        Kathy wrote “You don’t base your belief on facts. 90% of the people who die from lung cancer are active smokers (American Lung Association).”


        Mary is correct: it IS possible for someone genetically predisposed to lung cancer who *also* happens to smoke, to get lung cancer from that predisposition rather than from their smoking. Many people smoke for decades without ever developing lung cancer, whereas about 30,000 Americans who have never smoked will die this year from lung cancer that has likely formed, metastasized and killed them, all in less than a year. It is absolutely possible to have both the predisposition AND to be a smoker, and to get the cancer from the former rather than the latter.

        And the actual percentage of those in 2015 who die from lung cancer who are active smokers is closer to 80%, with 20% who have never smoked being afflicted with it and dying.

        Full disclosure: Neither my wife nor I have ever smoked, nor do we excuse people for smoking. Nevertheless, she was just diagnosed with stage-IV lung cancer.

      • Evan on 10.27.2015 at 9:12 pm

        Kathy, you are wrong. The most deadly of lung cancers, small cell, IS typically diagnosed in current or former smokers. 99.5% of males with small cell have a history. Non-small cell has a significantly higher percentage of non-somokers, and though not quite as lethal (percentage wise) it’s still kills most of it’s victims.

        Here’s the kicker. I HAVE NEVER SMOKED and I was dx’d with small cell a couple of months ago. I am going to die and see it coming. With treatment 20% can acheive a remission. Remissions last anywhere from 2-24 months. Maybe 2% are still alive at five years…..but constantly looking over their shoulders…. It sucks!!!!

  • teresa franks on 01.25.2013 at 7:38 pm

    my mother in law just passed the other day with stage 4 lung cancer quit smoking several yrs ago she had copd,does any one with copd need to be screened for lung cancer?

  • Leslie Vaigneur on 01.28.2013 at 9:40 pm

    My 28 year old daughter died 7 years ago from Stage IV lung cancer. She was a nonsmoker. She was also pregnant at the time of her diagnosis. Thankfully she delivered her son at almost 28 weeks. My daughter lost her battle against lung cancer just 6 months after his birth. No one else in our family has had lung cancer. What are the chances her son might also be diagnosed with lung cancer?

    • CtCorvus on 03.27.2014 at 10:24 pm

      Sorry to hear about your loss. YOu can test the child companies like 23 and me offer DNA testing. It doesn’t have to be lung cancer runing in your family it could be other types of cancer. She was to young almost sure it was due to a genetic mutation. About 50% of smokers never get cancer some people are extremelly resistant to it and their cells repais most of the damage. That why you hear stories about 96 year old guy who smoked all his life and he is just fine. But the other side of the coin some people cells fail to repair even minor damage.

  • Nathan Reese on 02.18.2013 at 5:16 pm

    looking forward to the day when stem cells will continue to be cultivated to replace diseased tissue, doesn’t look like it’s too far away http://bit.ly/11vw6Y5

  • Jim Pantelas on 03.08.2013 at 2:40 pm

    I’m a seven-plus year lung cancer survivor, an active advocate for research, and a very active member of the patient and family centered care movement. It is with that as a brief introduction that I write the following.

    I think it’s unfortunate that we still pit lung cancer victims against one another by perpetuating the conversation of lung cancer and smoking. Yes, we all know that smoking is a major contributor in the incidence of lung cancer. But there are also significant environmental and, as raised by the article, potentially genetic causes for the disease. If we are to address the causes of this disease I believe we must look at the cocktail of exposures that may be more significant than any one cause.

    If asbestos exposure increases a smoker’s likelihood of developing lung cancer by fifty times that of smoking alone, shouldn’t that be considered? If a genetic predisposition to lung cancer might increase the odds of developing the disease, how are those odds enhanced by regular exposure to urban smog, radon, or second-hand smoke? And how much more if you worked in an older government building that might have used asbestos tiles or insulation?

    I’m not trying to minimize the dangers of tobacco. If anything I believe there should be a prohibition on the products. But to act surprised when a non-smoker succumbs to lung cancer is also a way of indicting smokers and former smokers as complicit in their illness. It’s a stigma that haunts lung cancer victims and denies the research funding needed to aggressively address the disease.

    We don’t ask breast cancer patients why they didn’t have children, and we don’t ask colon cancer patients if they participated in anal sex – and yes, it is my intent to be absurd here! We got over the stigma’s attached to AIDS because we learned that it was infecting everyone. We need to do the same with the stigma of lung cancer.

