Cancer, Mostly Bad Luck? Not Really!
Late last month, a follow up study on the random nature of cancer was published. I consider this one of the most dangerous studies I have seen in quite some time--not because its conclusions are wrong--but rather because of how they were interpreted and how that interpretation was presented by the media.
Instead of inspiring people with a call to personal responsibility and action, this study is far more likely to inspire people to abrogate their own responsibility in terms of cancer and hand it over to their doctors. Unfortunately, in many cases, that's equivalent to a death sentence. Make no mistake, cancer is now the leading cause of death in the world.1
As I mentioned, this is a follow up study to one they published in 2015. In that study, they proposed that mutations due to the random mistakes made during normal DNA replication (R) can explain why cancers occur much more commonly in some tissues than others. As with the current study, I don't have a problem with the study's conclusions so much as the interpretation and presentation of those conclusions.
As they explained in the new study, their original hypothesis as presented in the 2015 study has generated much scientific and public debate and confusion, in part because of how the researchers' analysis was confined to explaining the relative risk of cancer among tissues rather than the contribution of each of the three potential sources of mutations (Environment, Heredity, and Replication--E, H, and R) to any single cancer type or cancer case. So, this time around, they've attempted to remedy that confusion. To their credit, in some ways they have. Unfortunately, in the process, they have provided even more ammunition to those who would misinterpret the results and disseminate even more disinformation. Before we get into the nature of that disinformation, let's take a look at the new study.
Cancer and the Unavoidable Factor
To summarize the study, Geneticist Bert Vogelstein and mathematician Cristian Tomasetti used statistical analysis to come to the conclusion that the vast majority of cancers are simply a mistake, an error in DNA replication--just plain bad luck.2 Every time cells divide, little mistakes appear in the copies of its DNA. (It has been extensively documented that approximately three mutations occur every time a normal human stem cell divides.3, 4) Most of the time, these errors are innocuous; but given enough errors through successive replications over the years, and if the errors appear in the right parts of the genetic code, those cells become cancerous.
According to the editorial staff at Science, which published the study:
"Most textbooks attribute cancer-causing mutations to two major sources: inherited and environmental factors. A recent study highlighted the prominent role in cancer of replicative (R) mutations that arise from a third source: unavoidable errors associated with DNA replication…They found that a substantial fraction of cancer driver gene mutations are indeed due to replicative factors."
At this point, as a bit of an aside, I have to say, "Really?" What are you talking about? I mean pretty much everyone knew that random mutations played a major role in cancer. Heck, I'm not a medical doctor, and I've known it for several decades. To quote from a talk I gave some 15 years ago, "As part of the normal metabolic process, you produce anywhere from a few hundred to as many as 10,000 cancerous cells each day. Everybody does." Anyway, let's move on. And see what the study itself says.
Essentially, the researchers announced that they had discovered that those organs that have tissue with more stem cell divisions are at higher risk for cancer, such as the colon. Whereas those which have few stem cell divisions, such as the brain, are less likely to develop it. In other words, the more times a cell divides, the more replication errors appear in the DNA. Tissues simply reflect those numbers according to how frequently they divide. Tissue that divides more frequently gets more "bad luck" cancer.
For each of 18 representative cancer types, the schematic depicts the proportion of mutations that are inherited, due to environmental factors, or due to errors in DNA replication (i.e., not attributable to either heredity or environment). The sum of these three proportions is 100%. The color codes for hereditary, replicative, and environmental factors are identical and span white (0%) to brightest red (100%).
B, brain; Bl, bladder; Br, breast; C, cervical; CR, colorectal; E, esophagus; HN, head and neck; K, kidney; Li, liver; Lk, leukemia; Lu, lung; M, melanoma; NHL, non-Hodgkin lymphoma; O, ovarian; P, pancreas; S, stomach; Th, thyroid; U, uterus.
The bottom line is that the researchers determined replication errors cause two-thirds of all cancers. Only twenty-nine percent are the result of environmental factors, and a mere five percent come from heredity. In any case, it's the "two-thirds of all cancers are caused by bad luck" headline that most of the media ran with.
Now, if taken at face value, that's an astounding conclusion. You might as well do what you want and live for maximum enjoyment since what you do would seem to have minimal impact on your chances of getting cancer. Then again, you might want to throttle back on your hedonism for a bit. There is less here than meets the eye. There are also a few things to nitpick with the study, and one giant hole that kind of renders its conclusions, if not exactly meaningless, marginalized.
First, we might want to remember a quote often attributed to Benjamin Disraeli reportedly, "There are three kinds of lies: lies, damn lies, and statistics."
