Why we get cancer: genetics, lifestyle, and just sheer chance

It has long been understood that many cancers occur as a consequence of errors in the replication of the genetic materials of cells (usually DNA) during the normal process of cell growth and replication. What has been much less clear has been the degree to which clinically evident cancers are caused by such errors.

In a new article in Science, just a few days ago, Thomasetti and Vogelstein claim to have been able to give us greater insight into just how common sheer chance really is (as opposed to inborn genetic differences and poor lifestyle, like years of smoking) in risk for getting cancer.

While the authors are clear that their study does not explain cancer risk in a definitive form for every subtype of cancer, what they have been able to show is that there is a direct correlation between a person’s lifetime risk for cancers of many different types and the total number of divisions of the normal self-renewing cells maintaining that homeostasis in the relevant organ tissues. Indeed, that correlation is really very strong, with a correlation factor of 0.81.

They use these data to argue that only about 30 percent of the variation in cancer risk among tissues can be attributable to environmental factors (diet, behaviors like smoking, etc.) or inherited (genetic) predispositions. To quote the authors:

The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.

This research is also discussed in detail in layman’s terms in an article posted yesterday on the web site of The New York Times.

We should be clear that this research did not specifically include data from prostate cancer patients (or breast cancer patients either) “because there was not enough data on rates of stem-cell division in those tissues,” but there is no good reason to think that risk for prostate cancer would not come with the same underlying issues and causes as most other types of cancer. Whether “bad luck” is the cause of half of all prostate cancers (or perhaps even more) is still to be determined, but it is surely the cause of many cases.

In statements quoted in the article in The New York Times, Dr. Thomasetti compared risk for a car accident to risk for cancer.

In general [he says] the longer the [car] trip, the higher the odds of a crash. Environmental factors like bad weather can add to the basic risk, and so can defects in the car.

By analogy, the longer one lives, the higher one’s risk for a diagnosis of cancer, and any one patient’s risk for a diagnosis of cancer is …

… really the combination of inherited factors, environment and chance. At the base, there is the chance of mutations, to which we add, either because of things we inherited or the environment, our lifestyle.

16 Responses

  1. Wow, that’s an eye opener. Plain bad luck? Ugh!!!

  2. Walt:

    We have always known that many cancers occur through plain bad luck (the right cells doing the wrong thing at the wrong time). The authors seem to be surprised that the “bad luck factor” is as high as it is. I can tell you that I am not as surprised as they seem to be. I have long believed that this was a major cause of many types of cancer, particularly in tissue types with high levels of cellular turnover and replication.

  3. I hear ya. Seems to contradict the whole “survival of the fittest” type thing.

  4. Walt:

    Not necessarily at all. Random mutations of this type also contribute to “survival of the fittest”.

  5. The dark underbelly of natural selection is that most random mutations are not beneficial, and are often downright lethal. Also, mutations that may be beneficial to survival and procreation in the peak reproductive years, may be detrimental as we age. An interesting hypothesis was put forth by W. D. Aiken (http://www.medical-hypotheses.com/article/S0306-9877(11)00470-1/abstract) that Africans who had a certain androgen receptor mutation were more likely to survive the horrors of the slave transport ships, and the same mutation may be responsible for the higher prevalence and aggressiveness of prostate cancer found in African-American (and African-Caribbean) men compared to Africans or Caucasians.

  6. See also this article from The Guardian (a newspaper in the UK).

  7. This conclusion of this paper seems to be only part of the picture. Presumably not all cancerous bad luck leads to cancer. The body’s own defenses are influential, and these can surely be affected by what we choose to do or not do.

  8. Dear John M:

    I am sure there was some very poor reporting related to this paper. However, it is worth noting that the term “bad luck” was actually used — and very deliberately — by the two scientists who published the paper, and one of them (Bert Vogelstein) not only holds a Nobel Prize but is one of the most respected cancer researchers of his generation. Their use of this term was clearly very deliberate. And it was inevitably picked up by the media and quoted.

    The two journalists who wrote the article in The Guardian that you linked to (see above) — one of whom doesn’t even have the courtesy to provide an actual name — seem to have missed the point of the paper entirely by focusing on a communication issue and then over-analyzing its importance as opposed to focusing on the implications of the research … which is that (at least for some forms of cancer) the occurrence of random mutations may well be more important in prediction of risk than any “logical” issue such as environment, lifestyle, or heredity.

  9. My take on it is that T&V are presenting a truism that left me yawning. We all know that cancer incidence goes up as we age. That is generally true for almost all types of cancer, except the relatively rare childhood cancers. As we are all aware, prostate cancer is almost always a disease of older men, and eventually most men, if they live long enough, will get it. This probably has a lot to do with telomere length. As cells repeatedly divide, they lose length of the DNA end-caps called telomeres. When telomeres get really short, genes start fusing inappropriately, triggering genetic changes that may result in cancers. This effect is in addition to random mutations in DNA whose probability increases with more replications. So age is the #1 risk factor in cancer (yawn).

    Since we can’t stop the passage of time, a more interesting question is: what are the controllable risk factors? The loss of telomeres may turn out to be one such controllable risk factor. Changes in diet and lifestyle affect it. There is an enzyme called telomerase that starts to appear in older people. Trials of telomerase-blockers have already begun.

    It’s as useless to blame luck as to blame anything else we may or may not have done in the past. What is useful is to take responsibility for what we do in the present moment. The huge volume of research presented on this site shows us how much we can and will be able to do about it.

  10. Without wishing to get into all the details of telomerase and telomere length and related factors, I do want to just make it clear that telomerase is an reverse transcriptase enzyme that is evident, functional, and working well in all human cells that are replicating efficiently and effectively (even prior to birth). The problems start to arise when telomerase is not evident, functional, and working well (and that is certainly one of the things that can happen as we age).

