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On Science: Why do non-smokers get lung cancer?

This article first appeared in the St. Louis Beacon, Nov. 25, 2009 - I don’t walk as much as I used to, or as I should, but last week I joined a crowd of about a hundred people walking in Creve Coeur Park in support of lung cancer survivors. Dubbed “The First Annual Fun Lung Run/walk” by its organizers (a group called the Lung Cancer Connection, sponsored by the Saint Louis University Cancer Center), the idea was for volunteers to recruit teams of people supporting a person they knew who has had lung cancer.

About a dozen teams supported a lung cancer survivor, the other teams honoring others who did not make it. I had a heavily smoking older brother who died of lung cancer four years ago, and a very sweet friend is only a few months post-surgery, so I had ample reason to attend.

The first thing I did is put my foot in my mouth.

At the registration desk where you sign in and get your team ID tag, the lady taking my information asked if I would sign a petition supporting increased funding for lung cancer research. Firmly inserting my foot, I said the best way we could reduce lung cancer would be to fund research on making it easier to quit smoking. You would have thought I had slapped her.

“My husband died of lung cancer,” she said, “and he never smoked.” She wasn’t smiling any more. My welcome was over. Proving that an inserted foot is not easily removed, I argued for a few moments with her – as if this were a debate and not a matter of life itself to her.

So its time to extract my foot from my mouth and address her point squarely. What I said to her, while true, was ignoring what she was feeling, and more importantly what she said. People die of lung cancer every day who have never smoked a cigarette. My recently diagnosed friend, the very person on whose team I was walking, has never smoked. I owed the lady not only an apology, but a considered reply. So here it is.

First, how big a problem are we talking about?

The number I was familiar with ( I had even published it in my textbook 10 years ago) was from the 1970s, and said that, on average, 17 lung cancers occur among people who had never smoked per 100,000 Americans. That at first glance does not seem like a lot of people, but closer examination reveals quite a different picture. The overall incidence of lung cancer among Americans in the 1970s was 78 per 100,000 – in other words, 17/78 or fully 21 percent of American cancer victims had never smoked!

So, we are talking about a big problem. The situation got a lot clearer two years ago, when Dr. Heather Wakelee of Stanford published a detailed analysis of the incidence of lung cancer among never-smoked individuals in the Journal of Clinical Oncology, a major cancer journal. She found that of 219,000 American lung cancer cases in 2007, 32,850 had never smoked a cigarette. That’s 15 percent, not very different from the number seen in the 1970s.

Importantly, more than two-thirds of the nonsmoker lung cancers were women. Fully 20 percent of the women diagnosed with lung cancer in 2007 had never smoked – one in five! Eight percent of the men diagnosed with lung cancer were nonsmokers.

These are pretty serious numbers, especially if you are a woman. The danger of contracting lung cancer for a woman is about the same as contracting cervical cancer. The danger of dying of the disease is even greater: 14,200 women who never smoked will die of lung cancer this year, four times the total who will die of cervical cancer. A big problem indeed.

So what is causing the problem? Why do people who have never smoked contract lung cancer, and why are women more than twice as likely as men to do so? There are four causes that seem worth looking into:

Second-hand smoke. It seems clear that exposure to second-hand smoke can increase the probability of contracting lung cancer, although the numbers are slippery and it does not seem to me likely that this cause could be responsible for anything like one-fifth of lung cancers.

Radiation from radon in the dirt beneath houses. Again, the science is clear that radon can in principle contribute to cancer incidence, but the contribution would be tiny -- far smaller than the effect we are looking at.

Genetic predisposition. Just as smoking causes lung cancer by mutating and so inactivating genes that normally act to prevent unbridled cell division, so nonsmoking lung cancer may reflect a genetic predisposition to the disease. This actually may make a significant contribution. Dr. M. You and co-researchers at Washington University’s Siteman Cancer Center published a paper in the journal Oncogene last week identifying a gene associated with spontaneous lung tumor incidence. They conducted a genome-wide association study in mice and identified a gene called Xm2 where mutations were highly correlated with spontaneous lung tumors. They went on to show that the gene is active in people as well, playing an important role promoting in cell proliferation. Mutations affecting this Xm2 gene are thus major candidates as causative agents for lung cancer among nonsmokers.

Endocrine disruptors. None of the three potential causes we have discussed do anything to explain why nonsmoking lung cancer is so much a woman’s disease. In this regard, it is very instructive to look for a moment at breast cancer, another disease that men don’t get as often as women. Why not? I have written in the column before about the answer to the question of why men don’t get breast cancer. The answer I favor is chronic low-level exposure to chemicals like bis phenol A (BPA) that mimic estrogen. In this instance, all my money is on chronic exposure to BPA and similar hormone disruptor chemicals as the cause of the excess lung cancer seen among nonsmoking women.

What can we do?

Just as the government elects to spend only a tiny fraction of its breast cancer research funding on a search for the CAUSE, so it spends almost nothing on attempts to find the cause of nonsmoking lung cancer. If you care about the issue, write your representatives and senators and tell them so. We cannot hope to cure what we do not understand.

George B. Johnson's "On Science" column looks at scientific issues and explains them in an accessible manner. 

Johnson, Ph.D., professor emeritus of Biology at Washington University, has taught biology and genetics to undergraduates for more than 30 years. Also professor of genetics at Washington University’s School of Medicine, Johnson is a student of population genetics and evolution, renowned for his pioneering studies of genetic variability. He has authored more than 50 scientific publications and seven texts.

As the founding director of The Living World, the education center at the St Louis Zoo, from 1987 to 1990, he was responsible for developing innovative high-tech exhibits and new educational programs.

Copyright George Johnson