As it turns out, the two-thirds number would seem to fall within Disraeli's definition. As stated in the study:
"The proportion of mutations caused by environmental factors is always less than the proportion of cancers preventable by avoidance of these factors. Thus, our estimate that a maximum of 29% of the mutations in these cancers are due to E is compatible with the estimate that 42% of these cancers [ according to Cancer Research UK] are preventable by avoiding known risk factors."
So right off the bat, things are getting less random, and how you live your life seems to be of more import.
Then we need to consider the things that the researchers didn't consider. Let's take lung cancer as an example. According to the researchers, lung cancer comes down to either random chance or the environmental impact of smoking. But what about radon gas. Exposure to radon seeping up from the ground and building up in energy efficient homes that don't provide venting may be responsible for as much as 30% of all cases of lung cancer.5 And yet, the study doesn't mention radon--even once. It's never even factored into the equation. Also, although the impact of certain drivers like smoking can be quantified, what about air pollution on top of tobacco use? Epidemiologist Dr. Graham Colditz at Washington University in St. Louis, says it may be harder to parse out the drivers of cancer than is presented here.6 "How these interplay with each other, I think is potentially more complex."
Okay, the researchers might counter with the argument that it doesn't matter. The fact that they didn't identify every possible environmental factor is irrelevant. It would just be rolled into what they identified as caused by smoking. What matters is the difference between the number of DNA mistakes that actually appear in any tissue's DNA VS those predicted by the rate at which those particular cells replicate at baseline. But then, what about hormones? Hormonal imbalances can change the baseline rate of cell division, and if you didn't specifically look for the impact on the rate of cell division, you wouldn't know that your baseline measurement was wrong. You would be tallying hormonally induced mutations into the random column, not the environmental column. That would mess up your numbers just a tad.
And let's take a look at prostate cancer. To quote from the study:
"A third class of cancers comprise those in which only a very small effect of E or H has been demonstrated, such as those of the brain, bone, or prostate. For example, a very high fraction of the driver gene mutations in prostate cancers can be attributed to R (95%)."
In other words, according to the study's analysis, 95% of all prostate cancers are the result of random genetic errors occurring during cell division. Only 5% are the result of environment or heredity. Given that, we would expect to see very little variation in the incidence of prostate cancer incidence across different male populations throughout the world since it's baseline replication, not environment, that is the overwhelming causative factor. But, in fact, we see just the opposite. The incidence of prostate cancer in North America is, astonishingly, almost 20 times higher than we see in South-Central Asia.7 The obvious conclusion is that something other than random errors resulting from replication is at play here. Either that, or North American men are just very, very, very unlucky.
Ultimately, though, the report hedges its bets as it says, "It is, of course, possible that virtually all mutations in all cancers are due to environmental factors, most of which have simply not yet been discovered. However, such a possibility seems inconsistent with the exhaustively documented fact that about three mutations occur every time a normal cell divides and that normal stem cells often divide throughout life." Or as they said in interviews about the study, "We're not saying the only thing that determines the seriousness of the cancer, or its aggressiveness, or its likelihood to cause the patient's death, are these mutations. We're simply saying that they are necessary to get the cancer."
And with that I agree.
The Giant Flaw
As it turns out, the study has a giant hole that is never addressed in the researchers' analysis:
Not all cancerous cells develop into cancers!
Fortunately, it is an incredibly rare occurrence.
Given the numbers of cells that develop cancerous mutations--anywhere from a few hundred to as many as 10,000 a day, each and every day of your life--this is obviously a big deal. So, why not? And the answer lies in what I first explained several decades ago.
The reason everybody doesn't "get" cancer all the time is because your immune system has the ability to recognize each and every one of those aberrant cells and remove them from your body…if it's functioning properly. That's what a healthy immune system does.
(Note: Before the immune system even comes into play, in most cases, cells are able to detect and repair DNA damage. If a cell is severely damaged and cannot repair itself, it usually undergoes so-called programmed cell death or apoptosis. And for those cells that don't self-destruct as they should, that's when the immune system kicks in to finish off the job. Cancer occurs when damaged cells escape that double gauntlet, grow, divide, and spread abnormally.)
Anything that can trigger an immune response is called an antigen. An antigen can be a microbe such as a virus, or even a part of a microbe, which is what vaccines use. Tissues or cells from another person (except an identical twin) also carry non-self markers and act as antigens. This explains why tissue transplants are rejected. And finally, there are cancerous cells, which also present as antigens.
You can think of cancer cells as homegrown terrorists. For years, they were friendly neighbors, doing their part to make your community work. Then, at some point after one too many DNA transcription errors, they turn. They no longer identify with the community (your body). They see the community as an enemy--something to feed upon and destroy. And like a homegrown terrorist, they present clues when they turn. Whereas a terrorist reveals himself in what he says, the websites he visits, and the deals for arms he tries to make with undercover Federal agents, cancerous cells present clues to your immune system--if your immune system is good enough to read and act on them.
