Cancer is not a random assault of genetic bad luck

Is cancer, the emperor of all maladies, preventable? The answer has been controversial. According to two influential studies (2015, 2017) published in Science, two thirds of cancer cases are due to intrinsic random genetic mutations during normal stem cell divisions and thus are unpreventable. The finding of these two studies gave rise to the “bad luck” theory which has been widely covered by mainstream media such as The New York Times and Los Angeles Times as well as social media.

Needless to say, the bad luck theory could have serious negative consequences for cancer prevention research and practice. Unfortunately or fortunately, the finding that two thirds of cancer cases are unavoidable is mistaken – the conclusion is derived based on a misconceived statistical metric named R-squared (R2), which is also called the coefficient of determination in statistics. The studies reached the conclusion based on the correlation between cancer incidence and random mutations during normal stem cell divisions: R2 = 0.65 (Pearson correlation coefficient (r) = 0.804), which has been universally interpreted as 65 percent of the cancer cases is explained by random mutations.

However, my recent study has demonstrated that R-squared substantially exaggerates the percent of variation in the outcome or dependent variable that is explained by the predictors or the model. In fact, with R2 = 0.65, it is about 40 percent rather than two-thirds of cancer cases that is explained by or due to random mutations and thus unpreventable.

Besides the fallacy of R-squared, studies also question the causal relationship between random genetic mutations and cancer development. For one thing, elephants or blue whales have 100 and 2,000 times more cells and random errors during cell divisions, respectively, than humans, but they rarely get cancer.

Moreover, emerging evidence indicates random mutations are not really random. A recent groundbreaking study published in the journal Nature shows organisms evolve to protect themselves and enhance survival rather than aimlessly drift.

There is no doubt that genetic mutations play a role in cancer development. For instance, BRAC1 and BRAC2 are well-recognized genetic risks for breast and ovarian cancer. However, a study published in Science revealed only about 24 percent of the mutation carriers developed breast cancer lifetime before 1940 while today the risk is over 80 percent. And keep in mind, although one cancer case is too many, according to CDC, BRAC1 and BRAC2 only contribute about three percent of all breast cancer (about 7,500 cases out of 240,000 per annum).

Other facts also contradict the bad luck theory. According to a study published by the American Cancer Society, the cancer mortality rate of all males in the US was 88.9 per 100,000 persons in 1930; by 1990, the mortality rate nearly tripled to 221.2 per 100,000. It is irrational to believe the mutation rate, or the gene pool of the nation, had changed during the 60 years. And bear in mind, the increase of cancer incident rate was likely much higher than mortality rate in the same period given the advances in cancer treatment.

Additionally, more and more younger people are diagnosed with cancer. The latest research published in 2023 by the BMJ Oncology concluded, “Global incidence of early-onset cancer increased by 79.1% and the number of early-onset cancer deaths increased by 27.7% between 1990 and 2019.”

More enlighteningly, a large cohort study published in the New England Journal of Medicine, which analyzed 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries, has shown the rates of cancer concordance in twins are generally below 0.1, indicating less than 10 percent of the cancers are a result of genetic factors.

Taken together, although many risk factors can contribute to cancer, it is as certain as 2 +2 = 4 that environmental factors are the principal driver behind the escalation of cancer prevalence for the last 80 years, which leads to an inescapable conclusion: most cancer cases are preventable.

In short, it cannot be any clearer that the best cure for cancer is prevention – avoiding environmental triggers.

Jian Gao, PhD, is the Director of Analytical Methodologies with the Office of Productivity, Efficiency, and Staffing, Quality and Patient Safety, Office of Analytics and Performance Integration, Department of Veterans Affairs.

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