Cancer Is Not Caused by Mutations

We find ourselves at the present time in the era of molecular biology, and we are perhaps unduly influenced by the genetic code as the dominant principle in biology. Perhaps, in a decade or two from now, the dominant principle may shift to another plane, which in turn will influence our speculations about tumor causation.

-- Biochemist Isaac Berenblum, 1974

Medical textbooks frequently attribute the development of cancer to the accumulation of mutations over time, and cancers are front and center among the conditions gene editing therapies are targeted to treat. However, the traditional paradigm that cancer is an inevitable consequence of aging doesn't hold water under closer investigation, as many hunter-gatherer groups around the world show little evidence of cancer.

The absence of cancer in these populations isn't due to shortened lifespans either - analyses have found a common lifespan of up to 78 years among hunter-gatherers, once the bottleneck of high infant mortality is bypassed. Additionally, the existence of the Blue Zones, those regions in the world where centenarians are not only common but also free of chronic diseases like cardiovascular disease, diabetes, and cancer, also contradicts the idea that cancer is an inescapable fate given the passage of enough time.

Contrary to conventional wisdom, the accumulation of genetic mutations is not sufficient to cause cancer; the tumor microenvironment must also be taken into account. In other words, the same mutation that is adaptive for cancer in altered tissue is not advantageous to cancer in healthy, homeostatic cells.

James DeGregori at the University of Colorado School of Medicine offers the following analogy: When tackling drug dealing in the inner city, arresting all the drug dealers is unlikely to work; the ones left behind will be smarter and more conniving. Instead, one might focus on creating better jobs, schools, and infrastructure, so citizens won't have to resort to crime as a means of survival. Addressing the environment that led to the problem will provide a more stable solution.

Similarly, instead of simply targeting the cancer, altering the microenvironment to disfavor its proliferation may provide a more viable long-term strategy, as the former immediately selects for resistance, accounting for the difficulty in keeping a patient in remission. Highlighting the importance of the microenvironment in regulating development, homeostasis, and cancer, biologist Mina Bissell writes,

The sequence of our genes are like the keys on the piano; it is the context that makes the music.

Cancer depends on context, as should our approach to treatment.

Of particular interest is the discrepancy between cancer frequencies at different sites. For example, colorectal cancer is very common while small intestinal cancer is 100 times less common despite the fact that the small intestine is five times longer (30 feet versus 6 feet for the colon) and characterized by nearly identical rates of mutation as the colon. The microenvironments are strikingly different, however, with the colon being host to more diverse and numerous microbiota.

In addition, colorectal cancer almost exclusively occurs in the distal colon rather than the proximal colon where fermentation is greatest and short-chain fatty acid (SCFA) concentrations are typically higher. Lack of sufficient dietary resistant starch may prevent production of a short-chain fatty acid called butyrate, which lowers colonic pH, prevents pathogen invasion, and appears to preclude carcinogenesis, lending further evidence to the role of the colonic ecosystem in preventing or promoting cancer. To further illustrate the importance of the tissue microenvironment, Bissell expounds,

Indeed, how else would one explain the tissue specificity of heritable cancers, for example, BRCA1 and breast cancer, where, despite mutations in all of more than 10 trillion cells, the tumors are not only tissue specific but also formed from just one or a few cells of those tissues?

Early work from Mina Bissell and William Hines has demonstrated the role of the tissue microenvironment in influencing cancer susceptibility. The authors examined the evidence that many people harbor "occult" tumors without showing any signs of overt disease and proposed that "initiation of tumors is unavoidable, but their progression to malignancy can and should be controllable." The first evidence hinting at the ubiquitous nature of tumors came in 1935 from Arnold Rich when he observed frequent "small carcinomata" in autopsied prostate tissues from men who had died of unrelated causes.

Later studies reported a 34 percent incidence of histologically frank prostate tumors among men in their forties. Another study conducted upon postmortem examination revealed a similar frequency (38 percent) of histologic breast cancer among women in their forties. The frequency of such findings in the thyroid gland is so high as to be considered "normal" while the high occurrence in lung tissue has given rise to concerns of overdiagnosis as a result of screening.

In some instances, a tumor is not initially detected in the organ of origin but as a metastasis, or secondary malignant growth due to spread from the primary site of cancer. One study examined 29 cases in which cancer initially manifested as axillary lymph node enlargement from an occult breast tumor. The primary breast tumors were often smaller than the lymph node metastases and even remained undetectable in 13 patients.

Taken together, these findings reveal that indolent and occult tumors are much more common than previously realized and not adequate for the progression to overt cancer in the absence of an altered tumor-promoting microenvironment. As Bissell and Hines summarize,

Once a tumor, not always a cancer.