The antigen signals expressed by cancerous cells and tumors have several sources:
- Some are derived from cancer causing viruses
- For example, HPV, which causes cervical cancer
- Other signals come from proteins normally found in your body's cells at low levels but reach high levels in tumor cells.
- One example is the enzyme tyrosinase that, when expressed at high levels, transforms certain skin cells into melanomas.
- A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival that can also cause the cell to mutate into cancer, inducing genes called oncogenes that can cause those cells designated for apoptosis to survive and proliferate instead.
Your immune system is "trained" during its development to ignore proteins that are part of the normal "self." Mutations, on the other hand, contain proteins that exist outside of this training (or proteins within the training but at abnormally high levels) that allow that cell to be identified as non-self. Each mutation, then, offers the opportunity for the immune system to identify it as unwanted and attack it. These proteins most frequently exist on the surface of the cell, which brings us to another comparison between homegrown terrorists and cancer cells. Since homegrown terrorists are familiar with their neighborhoods, know the customs, culture, and how law enforcement works, they can more easily blend in and hide from the law. In the same way, some cells, once they become cancerous, discard their external proteins so as to better escape detection by your immune system. Clever little buggers!
Fortunately, although they can discard proteins, they can't discard all markers. The Major Histocompatibility Complex Molecules (MHC class I) remain. MHC molecules, which are found in all jawed vertebrates, including humans, are present on the cell surface of all nucleated cells. Their function is to display peptide fragments of non-self proteins located inside the cell to cytotoxic T cells examining the cell's surface; this will trigger an immediate response from the immune system against any cell displaying a particular non-self antigen.
This actually works amazingly well in the early stages of cancer--before the cell has had an opportunity to divide and take root. In a healthy body that is not producing an abnormally large number of cancerous cells and that has an optimized immune system, it's pretty much 99.9999999999% effective. In fact, it has to be. Any less effective than a 12-log kill rate and enough cancerous cells will survive to take root and multiply. So, how do cancer cells escape your immune system?
Generally, one of three things happens (and, more often than not, all three together):
- You expose yourself to toxins and outside influences (such as heavy metals, radiation, rancid fats, viruses, bacteria, parasites, etc.) that dramatically increase the number of cancerous cells that your body produces so that not even a healthy immune system can handle the load. These are the environmental factors mentioned in the study.
- You compromise your immune system to the point that it can no longer handle all of the cancerous cells your body produces, thus allowing some of them to take root and establish themselves.
- Circulation (blood, lymph, energy) is impeded, leading to both 1 and 2 above.
The important point is that once a cancer cell takes root, it becomes much harder for the immune system to recognize it. There are several ways this can happen:
- As we've already discussed, tumor cells often have a reduced number of specialized molecules on their surface, thus allowing them to avoid detection by killer T cells.
- In the same way that bacteria can evolve around antibiotics, cancer cells likewise can "evolve" around your immune system--if given that initial chance to survive. Once a cancer cell has survived and divided multiple times, it becomes a tumor, and most tumors can make immunosuppressive substances such as cytokine TGF-ß, which suppresses the activity of macrophages and lymphocytes, that effectively weaken any immune cells that get too close. Remember, they know your body. They know it's defenses. They know how to work around them--even how to coopt them to their advantage. Clever buggers!
- And finally, given time, cancerous cells can develop immunological tolerance against tumor antigens so the immune system no longer attacks the tumor cells.
The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells. The secret to its success is an elaborate and dynamic communications network. Millions and millions of cells, organized into sets and subsets, gather like clouds of bees swarming around a hive and pass information back and forth in response to an infection or a malignancy.
The bottom line is that if your immune system is doing its job, the random replication factor is pretty much neutralized in terms of getting cancer. Yes, you are definitely producing a large number of aberrant cells every day, most as a result of pure bad luck. But if your immune system is doing its job, none of them ever gets to see the light of day.
There's one other fact to keep in mind that accounts for the effectiveness of the immune system in hunting down and destroying rogue cells--the sheer number of T cells in your body.
- Most people who are healthy and with no conditions have T cell levels in the range of 700 to 1300 per cubic millimeter of blood.
- There are 1,000,000 cubic millimeters per liter.
- The average person has about 5 liters of blood.
- That translates back to 5,000,000 cubic millimeters of blood in the average person.
- Which means that the average person has anywhere from 3.5 to 5 billion T cells coursing through their bloodstream at any moment in time--capable of reaching, identifying, and attacking every single aberrant cell in your body.