    So fight against tobacco by fighting against tobacco – not its victims. Tobacco use contributes to over six million deaths a year. It’s not just lung cancer, it’s heart disease, esophageal cancer, emphysema, and COPD to name just a few. And it’s becoming more dangerous because our environment has become all the more dangerous.

    The reality is that lung cancer is curable if caught early. The need for more effective and affordable screening tools is obvious. But that requires research and research requires funding, and few are willing to fund research for a disease that is perceived – even by its victims – to be self inflicted.

    I would beg you to be cautious of blaming lung cancer on its easiest victims. It works against all of us and does nothing for our cause.

    • Steve on 07.26.2013 at 8:30 pm

      Great post. It will probably take a full ban on all tobacco products and everyone smokefree to get decent research funding. Only then will they see that people STILL die from lung cancer – thus separating lung-cancer from smoking (finally).

  • Irene Dorado on 08.16.2013 at 12:50 pm

    my daughter also m died of lung cancer and never smoked although she had she had being exposed to a chemical from a cement company where she lived a few miles away also did some digging around the cement company for a project for ucr she was an was exposed to the chemical was found in her blood also she had developed other cancers because on this chemicail she survivied ll years lung cancer 8 months mo. sbe just passed 2 weeks ago too much sufferring endourded so much pain and harsh med. testing her arms full of brusis because the needs. but yet never complainded just want to live to finish raissing her l3 yr. old and 22 yr. old great single mother . the husbant left her because he could handle her cancer. a finncial strugglling mother yet she made sure her 22 stay in a city college which she could barely afford. she was known to all as a trooper. now she is in heaven with her maker the lord. loved her so much . thank you

  • Sagar on 08.12.2014 at 12:12 pm

    really sad to hear about your daughter, and heartly appreciate for her struggle to raise her children, just wish her soul REST IN PEACE!

  • Delene Kepler on 09.12.2016 at 10:09 am

    These testimonials are so sad due to the fact they lost their loved one. I am a former “closet smoker”, nevertheless a smoker. I own that and I was so ignorant to the fact of I could die from this. I was diagnosed with stage 4 lung cancer and I am fighting like hell and will continue to fight. It bothers me deeply that the funding for research and new meds is not there because of ME! I have the cancer that kills the nonsmokers, ironic as that is. I want to spread the word that cancer can kill anyone with lungs. The stigma of people killing themselves by smoking is not the only people in the arena of lung cancer. How can we change this and get more funding? I want to help make this happen for all people with lung cancer. I am on round 34 of my chemo and I am so blessed after 3 years with this terrible disease. The cards are stacked against me but I have HOPE that one day we will cure lung cancer.

  • Sherry on 07.16.2017 at 1:50 pm

    Sure, never-smokers contract diseases usually associated with tobacco use. I don’t personally find this surprising. We are biological beings – stuff goes wrong. I think of us a 1000-sided Rubik’s Cubes; very complicated with billions of combos involving genetics, environment, & lifestyle choices. To think that any one component can be pinpointed as THE cause of an individual’s cancer(s)/COPD seems simplististic at best & flat-out misleading at worst.

    Now, having said that – I come from a family where smoking kills. My grandfather of small-cell lung cancer at 60, grandmother of emphysema at 77, eldest sister at 47 of small-cell lung cancer. My mother died a suicide at 37, but I still remember her classic pre-emphysemic cough in her EARLY 30s! Had she not killed herself, I imagine smoking would have gotten her, too, sooner or later. My two remaining sisters are occasional smokers, a couple of nephews, a niece. You’d think our family history would have deterred them, right? Nope! I am 53 and one of a handful who have never even tried smoking, not even once. Additionally, I’m actually allergic to tobacco (or perhaps some additive in cigarettes.) Took weekly shots for 7 years in my youth for that allergy. Again, you’d think my relatives would have refrained from smoking around me – and again, that would be a big NOPE. I now have “emphysemic changes” in the upper part of my right lung. That was shocking to hear, since I have no symptoms. (Those chest x-rays were for something else altogether.)

    The Surgeon General’s report in 1964 officially stigmatized smoking, and rates have declined steadily since then. Still, there will always be smokers. I’m sorry if non-smokers with classic smoking-associated diseases feel insulted by the assumption that they smoked – but that is a momentary aggravation easily corrected. Much as cirrhosis of the liver is overwhelmingly linked to alcohol abuse, thus certain cancers/COPD are also behaviorally-driven maladies.

    If I ever end up with full-blown emphysema, surely most people will assume I am/was a smoker. I’ll tell them that no – I NEVER smoked. If they don’t believe me? C’est la vie, that’s no skin off my nose!

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