Random Chance: A Primary Driver of Cancer Mutations?

By Carl Engelking | March 23, 2017 1:22 pm
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(Credit: Shutterstock)

Whether we like to or not, we’re all gamblers.

Every waking moment, countless stem cells inside our bodies are dividing in order to replace worn out biological machinery. But every time these perfectly healthy cells divide, roughly three mistakes occur in the genetic code—no one’s perfect. These mutations, though unpredictable, are typically benign, but sometimes this molecular game of Roulette takes an unlucky turn.

“Most of the time these mutations don’t do any harm; they’re in junk DNA, or unimportant places,” says Johns Hopkins cancer researcher Bert Vogelstein. “That’s the usual situation, and that’s good luck. But occasionally they occur in a cancer driver gene, and that’s bad luck.”

Today, there’s little doubt that mutations cause cancer, but there’s less consensus regarding the primary instigators of those mutations.

Conventional wisdom holds that if we eat healthy, exercise regularly, breathe unpolluted air and drink clean water we can prevent cancer, so long as we aren’t genetically predisposed to the disease. But that’s only part of the story, according to Vogelstein.

dumb-luck

Random chance is a primary driver behind most of the cancers in the latest study from researchers at Johns Hopkins. (Credit: Tomasetti et. al., Science [2017])

In 2015, Vogelstein and his colleague Christian Tomasetti turned convention on its head when they presented evidence that random mutations were a third, primary driver of cancer in addition to environment and hereditary. They found that in the United States, the lifetime risk associated with 25 different cancers was strongly correlated to the total number of cell divisions that occur in those tissues. They likened their results to a car trip: the longer the drive, the higher the risk of being involved in an accident; the more your cells divide, the higher the risk of an unpredictable, cancer-causing error.

That random chance played a significant role in cancer was a conclusion that provoked significant debate at the time.

But that initial study was limited in scope to the United States, and didn’t include prostate and breast cancers—two of the most common. Two years later, in a study published Thursday in the journal Science, they’ve strengthened the argument that cancer is a bit of crapshoot, offering more details about the odds we’re playing with.

“The main purpose of the new paper is to try, for the first time, to calculate how many of these mutations found in cancers are due to the environment, heredity or random mutations,” Vogelstein said.

In their latest study, they analyzed biological data from 32 cancer types — including breast and prostate cancer — and found that two-thirds of mutations found in these cancers were spontaneous mistakes. They also collected data from 69 countries on six continents, and found the strong correlation between cancer incidence and the total number of stem cell divisions held up globally, regardless of environment.

“It seems to make sense: the more divisions in stem cells, the more random mutations, the more cancer,” says Tomassetti.

Let’s Stop and Take a Breath

In cancer, the interplay between environment, heredity and random chance is a bit like pulling the lever on a slot machine. With each spin, or cell division, a different combination of all three factors could affect the result, and each type of cancer, in a sense, is weighted with odds.

Bone and brain cancers seem to be ruled by chance, as most of the mutations are caused by unpredictable replicative errors. Lung cancer and prostate cancer mutations, on the other hand, are primarily driven by environmental factors — random errors play a role, but carcinogens that enter the body hold more influence. Extremely rare cancers tend to be driven by mutations passed down through the family tree.

Their results gel with available evidence about the proportion of preventable cancers. According to Cancer Research UK, 42 percent of cancer cases are preventable, while the U.S. Centers for Disease Control estimates that 21 percent of annual cancer deaths could be prevented. In other words, the study in no way discounts the importance of early detection and making healthy choices to prevent cancer.

Rather, researchers findings add a little clarity to why a perfectly healthy person with no history of cancer in the family could, nonetheless, be diagnosed with cancer. And for researchers, knowing there’s a third, powerful factor underlying cancer risk could inform the design of future investigations. Further, although random mutations may seem unavoidable now, they could someday be brought under our control.

Though we can’t predict how random mutations will cause cancer, knowing what we don’t know is a marked improvement from swimming in unknown unknowns.

“It never was measured before, and if you don’t measure something, you can’t get a sense of how important that is,” Tomasetti said.

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  • kenrubenstein

    The idea that many common cancers are caused by ‘driver mutations’ is far from universally accepted. Vogelstein is highly committed to the Somatic Mutation Theory of cancer, but a great many other highly respected mainstream scientists think otherwise. In other words, his paper may well be irrelevant.

    • http://adjunctorium.com/ Melete

      His paper is irrelevant because it doesn’t echo the party line?

      • kenrubenstein

        His paper is the party line. He’s the majority leader.