So, what does it look like when those T cells are doing their job and eliminating 99.9999999999% of all the cancerous cells produced in your body?
Why this Study Is So Dangerous
Again, I have no problem with the fundamental conclusion of the study that randomness plays a major role in the development of cancer. It may have been a surprise to the researchers, but certainly not to many others in the field. No, the problem is in how that conclusion was spun--both by the researchers and then the media.
Their spin is that two-thirds of all cancers are beyond our control. Avoiding toxins and eating better will make little difference--so why bother? Instead, you need to rely on more checkups for early detection, followed by medical intervention. Think I'm exaggerating, then consider this quote found in a write up on the study found in the journal Nature, titled, not surprisingly, DNA typos to blame for most cancer mutations.8
According to the geneticist [Vogelstein], the case for environmental factors may have been overemphasized. He told Nature, "If we think of the mutations as the enemies, and all the enemies are outside of our border, it's obvious how to keep them from getting inside. But if a lot of the enemies -- in this case close to two-thirds -- are actually inside our borders, it means we need a completely different strategy." In addition to a healthy lifestyle, healthcare professionals should advocate for early and periodic screenings, in this view.
Or as the study itself says:
As a result of the aging of the human population, cancer is today the most common cause of death in the world. Primary prevention is the best way to reduce cancer deaths…Fortunately, primary prevention is not the only type of prevention that exists or can be improved in the future. Secondary prevention, i.e., early detection and intervention, can also be lifesaving. For cancers in which all mutations are the result of R [random chance], secondary prevention is the only option.
And therein lies the great danger. It absolves you of your responsibility for preventing cancer--in at least two-thirds of those cases. It minimizes your options for preventing cancer to pretty much:
- Don't smoke (lung cancer)
- Stay out of the sun (melanoma)
- Treat ulcers and gastritis quickly (stomach cancer)
- Get an HPV vaccination (cervical cancer)
Anything else you do ranges from zero to at most 33% effective. Again, think I'm exaggerating? Take another look at the diagram from the study that I included.
If by any chance you still think that estimate is accurate, then you might want to reread the section above on prostate cancer where I explain that one of the cancers that's supposed to be 95% random varies almost 20-fold according to environment.
Think there's nothing you can do to prevent randomly occurring cancer, then reread the section immediately above on the role of the immune system. Look, does reducing the environmental factors that accelerate the speed at which cells mutate and optimizing your immune system to destroy rogue cells the moment they appear guarantee that you won't get cancer? Of course not! But it dramatically changes the odds, and isn't that enough?
Finally, click on the two links below.
- Using antipathogens to free up your immune system to work on the really important things--like destroying malignant cells
- Optimizing your immune system so that it's better able to seek out and destroy 99.9999999999% of all the cancerous cells produced in your body
- 1. B. W. Stewart, C. P. Wild, Eds., World Cancer Report 2014 (IARC, Lyon, France, 2014). http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014
- 2. Cristian Tomasetti, Lu Li, Bert Vogelstein. "Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention." Science 24 Mar 2017 : 1330-1334. http://science.sciencemag.org/content/355/6331/1330.full
- 3. M. Lynch. "Rate, molecular spectrum, and consequences of human mutation." Proc. Natl. Acad. Sci. U.S.A. 107, 961--968 (2010). http://www.pnas.org/content/107/3/961.full
- 4. C. Tomasetti, B. Vogelstein, G. Parmigiani. "Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation." Proc. Natl. Acad. Sci. U.S.A. 110, 1999--2004 (2013). http://www.pnas.org/content/110/6/1999.full
- 5. Si-Heon Kim, Won Ju Hwang, Jeong-Sook Cho, Dae Ryong Kang. "Attributable risk of lung cancer deaths due to indoor radon exposure." Annals of Occupational and Environmental Medicine The official journal of the Korean Society of Occupational and Environmental Medicine 201628:8. https://aoemj.biomedcentral.com/articles/10.1186/s40557-016-0093-4
- 6. Philip Perry. "More Cancers Occur by Random Chance Than for Any Other Reason, Study Finds." big think. March 26, 2017. (Accessed 2 April 2017.) http://bigthink.com/philip-perry/more-cancers-occur-by-random-chance-than-for-any-other-reason-study-finds
- 7. "Prostate Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012." WHO IARC 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
- 8. Heidi Ledford. "DNA typos to blame for most cancer mutations: Environment and heredity might not contribute as much to cancer risk as researchers thought." Nature 23 March 2017. (Accessed 2 April 2017.) http://www.nature.com/news/dna-typos-to-blame-for-most-cancer-mutations-1.21696