One Mutation per 15 Cigarettes Smoked

Now that’s a memorable factoid. Nature recently published a paper titled “A small-cell lung cancer genome with complex signatures of tobacco exposure” (Nature 463, 184-190 (14 January 2010), Pleasance et al), which as its title implies, contains the summary of the sequence of a cancer genome derived from a lung cancer tumor. It’s an interesting read; I can’t claim to understand it all. At a high level, they found 22,910 somatic substitutions, 65 insertions and deletions, 58 genomic rearrangements, and 334 copy number segment variations were identified; as I understand it, these are uncorrectable errors, i.e. the ones that got past the cell’s natural error-correction mechanisms. That’s out of about 3 gigabases in the entire genome, or an accumulated error rate of about 1 in 5 million.

I’m not an expert on cancer, but the way it was explained to me is that basically every cell has the capacity to become a cancer, but there are several dozen regulatory pathways that keep a cell in check. In a layman sort of way, every cell having the capacity to become a cancer makes sense because we come from an embryonic stem cell, and tumorigenic cancer cells are differentiated cells that have lost their programming due to mutations, thereby returning to being a (rogue) stem cell. So, a cancer happens when a cell accumulates enough non-fatal mutations such that all the regulation mechanisms are defeated. Of course, this is basically a game of Russian roulette; some cells simply gather fatal mutations and undergo apoptosis. In order to become a cancer cell, it has to survive a lot of random mutations, but then again there are plenty of cells in a lung to participate in the process.

Above: a map of the mutations found in the cancer cell. The 23 chromosomes are laid end to end around the edge of the circle. There’s a ton of data in the graph; for example, the light orange bars represent the heterozygous substitution density per 10 megabases. A higher resolution diagram along with a more detailed explanation can be found in the paper.

The tag line for this post is lifted from the discussion section of the paper, where they assume that lung cancer develops after about 50 pack-years of smoking, which roughly translates to the ultimate cancer cell acquiring on average one mutation every 15 cigarettes smoked. Even though this is an over-simplification of the situation, the tag line is memorable because it makes the impact of smoking seem much more immediate and concrete: it’s one thing to say on average, in fifty years, you will get cancer from smoking a pack a day; it’s another to say on average, when you finish that pack of cigarettes, you are one mutation closer to getting cancer.

18 Responses to “One Mutation per 15 Cigarettes Smoked”

  1. Raymond Lutz says:

    Ouah! Belle image! I’m going to display it in my college corridor near our sciences department alongside an image of LHC detectors traces (ATLAS or CMS). Bio, meet physics… too bad the pdf version is still bitmap: numbers in the ideogram are blurred.

    Merci for the head-up!

  2. Abdullah Ali says:

    I felt a bulge in my throat and had trouble finishing my cigarette when this came up in my RSS reader.

    Thanks for the reference, will read that in detail later tonight.

  3. Aris says:

    One has to wonder what the ethical justification is for keeping cigarettes legal.

    • KoBach says:

      The same reason fast food is still legal. People still have free will and will do whatever regardless of whatever law you put in place. Better to tax the crap out of it and educate the public.

  4. This seems like a rather weak set of results. I looked at it to see whether they had any way of distinguishing between mutations that took place to make the cancer, and mutations that took place after the cancer got going (of which there are commonly plenty, since being a cancer cell in a cancer is a deeply Darwinian environment), and found that not only was this a laboratory cancer line — propagated for many generations in petri dishes, another environment in which mutations and Darwinian selection occur — but that they weren’t even sure whether the original cancer that founded the line came from a smoker. 95% of such cancers (small-cell lung cancers) are from smokers, so it’s very likely… but on the other hand, that means there’s also a 5% chance that they’re just blowing smoke. As for whether the mutations they found were acquired when the cancer was alive in the lung, about all they have to say is that

    “G>T/C>A transversions were the commonest change observed
    (34%), followed by G>A/C>T (21%) and A>G/T>C (19%) transi-
    tions (Fig. 2a). This distribution is remarkably similar to the pattern
    of substitutions observed in TP53 in SCLC cases curated from the
    published literature (Supplementary Fig. 3). This implies first that
    the NCI-H209 genome is typical of SCLC, and therefore of tobacco-
    associated mutational profiles, and second that most mutations were acquired in vivo, not during cell culture.”

    I’m not a specialist, so maybe those sort of numbers are more meaningful than they sound; but to me that isn’t even a claim of statistical significance, let alone factual certainty.

