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Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

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Science  24 Mar 2017:
Vol. 355, Issue 6331, pp. 1330-1334
DOI: 10.1126/science.aaf9011

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  • RE: Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention
    • Suresh Moolgavkar, Epidemiologist and Biostatistician, Fred Hutchinson Cancer Research Center
    • Other Contributors:
      • Georg Luebeck, Biomathematician, Fred Hutchinson Cancer Research Center

    That age is a strong independent risk factor for cancer because it is the end result of sequentially acquired random (i.e., probabilistic) mutations in dividing stem cells, the rates of which can be modified by genetic and environmental factors, has been known for decades [1-4]. A small number of driver mutations are sufficient to cause malignancy [4-7]. Tomasetti and Vogelstein’s [8]) original contribution to this vast body of literature is the observation that the number of stem cell divisions in tissues is correlated with the lifetime probability of cancer of these tissues.
    Recently, these authors [9] extended their calculations to multiple countries around the world and provided estimates of the fraction of mutations due to environmental (E), hereditary (H) and replicative (R) factors. These estimates are of dubious validity. First, the interactions of environment with cancer genes will be different for genes that lie on a pathway to cancer, such as the RB, TP53 or APC, and genes that increase the rates of mutations, such as the XP gene. Moreover, weaker genes such as those determining polymorphisms of enzymes for metabolism of environmental agents are also clearly hereditary factors influencing cancer development. Finally, these authors ignore completely the phenomenon of clonal expansion of partially altered cells on the pathway to malignancy [4]. Consideration of this phenomenon of promotion, which is often modified by exposure to non-mutagenic environmental...

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    Competing Interests: None declared.
  • Appearance of somatic mutations can be subjected to the influences of inherited factors
    • Qiuyun Liu, Professor, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, China.
    • Other Contributors:
      • Jiaming Zhang, Student, School of Chemistry and Chemical Engineering, Sun Yat-sen University, China.
      • Man Tang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
      • Yunfan Shi, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
      • Yulin Wan, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
      • Xiaoyi Hu, Student, Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, USA.

    Tomasetti et al. (1) discovered correlation between the number of normal stem cell divisions and the risk of numerous cancer types in an extensive study. They concluded that unavoidable R mutations (DNA replication errors), as non-inherited factors, are responsible for two-thirds of the mutations in human cancers. We believe that a substantial fraction of somatic mutations can be generated by the influences of genetic polymorphisms in the genome, which may be preventable by adjusting the local acidic microenvironment via the supplement of non-proton cations and weak acids, etc. The aforementioned genetic polymorphisms can be viewed as cancer predisposition factors which create a microenvironment for somatic mutations to occur. Therefore appearance of somatic mutations may depend upon inherited factors as described below.

    A published hypothesis proposed that high content of hydrogen donors and acceptors, and basic amino acids in proteins trigger the intracellular trapping of the H+ and Cl- ions (2), which increases cancer risks as local buildup of HCl increases DNA damage under acidic conditions This is corroborated by the fact that cancer risks were substantially reduced by the administration of calcium tablets in human subpopulation (3), as cations can neutralize strong acids. Workers have been reported to be virtually cancer free in China-based vinegar factories (4-6), and weak acids may counteract the local formation of HCl. The constant mutations that result fro...

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    Competing Interests: None declared.
  • RE: Slippery foundations of "bad luck"
    • Vibishan B, Graduate student, Department of Biology, Indian Institute of Science Education and Research, Pune
    • Other Contributors:
      • Milind G Watve, Professor, Department of Biology, Indian Institute of Science Education and Research, Pune

    In the current publication, Tomasetti et al. reiterated their earlier claim from the paper titled "Variation in cancer risk among tissues can be explained by the number of stem cell divisions", that cancer is largely a product of random mutations and therefore, “bad luck”. In evidence, they used an association of cumulative cancer risk with number of lifetime stem cell divisions (lscd), on a global scale with data from 423 different databases across the world. Throughout the paper, they state that there is a linear relationship between the two variables, as expected by the “bad luck” hypothesis. However, the earlier paper’s supplementary information and a re-examination of the data sets used in the current paper reveal that the correlations are performed on a log-log scale, in which case, a slope other than 1 implies a non-linear relationship. Using the same data source, we re-examined the correlations, and obtained a distribution of r values identical to that reported in the paper, but a median slope of 0.334 for all the regressions. This indicates that cumulative cancer risk holds a fractional power relationship with lscd, which deviates substantially from the expected linearity, and requires explanation before we infer anything about bad luck or environmentally-induced carcinogenesis. The narrow distribution of slopes also indicates that this relationship is quite consistent across data sets. The authors could have avoided misleading the reader by clearly stat...