    Uncontrollable random mutations that can be replicated and lead to modifications in cellular function (for better or for worse) are a whole other kettle of fish.

  11. Sitemaster,

    I’ll have to disagree with you on that, based on my reading. Here’s what it says in one reference written by Dr. Shay at UT Southwestern (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163052/):

    “Telomerase is active during early human fetal development, then becomes silenced in most tissues. Thus, when telomeres reach a certain length (~15-20 kb) during human development, chromatin modifications involving telomere position effects (TPE) may silence the hTERT gene (3). As part of cancer progression, as telomeres shorten the chromatin silencing effects may become relaxed making a permissive environment for telomerase reactivation. This is consistent with the observation that almost 70% of all cancers are in the 65 and older segment of the population.”

    Shay goes on to write:

    “One way to progress these observations into translational opportunities is to use telomerase inhibitors in selective cohorts of men with the highest risk factor for recurrence of disease. Following prostatectomy, the small pool of residual cancer cells with greatly shortened telomeres may be removed by a period of anti-telomerase treatment. The telomerase enzyme seems like a perfect cancer target as it is only expressed in a small subset of proliferative stem cells and cancers. Telomerase expression is essential for the proliferation of most advanced cancer cells, but the enzyme is inactive in the vast majority of normal human tissues.”


    “Incidence” statistic is tricky: The Post carried this story on 1/1/2015 under the title: “Biological bad luck blamed in two-thirds of cancer cases, researchers say” (by Will Dunham). The reporter’s version was good, but the text did not clarify some important points. For instance, that “two-thirds” figure was based on cancer types, with each type getting one statistical “vote” no matter the incidence rate. Therefore, rare cancers counted the same as lung, breast, prostate and colorectal cancer. It seems to me that the researchers could easily attach an incidence coefficient to their figure for each type and give us the result for each cancer and a weighted average for all cancer. Does that make seem practical?

    Seriousness, aggressiveness not covered: as useful as this information promises to be, neither the article nor the abstract/press release related cell division to the critical issue of the aggressiveness of a particular cancer or case. I’m curious about the division number for pancreatic cancer, which is very aggressive. I’m curious about the number for prostate cancer, where aggressiveness is all over the map. Perhaps for many cancers aggressiveness depends on other factors, such as the “epigenetic” environment in which the cancer cells live. That has been a heavy focus of research in recent years but is not covered in the article.

    There was a dangerous fatalism evident in some of the reader comments. This paper will very likely do good, but some readers of reports such as that in the Post are likely to take away the wrong messages about what we can do to foster good health and reduce the odds that serious cancer will affect us. The primary researcher addressed this in a comment in the John Hopkins press release: “… Vogelstein, who cautions that poor lifestyles can add to the bad luck factor in the development of cancer.” (I would add “aggressiveness” to that statement; lifestyle can affect more than just the basic cause.)

  13. OK. If most cancer is bad luck, then how come all the people with “bad” DNA haven’t died off out of the gene pool and only the “strongest” have survived? Wouldn’t natural selection have weeded out the people with these bad mutations. Now granted most cancers occur later in life, giving these people a chance to reproduce when young, but I would have thought that after the supposed 250,000 years man has been around and even longer then that if you count what we evolved from that cancer-type mutations would have been cleaned out. But … mutations are what helps species adapt to their changing environment. Could the very thing that has allowed us to adapt and survive for millions of years also have a dark side that kills us? Maybe cancer is as natural a process as aging …. Without the ability to mutate none of us may have ever existed.

    What if we can one day fix every bad mutation that occurs in someone’s DNA before they are merged with each other. The human race may one day loose it’s ability to evolve and we then die off as a race.

    I say we keep cancer and don’t try to get rid of it. … Na … I still hated having it ….

    This is all hypothetical, of course. …

  14. We seem to be drifting way, way, away from what was actually presented in this article, but briefly:

    Chris: Yes, random mutations have, for most of the last several million years, been a key factor in driving evolution … with both good consequences and poor ones … And I know of no reason why these types of random mutation should go away at any time in the next few million years.

    Jim: You are focused on topics that the study carried out was not designed to even consider addressing. And I would again note that the study didn’t even address either prostate or breast cancers at all (for reasons explained above). Whether these topics are even addressable based on the techniques used by the authors is questionable.

    Allen: I think that we need to understand that there is a huge difference between the degree of activity of telomerase enzymes in particular cell types in particular tissues at particular points in time during the development, growth, and aging of humans and whether the telomerase function is “alive and well”. Lots of enzymes are “silent” (i.e., present at extremely low levels and fundamentally “inactive”) lots of the time, but that doesn’t mean that the capacity to function at a required level can’t be “turned on” extremely rapidly. When telomeres aren’t losing functionality in particular cells as they divide (e.g., in prostate cells or in prostate cancer cells) then the relevant telomerases will be largely inactive, but that doesn’t mean that they can’t be activated if there are signs of changes in telomere functionality. Dr. Shay’s use of the term “silenced” which you quote is a little misleading because it is a gross generalization.

  15. Interestingly enough, in part the data suggests that as life expectancy increases, so do cancer occurances. I wonder if there is a natural balance point that we, as a species, may not be able to overcome without a major breakthrough. (Which of course would redefine our species from organic to non-organic to some degree should medical science start altering our biochemistry to eliminate that “design defect”)

  16. Dear Newton451:

    It has been well understood for years that there is a close correlation between age and risk for some (but not all) forms of cancer — prostate cancer very specifically being one of them.

    I am not at all sure that I understand what you mean by “redefine our species from organic to non-organic” since any alteration to human biochemistry to overcome this problem would have to be a molecular biological change, and therefore “organic” by chemical definition.

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