| Story Views | |
| Now: | |
| Last Hour: | |
| Last 24 Hours: | |
| Total: | |
The (bad) luck of the draw; more evidence
A while back, Vogelstein and Tomasetti (V-T) published a paper in Science in which it was argued that most cancers cannot be attributed to known environmental factors, but instead were due simply to the errors in DNA replication that occur throughout life when cells divide. See our earlier 2-part series on this.
Essentially the argument is that knowledge of the approximate number of at-risk cell divisions per unit of age could account for the age-related pattern of increase in cancers of different organs, if one ignored some obviously environmental causes like smoking. Cigarette smoke is a mutagen and if cancer is a mutagenic disease, as it certainly largely is, then that will account for the dose-related pattern of lung and oral cancers.
This got enraged responses from environmental epidemiologists whose careers are vested in the idea that if people would avoid carcinogens they'd reduce their cancer risk. Of course, this is partly just the environmental epidemiologists' natural reaction to their ox being gored–threats to their grant largesse and so on. But it is also true that environmental factors of various kinds, in addition to smoking, have been associated with cancer; some dietary components, viruses, sunlight, even diagnostic x-rays if done early and often enough, and other factors.
Most associated risks from agents like these are small, compared to smoking, but not zero and an at least legitimate objection to V-T's paper might be that the suggestion that environmental pollution, dietary excess, and so on don't matter when it comes to cancer is wrong. I think V-T are saying no such thing. Clearly some environmental exposures are mutagens and it would be a really hard-core reactionary to deny that mutations are unrelated to cancer. Other external or lifestyle agents are mitogens; they stimulate cell division, and it would be silly not to think they could have a role in cancer. If and when they do, it is not by causing mutations per se. Instead mitogenic exposures in themselves just stimulate cell division, which is dangerous if the cell is already transformed into a cancer cell. But it is also a way to increase cancer by just what V-T stress: the natural occurrence of mutations when cells divide.
There are a few who argue that cancer is due to transposable elements moving around and/or inserting into the genome where they can cause cells to misbehave, or other perhaps unknown factors such as of tissue organization, which can lead cells to 'misbehave', rather than mutations.
These alternatives are, currently, a rather minor cause of cancer. In response to their critics, V-T have just published a new multi-national analysis that they suggest supports their theory. They attempted to correct for the number of at-risk cells and so on, and found a convincing pattern that supports the intrinsic-mutation viewpoint. They did this to rebut their critics.
This is at least in part an unnecessary food-fight. When cells divide, DNA replication errors occur. This seems well-documented (indeed, Vogelstein did some work years ago that showed evidence for somatic mutation–that is, DNA changes that are not inherited–and genomes of cancer cells compared to normal cells of the same individual. Indeed, for decades this has been known in various levels of detail. Of course, showing that this is causal rather than coincidental is a separate problem, because the fact of mutations occurring during cell division doesn't necessarily mean that the mutations are causal. However, for several cancers the repeated involvement of specific genes, and the demonstration of mutations in the same gene or genes in many different individuals, or of the same effect in experimental mice and so on, is persuasive evidence that mutational change is important in cancer.
The specifics of that importance are in a sense somewhat separate from the assertion that environmental epidemiologists are complaining about. Unfortunately, to a great extent this is a silly debate. In essence, besides professional pride and careerism, the debate should not be about whether mutations are involved in cancer causation but whether specific environmental sources of mutation are identifiable and individually strong enough, as x-rays and tobacco smoke are, to be identified and avoided. Smoking targets particular cells in the oral cavity and lungs. But exposures that are more generic, but individually rare or not associated with a specific item like smoking, and can't be avoided, might raise the rate of somatic mutation generally. Just having a body temperature may be one such factor, for example.
I would say that we are inevitably exposed to chemicals and so on that will potentially damage cells, mutation being one such effect. V-T are substantially correct, from what the data look like, in saying that (in our words) namable, specific, and avoidable environmental mutations are not the major systematic, organ-targeting cause of cancer. Vague and/or generic exposure to mutagens will lead to mutations more or less randomly among our cells (maybe, depending on the agent, differently depending on how deep in our bodies the cells are relative to the outside world or other means of exposure). The more at-risk cells, the longer they're at risk, and so on, the greater the chance that some cell will experience a transforming set of changes.
Most of us probably inherit mutations in some of these genes from conception, and have to await other events to occur (whether these are mutational or of another nature as mentioned above). The age patterns of cancers seem very convincingly to show that. The real key factor here is the degree to which specific, identifiable, avoidable mutational agents can be identified. It seems silly or, perhaps as likely, mere professional jealousy, to resist that idea.
These statements apply even if cancers are not all, or not entirely, due to mutational effects. And, remember, not all of the mutations required to transform a cell need be of somatic origin. Since cancer is mostly, and obviously, a multi-factor disease genetically (not a single mutation as a rule), we should not have our hackles raised if we find what seems obvious, that mutations are part of cell division, part of life.
There are curious things about cancer, such as our large body size but delayed onset ages relative to the occurrence of cancer in smaller, and younger animals like mice. And different animals of different lifespans and body sizes, even different rodents, have different lifetime cancer risks (some may be the result of details of their inbreeding history or of inbreeding itself). Mouse cancer rates increase with age and hence the number of at-risk cell divisions, but the overall risk at very young ages despite many fewer cell divisions (yet similar genome sizes) shows that even the spontaneous mutation idea of V-T has problems. After all, elephants are huge and live very long lives; why don't they get cancer much earlier?
Overall, if if correct, V-T's view should not give too much comfort to our 'Precision' genomic medicine sloganeers, another aspect of budget protection, because the bad luck mutations are generally somatic, not germline, and hence not susceptible to Big Data epidemiology, genetic or otherwise, that depends on germ-line variation as the predictor.
Related to this are the numerous reports of changes in life expectancy among various segments of society and how they are changing based on behaviors, most recently, for example, the opiod epidemic among whites in depressed areas of the US. Such environmental changes are not predictable specifically, not even in principle, and can't be built into genome-based Big Data, or the budget-promoting promises coming out of NIH about such 'precision'. Even estimated lifetime cancer risks associated with mutations in clear-cut risk-affecting genes like BRCA1 mutations and breast cancer, vary greatly from population to population and study to study. The V-T debate, and their obviously valid point, regardless of the details, is only part of the lifetime cancer risk story.
Source: http://ecodevoevo.blogspot.com/2017/03/the-bad-luck-of-draw-more-evidence.html