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    Competing Interests: None declared.
  • RE:CANCER ≠ MATHEMATICS: IT’S FAR MORE COMPLEX AND EVER-CHANGING
    • Lary A. Robinson, M.D., Thoracic Surgeon and Carcinogenesis Investigator, Division of Thoracic Oncology, Center for Infection Research in Cancer, Moffitt Cancer Center, Tampa, Florida, USA

    The cogent, erudite paper on carcinogenic somatic mutations of Tomasetti, et.al.(1) presented a controversial(2,3) mathematical model suggesting two-thirds of cancers are caused by random, unpreventable mutations (“bad luck” hypothesis). At face value, this discouraging conclusion should worry investigators involved in carcinogenesis and cancer control, implying that their research is relatively futile. Neglected factors in their analysis include rapidly changing cancer prevalence such as the disturbing rise of lung cancer in never-smokers, or the epidemic of pancreatic, thyroid and liver cancer.(4) Has the rate of random somatic mutations accelerated in some tissues? Also omitted is the growing field of microbial carcinogenesis—at least 20% of cancers are known to have a microbial contribution(5) and many others are suspected.(6,7) Moreover the exploding field of microbiome research suggests that dysbiosis may cause or contribute to carcinogenesis.(8,9)

    Indeed, the authors imply cancers have primarily one cause: 20% environmental, 10% heredity or 70% “bad luck” random mutations. This short-sighted view ignores current knowledge that points to multi-factorial causation of virtually all cancers. For example, smoking doesn’t cause lung cancer since only one of six smokers ever develops lung cancer.(10) Rather, smoking strongly contributes—but it’s only one of many factors in the necessary “perfect storm” of causes including random mutations resulting in lung cance...

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    Competing Interests: None declared.
  • RE: Cancer Prevention is Crucial
    • Mingyang Song, Instructor of Medicine, Massachusetts General Hospital and Harvard Medical School
    • Other Contributors:
      • Walter Willett, Professor of Nutrition and Epidemiology, Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health
      • Edward Giovannucci, Professor of Nutrition and Epidemiology, Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health

    Recently, Tomasetti et al. performed statistical modeling of the contributions of environmental factors (E), heredity (H), and DNA replication errors (R) to driver gene mutations, and estimated that 66% of the mutations in cancers occurring in the UK were attributable to R, whereas only 29% were attributable to E and 5% to H.(1) However, these components are well known to interact with each other,(2, 3) and, as noted by the authors, both environmental and inherited factors can directly or indirectly influence replication and the mutation rate. Most importantly, the authors ignored the major influences of environmental factors in promoting or inhibiting the growth of mutated cells that can determine whether they become a clinical cancer. Thus, contrary to their conclusion, even tumors with all R mutations can still be prevented from becoming detectable cancers. Further research will likely identify more preventive approaches for these cancers. In addition, their conclusion that their estimate of E to the etiology of driver gene mutations is consistent with epidemiologic estimates of the preventability of cancer is misleading, and has led to wide misinterpretation by the press. Numerous reports demonstrate that 50-60% of cancer deaths in the US can be prevented through modification of lifestyle and known environmental risk factors,(4-6) but the authors cited a report of 21%, which was calculated by comparing the death rates in all states to the average rates of the three sta...

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    Competing Interests: None declared.
  • RE: Cancer risk: What did cause cancer?
    • Jun-Wen Li, Professor, Tianjin Institute of Health and Environmental Medicine, China
    • Other Contributors:
      • Zhaoli Chen, Doctor, Tianjin Institute of Health and Environmental Medicine, China

    Cancer risk: What did cause cancer?

    Zhaoli Chen, Jun-Wen Li*

    Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, No. 1, Dali Road, Tianjin 300050, China. Zhaoli Chen, ZhaoliChen@126.com. Jun-Wen Li, junwen9999@hotmail.com
    * Corresponding author. E-mail: junwen9999@hotmail.com (J. L.)
    All authors have equally contributed to this work.