    With all the effort they put into sequencing, it’s surprising that they couldn’t get an actual sample of cancer from a patient who’d done a lot of smoking, to sequence.

    On the general subject of cancer, by the way, I recommend Ian York’s weblog:

    He has a lot of interesting stuff.

    • bunnie says:

      I think a lot of your criticisms are valid, and there is a lot more science to go as far as the personalized sequencing of cancer variants are concerned.

      While you are correct that the paper doesn’t report the ideal case — i.e., take a confirmed lung cancer cell directly from a smoking patient as well as a non-cancer cell from the same patient and sequence both and do a direct comparison of the two — I think it is still a good, solid step in the right direction and a powerful demonstration of the potential of personalized sequencing in the future. There’s a lot of regulatory and medical complications as well as ethical issues in securing live cell lines for papers like this, but I imagine there is probably a paper coming in the near future that does exactly what you are asking for.

      However, I think the broader point here is that the science is probably good enough (95% likelihoods aren’t bad) to be a basis for public health generalizations such as one mutation per pack of cigarettes. The equation itself — one mutation per pack of cigarettes — is already a gross generalization and one can find a dozen ways that it’s not precisely correct. I’m guessing that probably what matters is *where* the mutation happens, so perhaps the actual mutation rate is much higher. Most cells either die or correct the mutations, until eventually you get unlucky and one of them gets just the right combination that turns it into a cancer. The accumulation of mutations also probably happens in fits and starts, rather than at a constant rate, due to the nature of the selective pressures of smoking. However, from a public health perspective I think it’s a passable summary of the pertinent issue, and it’s done it’s trick — smart people like you are looking deeper into the paper and sparking more debate, finding ways to improve the data and spreading general awareness of the situation.

      • Extracted cancers are commonly thrown in the trash. Genuine ethical issues in using that trash for research are nonexistent. But yes, getting permission from the professional naysayers known as medical ethicists can nevertheless be difficult, and yes, regulations do dictate that permission is required.

        To really measure the mutation rate from smoking, the best thing would be to analyze a non-cancerous cell from a smoker’s lung. The comparison would not be with a cancer cell, but with a cell from the lung of a non-smoker of the same age and similar background. But my guess is that this would not have been feasible using the technologies that this paper used; I think they needed a lot of cells to do the sort of sequencing they did, and that that was why they used cancer cells. (I didn’t look into their techniques in detail, but “massively parallel sequencing” sounds like something that must gobble a lot of DNA.)

        What I’ve said isn’t really an objection to the bulk of the paper, just to the mutations-per-cigarette soundbite. We’re in an age where DNA sequencing just got inexpensive enough that these sorts of experiments can be done. Just about anything that is sequenced like this for the first time is interesting in some way or another; even a knowledge of the mutations in a laboratory cancer line can be quite useful. But as for public health purposes, I don’t think it adds much: if someone is contrary enough to doubt the massive correlations between smoking and cancer, there’s not much chance he’ll pay attention to this result.

        • Seth says:

          Wouldn’t then the ideal followup be to find twins in their 60s or 70s, one of whom never smoked, the other who has smoked his entire adult life? Tissue samples from both of their lungs (and from cancerous lung tissue) would provide a wealth of information on mutation rates.

  5. th0mas says:

    Thank you bunnie. I have to say I never understood any biology ever, but when you post about it it makes sense.

    You should do to cancer as you did the xbox! :D

  6. Jake says:

    Say what lol… this makes me feel dumb!

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  8. Lung Cancer scared the hell out of me that is why i do not smoke cigarettes anymore.’;*

  9. E-cigarettes says:

    E-cigs are a much safer alternative to trditional tobacco cigarettes.

  10. chuck says:

    They could introduce comparably priced nicotrol inhalers at the point of sale as another consumer option. They could work on providing a synthetic analog that mimics the effects of nicotine, without the toxic load or carcinogenicity. Then they could work on loading their inhalers with that substance instead of pure nicotine. But they won’t do any of these things, and why not.

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  12. lung cancer is almost alway caused by heavy cirgarette smoking”-,

  13. John Dee says:

    Now THAT’S scary. I have to admit, I’m a heavy smoker and I don’t really pay attention to any studies or warnings but the way you explained it was enough to make me think twice.

  14. jimmy choo says:

    But now I have. All in the day that changed my mind when we have a great public debate. We went to production and even a few days later.I’m not familiar with the sale to have, but I, who was surprised initially to act as advocates honest, much of this I have seen since.