        • http://www.RNA-mediated.com jvkohl

          Thanks. Harvard researchers filed this patent. “RNA-Guided Human Genome Engineering” Clearly they know that most pathology is prevented by energy-dependent endogenous RNA interference and RNA-mediated DNA repair.

          This makes their CRISPR CAS9 patent relatively worthless because endogenous RNA interference is a naturally occurring process by which the nutrient energy-dependent pheromone-controlled physiology of reproduction is linked to supercoiled DNA, which protects all organized genomes from virus-driven energy theft and genomic entropy.

      • mark

        Does this comment section actually work? I just posted this comment and it has not shown up. Going to try one more time.

        I agree with Ken. How would they know after the fact what caused the mutations? They wouldn’t. The older you are, the more exposed you are to various environmental factors that can have epigenetic effects, so the total number of cell divisions still does not tell you that these are random mutations.

        It is disappointing that the media picked this up and ran with the idea that environmental causation is now out.

        Another person posted that lung cancer in a non-smoker is proof that environment is not involved. Sorry, second hand smoke and living in areas of high radon can certainly be involved and likely killed a relative who had never smoked.

        The article says brain tumors are not environmentally related. Sorry, someone who was exposed to lead, asbestos, and other known carcinogens can have fatal brain tumors.

        The trouble with studies of environmental causation of cancer, where they exist, is that they look at one factor at a time. Many people are exposed to more than one and are not studied.

        I think this paper and the interpretation of it are misleading and harmful to public health.

        • Maia

          MOST people are exposed to more than one toxin at a time, it’s almost the norm now, since there are thousands of lab-made chemicals in our environment and thus, our food and water.

          Plus there is the interaction of “genetic mistakes” with environmental factors AND age (number of replications). How would we parse out which is which and how much?

          This article is only harmful, though, if you don’t read it carefully and if you take it literally. It does not say that “environment is out” or anything close to that, but newspapers like snappy headlines. What I mean by “literally” is the assumption that the percentages are anything more than very rough guesses at this point. No matter if only 20% of cancers were caused by environmental factors, it would still be well worth it to avoid toxic chemicals and eat an anti-cancer diet: high in vegetables/fruits especially those dense in phyto-nutrients, legumes, seeds/nuts, healthy oils.

        • Sharon Ann Clark

          I think you may have been referring to me. Obviously I did not make what I said clear. I was not disputing that tobacco smoke causes lung cancer in both smokers and those exposed to second-hand smoke. Nor was I disputing that there are many environmental causes for cancer as well as genetic factors. What I was trying to say was that not ALL cancers have an identifiable cause, yet many people believe that as long as they lead a healthy lifestyle – exercise, don’t smoke, don’t drink, etc., then they will not get cancer, as long as they also don’t have any genetic predispositions. But this is a simplistic view and also not true. Yet I’ve still heard people pass judgement on those with cancers that have no identifiable environmental or genetic cause. This is hurtful and harmful to those who already have so much stress to deal with.

  • Hard Little Machine

    Cancer was invented by white people, Trump and of course, the Jews.

  • Discuss

    What if some people are more prone to random mutations that is a genetic vulnerability to mistakes in DNA repair?

    • Maia

      Yes, and a genetic vulnerability to environmental factors is possible too! Many varieties of interaction going on.

  • Jakob Stagg

    To accept this theory would destroy the cash cow of the tobacco industry. All those who took money from the tobacco industry might have to pay it all back if something other than tobacco is implicated.

  • George286

    Okay, so what? I am surprised anyone ever thought it was different than that, cancer is caused by random replication screw-ups (or genetic predisposition to replication screw-ups) or by environmental factors, either can cause a cell to go rogue. Environmental probability is proportional to cell replication rate and particular tissue exposure to carcinogenic environmental causes (lung, prostate, colon). It changes nothing, life is risk management and there are some things we can control and others we can’t. What is silly is that people expect some sort of guarantee. So we do what we can for what we can control and not worry about what we can’t, THAT’S LIFE. You can say the same thing about auto accidents, heart attacks and being a victim of crime, but who wants to live in a closet their whole lives? We probably get carcinogenic mutations our whole lives, there are trillions of cells dividing but our immune system probably destroys most of them until one also learns to hide from the immune system or damages the immune system itself (like Kaposi’s sarcoma after AIDS has disabled the immune system).

  • Scott Burdick

    It seems to me, in the near future scientists could cure cancer by preserving healthy cells (ideally when very young before mutations have accumulated) and periodically using a modified virus or gene drive similar to CRISPR/Cas9 to swap out the genes of every cell in our body. This would essentially cure all forms of cancers.