    Two years ago, Tomasetti and Vogelstein published a report entitled “Variation in cancer risk among tissues can be explained by the number of stem cell divisions” in Science, where they inferred that the lifetime risk of cancer had a strong correlation with the total number of divisions of normal stem cells among 25 different tissues in the United States, and that random mutations arising during DNA replication in normal, noncancerous stem cells played a major role in cancer etiology (1). This result led to much scientific and public debate and confusion. In a recent study, they collected mass data which covered 4.8 billion people in 69 countries to evaluate the correlations between the incidence of 32 cancer types and DNA replication errors of the normal stem cell divisions. Their results indicated that the mutations inherited (H), induced by environmental factors (E), or resulting from DNA replicatio...

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    Competing Interests: None declared.
  • RE: mtDNA mutations may affect random nuclear DNA mutations of Stem cells
    • Vasilios Makropoulos, Professor, National School of Public Health, Athens, Greece
    • Other Contributors:
      • Emmanouil Papadogiannakis, Assist. Professor, National School of Public Health, Athens, Greece
      • Gregory Spanakos, Biologist PhD, National School of Public Health, Athens, Greece
      • Kostas Kotrokois, Assist Professor, National School of Public Health, Athens, Greece

    The recent publication by Tomasetti et al., in Science concludes that DNA replication errors (R) of normal Stem cell divisions are responsible for two-thirds of the mutations in human cancers.
    We fully agree with Sergio Stagnaro et al., response to this article that the site of a possible "mutation" could be the mitochondria. Tomasetti et al., did not focus on mtDNA of Stem cells for possible mutations. According to novel scientific findings, there is a significant interplay between mitochondria and the cell nucleus. Mutations in the nucleus could be the result of mtDNA mutations, and therefore the former could not be called "random".

    Competing Interests: None declared.
  • RE: "Random" mutations during replication

    Have you considered that some of those mutations you have categorized as random actually may not be completely random after all, or at least, could have been repaired before they were passed on to daughter cells? While random mutations during replication may be inevitable, so too are DNA repairs during replication. Some of those random mutations that you attribute to the inevitable nature of DNA replication could actually be mutations that would have been repaired if not for the exposure of the cell to exogenous deleterious environmental factors that might have impaired DNA repair mechanisms (but were not themselves mutagenic). Therefore, these random mutations might not have remained if not for the cell's exposure to exogenous toxicants, and their categorization as random (R) might not be completely accurate; they may be better categorized as environmental (E), or (R-E).

    Competing Interests: None declared.
  • RE: H, E, and R factors of cancer onset
    • Sergio Stagnaro, Director, Quantum Biophysical Semeiotic Research Laboratory
    • Other Contributors:
      • Marco Marchionni, Neurosurgery, Department of Neurosurgery University Hospital of North Staffordshire Stoke on Trent, UK
      • Simone Caramel, President, International Society of Quantum Biophysical Semeiotic

    The recent publication by Tomasetti et al. in Science appears as a fascinating contribution to solving a central problem, till now open, in oncogenesis. As a matter of fats, because such a R factors do not act in all individuals, we unavoidably and necessarily have to admit the existence of something heritable somewhere in human body. Really, we are not all born equal. I think that the site of a possible inherited "mutation" could be the mitochondria. In fact, mitochondria play notoriously a flurry of biologically essential functions, among them proteine-lipid-glucose metabolism regulation, Fe metabolism control, Fe/S-Cluster production in its assembly machinary (CIA is working exclusively in presence of a substance, till now only partially known, i.e., XS, that is synthetized in mitocondria), n-DNA duplication, and Telomere lenght regulation, realized by the action of Fe/S-Cluster via RTL-1 and -2. In conclusion, if this theory on the central role of mitochondria in oncology will be supported on very large scale, it opens an interesting therapeutic way to combat oncogenesis.

