Scott Gerson, M.D., Ph.D. (Ayurveda), M. Phil. (Ayurveda) The Gerson Institute of Ayurvedic Medicine, 25 January, 2016
Lifetime risk of cancer now approximates 50% in Western societies. And, despite advances on many fronts, the outcome for patients with advanced or disseminated disease remains poor—mainly attributed to the inevitable development of chemotherapy drug resistance. Continued research is needed to unravel the mysteries of this dreaded disease. Last year, a paper was published in the prestigious journal Science with the following abstract:
Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.(C. Tomasetti and B. Vogelstein Science 347, 78–81; 2015). [italics added for emphasis]
In plain English, this paper asserted that differences in inherent cellular processes involved with cell division (and not either genetics or environment) are the chief reason that some tissues become cancerous more frequently than others. In their paper, mathematician Cristian Tomasetti and cancer researcher Bert Vogelstein at Johns Hopkins University in Baltimore, Maryland, calculated the relationship between the number of stem-cell divisions and the risk of developing cancer in various tissues. Every instance of cell division comes with a risk that DNA will be incorrectly copied, leading to mutations — some of which could contribute to cancer. Indeed, a correlation was found: the more stem-cell divisions that occur in a given tissue type over a lifetime, the more likely it is to become cancerous. The authors argued that although some cancers clearly had strong environmental links — such as skin basal cell cancer caused by ultraviolet exposure or lung cancer resulting from smoking — there were others for which the variation was explained mainly by randomly occurring defects in stem-cell division. The paper led to interpretations that certain forms of cancer are mainly the result of “bad luck”(a term the authors actually used in their abstract as you can see above), and suggested that these types of cancer would be relatively resistant to prevention efforts. In those cases, they argued, early detection and treatment would be more effective than prevention.
When I read this paper several months ago (2015), I was frankly dumbfounded and couldn't believe that no one was seeing the obvious flaw in this so-called “scientific” paper. I believe that any high school biology student would see this same unmistakeable error. Here it is:
The authors compared two separate variables to determine the risk of developing cancer: intrinsic stem cell divisions versus extrinsic environmental exposure. They then concluded that the intrinsic stem cell divisions were overwhelmingly more significant than the environmental exposures. But what if environmental exposures affect stem cell division rates??? For God sakes, guys! Fancy charts and graphs, authoritative language, sophisticated mathematical terms, Johns Hopkins credentials and you actually produced this pseudo-scientific and dangerously misleading paper?
Did they somehow miss the research accumulating over the past century which confirms that environmental exposure to ionizing radiation (e.g. Hiroshima survivors) affects white blood cell stem cell division rates? Or that human papilloma virus affects cervical stem cell division rates? Or the findings that high protein diets and insulin levels affect ovarian stem cell division rates?(1) Or that fluctuating androgen and estrogen hormone levels affect neural stem cell division rates?(2) Well, apparently I wasn't the only one who found this paper “unbelievable”. Yusuf Hannun, a cancer researcher at Stony Brook University in New York, and his team decided to look much more deeply into this question of whether cancer is simply a question of random “bad luck” or is it something that can be prevented. Hannun, et. al. looked at, among other pieces of evidence, epidemiological data showing that people who migrate from regions of lower cancer risk to those with higher risk soon develop disease at rates consistent with their new environments. Equally important, they also examined specific patterns in the “driver” mutations(3) associated with certain cancers; UV light, for example, creates a unique “signature” of mutations in DNA. And they also used improved mathematical models than used in the Tomasetti paper.
(1) DUBAL, D. B., S. W. RAU, P. J. SHUGHRUE, H. ZHU, J. YU et al., 2006 Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERalpha in estradiol-mediated protection against delayed cell death. Endocrinology 147: 3076–3084.
(2) LAMARCA, H. L., and J. M. ROSEN, 2008 Hormones and mammary cell fate: What will I become when I grow up? Endocrinology 149: 4317–4321.
(3) Not all mutations present in a cancer cell's genome are involved in development of the cancer. Indeed, many are known to make no contribution at all. To embody this concept, the terms 'driver' and 'passenger' mutations have been coined. A “driver” mutation confers some growth advantage to the cancer cell and has been positively selected in the microenvironment of the tissue in which the cancer arises. A driver mutation isn't required for maintenance of the final cancer (although it often remains) but it must have been selected at some early point along the lineage of cancer development. A “passenger” mutation does not confers any clonal growth advantage and therefore does not contribute to cancer development. Passenger mutations are found within cancer genomes because mutations without functional consequences often occur during cell division. Thus, a cell that acquires a driver mutation will already have biologically inert somatic mutations within its genome.