    Because these young genes would also have the full compliment of telomeres, it’s also possible it would halt or even reverse aging to some extent. One could even correct genetic errors or add improvements in these gene “updates.”

    Even if one hadn’t preserved the younger version of un-mutated genes early in life, it might be possible through comparing large numbers of an individual’s genes to identify the mutations and create a pristine sample to manufacture in the laboratory and then re-insert.

    The challenge would come during the replacement to make sure each portion of the genes in a particular cell was correctly primed to know the role it played (as a brain cell, as opposed to a liver cell). Possibly the gene drive would have to compare the replacement against the old cell and fix only those things that are different than the un-mutated younger template and leave the rest intact to retain the epigenetic switches or whatever mechanism is used to activate the specialized functionality.

    It would be interesting to learn how the handful of “functionally immortal” organism in nature deal with this problem.

    Since I’m not a scientist, there are probably many things wrong with this idea—or others have already thought of it.

  • Sharon Ann Clark

    I think the results of this study are important for another reason – social. Most people WANT to believe that there is a cause and effect for cancer that is totally within their control. If they see that someone who was a smoker has come down with cancer, they are reassured that they will never get lung cancer because they don’t smoke. Yet this is a fallacy. People who have never smoked also can get lung cancer even when no identifiable carcinogen is evident. But the really harmful aspect of thinking that all cancers are caused by things we can control, is the judgement of others. I am so disheartened to hear someone say that a person with cancer must have done this or that wrong. Furthermore, such opinions expressed to the individual add unnecessary stress and guilt to an already very stressful situation. I hope the findings of this study will encourage people to show more understanding and compassion to those with cancer and help them refrain from judgement.

    • New Jersey Taxpayer

      I agree. A good friend of mine at sixty years of age recently died from a brain tumor. It did not run in his family and he lived a very healthy lifestyle. He never even smoked.

  • mcgyver SEO

    Digital health dilemma: Albert Einstein, once noted, “A lot of what can be counted doesn’t count, and a lot of what counts can’t be counted.”

  • http://www.RNA-mediated.com jvkohl

    This was published on the same day as the nonsense published by Johns
    Hopkins cancer researchers.

    “A conserved NAD+ binding pocket that
    regulates protein-protein interactions during aging”

    Harvard researchers linked the energy-dependent transfer of hydrogen atoms in DNA base pairs in soluton to all healthy longevity in all living genera via endogenous RNA interference in the context of the physiology of reproduction.

    They inadvertently refuted every aspect of neo-Darwinian pseudoscientific nonsense because the energy-dependent pheromone-controlled physiology of reproduction protects all organized genomes from virus-driven energy theft and genomic entropy.

  • http://www.RNA-mediated.com jvkohl

    Identification and Evaluation of Suitable Reference Genes for Normalization of MicroRNA Expression in Helicoverpa armigera (Lepidoptera: Noctuidae) Using Quantitative Real-Time PCR Excerpt: “The suitable candidate reference genes were shown as follows: miR-9 and U6 snRNA for developmental stages, miR-100 and U6 snRNA for larval tissues, miR-100 and miR-305 for adult tissues, miR-9 and miR-279 for parasitic treatment, miR-998 and U6 snRNA for nuclear polyhedrosis virus infection, miR-9 and U6 snRNA for insecticide treatment, miR-92a, miR-100, and miR-279 for temperature treatment, miR-92a, miR-305, and miR-998 for starvation treatment, miR-9 and miR-279 for light treatment, miR-305 and miR-998 for hormone treatment, and there was not one reference gene suitable for all samples.”

    • Joseph Daniel

      Simply put, your interpretation has exactly zero to do with the paper you cite. Nothing about evolution was refuted. The paper didn’t even deal with anything related to evolution. All that paper did was determine the best genes to use as reference points for gene expression studies in that species. You either completely misunderstood the paper, or more likely, you are simply lying. I fall on the side of lying because you threw up an excerpt taken out of context, containing a bunch of sequence names which says nothing about what you claim, but looks impressive to people who don’t bother to actually read it, and your interpretations of the paper are so off they aren’t even wrong. They are in a completely different field. Your other post is no better. So what game are you playing?

  • Maia

    Can we please stop using the phrase “junk DNA”? Or at the very least put it in quotes. This has been shown to be a false label and yet articles persist in using it. What we now consider unimportant will change, just as it did in the past, so many times that no one has been able to keep count. Calling something “junk” is not scientific, it’s careless.

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