    Competing Interests: None declared.
  • Cancer etiology: the evolutionary ecology of organs may help to understand the frequency distribution of E and R mutations
    • Frederic THOMAS, Directeur de Recherche, CNRS
    • Other Contributors:
      • Beata Ujvari, Lecturer, Deakin Unversity
      • Benjamin Roche, Chargé de Recherches, IRD

    Cancer etiology: the evolutionary ecology of organs may help to understand the frequency distribution of E and R mutations

    Frédéric Thomas 1, Beata Ujvari2, Benjamin Roche1,3

    All authors have equally contributed to this work

    1- Centre for Ecological and Evolutionary Research on Cancer (CREEC), UMR CNRS/IRD/UM1 MIVEGEC, Montpellier, France
    2- Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Australia
    3- UMI IRD/UPMC 209 UMMISCO, Paris, France

    Disentangling the relative contribution of intrinsic and extrinsic risk factors in cancer etiology is traditionally accepted as a crucial aspect of the prevention, early detection and treatment “triage”. The recent publication by Tomasetti et al. in Science appears as an important contribution to the debate previously sparked by the same authors1 2 3 4 5. Cancers are caused by mutations that can be inherited (H mutations), induced by environmental factors (E mutations), or that result from DNA replication errors (R mutations). In their 2014’s paper, Tomasetti and Volgestein proposed that two-thirds of cancers can be attributed to random mutations arising during DNA replication in normal, noncancerous stem cells, i.e. R mutations. Thus, organs with high rates of stem cell divisions would be simply more likely to carry cancer-causing mutations and thus subject to “bad luck”. Their recent study confirms the major role of R mutations in cancer...

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    Competing Interests: None declared.
  • RE: Tomasetti et al. Chance events in cancer - is this the right focus?
    • Sui Huang, Professor, Institute for Systems Biology

    The premise of this work, captured in the opening sentence: “Most textbooks attribute cancer-causing mutations to two major sources: inherited and environmental factors” is fundamentally flawed –both in substance and logics.

    First, I don’t know of such any such textbook. Wait: environment and inheritance as major source of mutations? Sounds at first glance utterly Lamarckian! But the premise also contradicts Vogelstein’s very school of thought that is pure Darwinian orthodoxy. The standard view that Vogelstein has promoted in the past decades (albeit there is now accumulating finding that is inconsistent with it), is that tumorigenesis represents a somatic Darwinian evolution: The selection of cells that have acquired, BY CHANCE, mutations that confer to the tumor cell a fitness (growth) advantage in the tissue. Thus, by definition the mutations ARE random, and chance events is what drives tumor progression. This is the tacit paradigm anyway! Nothing new here. Germline mutations and environmentally induced mutations (e.g., Chernobyl) as causes of cancer have always been considered relatively rare compared to the bulk of cancer due to accumulation of spontaneous RANDOM mutations.

    The relative large proportion of cancer without obvious preventable cause is also naturally manifest in clinical attitudes: Unlike for cardiovascular diseases, clinicians do not even seek to link a diagnosis of cancer to some evitable risk in the patient history (excep...

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    Competing Interests: None declared.
  • RE: Exposure of Oncogenetic Mutations is Required for Cancer Initiation

    I suggest initiation of cancers, caused by DNA mutations, as described by Tomasetti and Volgelstein, Science 2017: "Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention," is caused by a mechanism that increases cell surface area of cells containing oncogenetic mutations.

    This mechanism also causes the "Warburg Effect," that is, increased metabolism / increased glucose utilization of cancers. I suggest the basis of this effect is increased cell surface area caused by reduced support of cell adhesions because of low dehydroepiandrosterone (DHEA). ("Use Of DHEA By Cancer Explains The "Warburg Effect" ...Increased Cancer Metabolism (New Support of Cancer Explanation)," at: http://anthropogeny.com/lactatecancer.html .

    Competing Interests: None declared.
  • RE: Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention
    • Archil Kapanadze, Scientist, Oncology, Universal Medical Center, Tbilisi, Georgia

    This estimates will be truth if Cancer Cell is a cause of Cancer. But, if the Cancer Cell is not a cause of Cancer, is only the symptom, this statement is the result of wasting of time (and money).
    With respect,
    Archil Kapanadze MD. PhD

    Competing Interests: None declared.
  • RE: telomeres and random mutations
    • Desmond Ebanks, Internal medicine physician, Alternity Healthcaare, LLC

    What role, if any, does telomere length and rate of telomere attrition play in the effects and/or number of random mutation that result in cancer?

    Competing Interests: None declared.

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