Their results (S. Wu, et.,al., Substantial contribution of extrinsic risk factors to cancer development, http://dx.doi.org/10.1038/nature16166; Nature16 December 2015) revealed the exact opposite of the “bad luck” study: that it is mostly environmental and external factors like smoking, drinking, diet, obesity, excess sun, and exposure to toxic chemicals that cause cancer, rather than intrinsic factors like random cell mutations. Extrinsic risks factors were in fact found to account for 70% to 90% of most common cancers, while intrinsic mutations accounted for only 10% to 30%. The data showed that mutations during cell division rarely build up to the point of producing cancer, even in tissues with relatively high rates of cell division. In almost all forms of cancer, some exposure to carcinogens or other environmental factors are needed to trigger disease. Cancer risk is heavily influenced by extrinsic factors and can be reduced, perhaps even more than previously thought, through intelligent lifestyle modifications and detoxification strategies. Remember that inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis as well as immune surveillance.
Potential Extrinsic Risk Factors for Different Cancers
Cancer Type: Breast. Potential Extrinsic Carcinogenic Risk: Very significant. Oral contraception, hormone replacement therapy (estrogen + progesterone), diet, smoking, alcohol, obesity, chemicals with estrogen-like properties (i.e. some plastics, cosmetics, pesticides (such as DDE), and PCBs (polychlorinated biphenyls)
Cancer Type: Prostate. Potential Extrinsic Carcinogenic Risk: Very significant. Diet (red meat; very high calcium), obesity, smoking, cadmium, folate, soy (- risk)
Cancer Type: Lung. Potential Extrinsic Carcinogenic Risk: >90%. Smoking, air pollution, dioxin, arsenic
Cancer Type: Colo-rectal. Potential Extrinsic Carcinogenic Risk: >75%. Diet (red and processed meat), smoking, alcohol, obesity, physical inactivity
Cancer Type: Melanoma. Potential Extrinsic Carcinogenic Risk: 65-86%. Sun exposure
Cancer Type: Basal cell. Potential Extrinsic Carcinogenic Risk: ~90%. UV exposure
Cancer Type: Hepatocellular. Potential Extrinsic Carcinogenic Risk: ~80%. Hepatitis B and C viruses, aflatoxins, vinyl chloride, arsenic, anabolic steroids, schistosomiasis infection (parasite), smoking, obesity, alcohol
Cancer Type: Gastric. Potential Extrinsic Carcinogenic Risk: 65-80%. H. pylorii
Cancer Type: Cervical. Potential Extrinsic Carcinogenic Risk: ~90%. Human papilloma virus (HPV)
Cancer Type: Head and Neck. Potential Extrinsic Carcinogenic Risk: ~75%. Tobacco (all forms), alcohol
Cancer Type: Esophageal. Potential Extrinsic Carcinogenic Risk: >75%. Smoking, alcohol, diet, obesity
Cancer Type: Oropharyngeal. Potential Extrinsic Carcinogenic Risk: ~70%. Human papilloma virus (HPV)
Cancer Type: Thyroid. Potential Extrinsic Carcinogenic Risk: >72%. Radiation, diet low in iodine
Cancer Type: Renal. Potential Extrinsic Carcinogenic Risk: >58%. Smoking, obesity, cadmium, organic solvents (e.g. trichloroethylene), herbicides
Cancer Type: Thymus. Potential Extrinsic Carcinogenic Risk: >77%. Upper chest radiation exposures, age
Cancer Type: Small Intestine. Potential Extrinsic Carcinogenic Risk: >61%. Diet (low fiber), smoking, alcohol, celiac disease
Cancer Type: Non-Hodgkins Lymphoma. Potential Extrinsic Carcinogenic Risk: >71%. Radiation, immune deficiency states
Cancer Type: Testicular. Potential Extrinsic Carcinogenic Risk: >45%. Hormonal imbalance, HIV, undescended testis
Cancer Type: Anorectal. Potential Extrinsic Carcinogenic Risk: >63%. Human papilloma virus (HPV), smokingupdated and modified from cancer.org
The implication is that since not all environmental and intrinsic factors directly cause driver mutations which result in cancer, their effect is most likely mediated via epigenetic changes in non-coding regulatory regions of the human genome. The human genome is the complete assembly of DNA--about 3 billion base pairs arranges in 23 pairs of chromosomes--that makes each individual unique. The epigenome is a multitude of chemical compounds that attach to the genome and tells it what to do. Epigenetic gene regulation alters the activities and abilities of a cell without directly affecting or mutating the sequence of the DNA. A growing number of studies have provided details on epigenetic mechanisms and their involvement in cancer. In an effort similar to the mapping of single-nucleotide polymorphisms (mutations), large-scale attempts to link epigenetic cancer-associated variations, such as methylation-variable positions, are currently being undertaken by The Human Epigenome Consortium and other research groups. Such approaches promise to yield valuable tools for future research into links between lifestyle, environment, epigenetics and cancer. In a future paper I will discuss what a cancer-preventing epigenetic diet and lifestyle should consist of.