• Random Chance’s Role in Cancer

    January 22, 2015 MVP Blog comments

    NYTimes. Unlike Ebola, flu or polio, cancer is a disease that arises from within — a consequence of the mutations that inevitably occur when one of our 50 trillion cells divides and copies its DNA.

    Some of these genetic misprints are caused by outside agents, chemical or biological, especially in parts of the body — the skin, the lungs and the digestive tract — most exposed to the ravages of the world. But millions every second occur purely by chance — random, spontaneous glitches that may be the most pervasive carcinogen of all.

    It’s a truth that grates against our deepest nature. That was clear earlier this month when a paper in Science on the prominent role of “bad luck” and cancer caused an outbreak of despair, outrage and, ultimately, disbelief.

    The most intemperate of this backlash — mini-screeds on Twitter and hit-and-run comments on the web — suggested that the authors, Cristian Tomasetti and Bert Vogelstein of Johns Hopkins University, must be apologists for chemical companies or the processed food industry. In fact, their study was underwritten by nonprofit cancer foundations and grants from the National Institutes of Health. In some people’s minds, those were just part of the plot.

    What psychologists call apophenia — the human tendency to see connections and patterns that are not really there — gives rise to conspiracy theories. It is also at work, though usually in a milder form, in our perceptions about cancer and our revulsion to randomness.

    It takes several mutations, in specific combinations, for a cell to erupt into a malignant tumor. The idea that random copying errors are prominent among them is thoroughly mainstream. What was new about the paper was its attempt to measure this biological bad luck and see how it compares with the two other corners of the cancer triangle: environment and heredity — mutations we inherit from our parents that can give cancer a head start.

    The mix of these influences varies. A lifetime of heavy smoking has been shown to multiply the risk of lung cancer — the most common malignancy in the world — by some twentyfold, or about 2,000 percent. But that is an anomaly. One of the great frustrations of cancer prevention has been the failure to find other chemical carcinogens so definitive or damaging, especially in the dilute amounts in which they reach most of the public.

    For a handful of cancers, biological agents are important, like human papilloma virus in cervical cancer and helicobacter pylori in stomach cancer. On another level, inflammation and hormonal imbalances, like those associated with obesity and diabetes, can drive cells to multiply more frequently, increasing the chance of mutations causal and accidental.

    Finally, heredity — like the BRCA mutations involved in some breast cancers — can have a profound effect in individual cases. But inheritance appears to be involved in just 5 to 10 percent of all cancers.

    What that leaves is a large role for random, spontaneous mutations — the ones that just happen because of the microscopic grind of life.

    That is not a reason for resignation. It is frequently estimated that some 40 percent of cancers are preventable. But that means some 60 percent are not.

    To get a feel for that balance, the authors looked at stem cells — those that are capable of dividing indefinitely and renewing themselves. First, they estimated the number of these cells in different tissues of the body and how many times they would copy themselves during a human lifetime. The higher the count, the greater the vulnerability to mutations.

    Then they compared that number with the likelihood that a tissue would develop a malignant tumor. The result was a strong correlation, a steep sloping line suggesting that two-thirds of the difference in cancer susceptibility could be explained by spontaneous errors.

    Tissues that deviated from the relationship, contracting cancer at a higher rate, were presumably swayed more strongly by something else.

    For cancers like those of the bone and brain, chance seemed to rule. But at the other end of the spectrum were those that were more “deterministic” — like lung cancer and basal cell carcinoma, a usually harmless skin malignancy where sunlight plays a deciding part. Also at that extreme were rare cancers mostly determined by inherited defects, like some familial forms of colon cancer.

    The more common colon cancers were near the middle of the range. Random mutation was important, but environment — like the carcinogens in digestive waste — seemed to hold a modest edge.

    There are still ambiguities to resolve. The cellular dynamics of two of the most common cancers, breast and prostate, were not certain enough to be included in the analysis. But however they might tilt the lineup, random mutations will remain a dominant driver.

    It is always possible that what we call randomness will turn out to be complexity in disguise. Some mutations attributed to chance may eventually be revealed to have subtle causes.

    Over the years, however, the scale seems to be tipping the other way, with the discovery that some long-suspected agents like dietary fat and artificial sweeteners may not be so potent after all.

    For all our agonizing, it can be liberating to accept and even embrace the powerful role chance plays in the biology of life and death. Random variation, after all, is the engine of evolution.

    Because of spontaneous mutations in germ cells — sperm and eggs — each generation of our species is subtly different. Some of the variations confer an advantage and others a vulnerability. They are sifted by natural selection, and so we adapt and evolve.

    In the ecosystem of the body, cancer cells go through a much faster version of this same process. The fittest of the bunch develop the weaponry to invade and destroy their surroundings, like a fractal reflection of what humans do in their own world.

    The evolution of our brains, so compelled to find patterns, has given us an edge — discovering cancers that can be avoided or, failing that, identified and excised before their deadly storm. But try as we might, we can never be in complete control of a condition so deeply rooted in the trade-offs of being alive.