On 2015 Dec 26, Miguel Lopez-Lazaro commented:

Most cancer risk is unavoidable, but most cancer cases are preventable.

Tomasetti and Vogelstein recently reported in Science a highly positive correlation between the lifetime number of stem cell divisions in a tissue and the risk of cancer in that tissue. Based on this correlation, they proposed that most cancers are unpreventable ('the bad luck of cancer'), and that early detection may be more effective than prevention to reduce cancer mortality [1]. Fortunately, 'the bad luck hypothesis' does not seem to be correct. It was based on the assumption that the parameters 'stem cell divisions' and 'DNA replication mutations' are interchangeable. These parameters cannot be interchanged, mainly because the mutations arising during DNA replication are random and unavoidable, while the division of stem cells is not a random and unavoidable process (the division of stem cells is highly influenced by external factors and physiological signals that can be controlled). A second important reason is that the parameters 'cancer risk' and 'cancer incidence' cannot be interchanged either [2].

In this Nature article, Wu et al. use several modeling approaches to propose that most cancer risk is avoidable. They conclude that unavoidable intrinsic factors contribute only less than 10-30% of the lifetime cancer risk. However, cancer statistics make this conclusion very difficult to accept. Age (an 'unavoidable' intrinsic factor) is by large the most important risk factor for the development of most cancers. For example, according to SEER Cancer Statistics Review 1975–2012, the risk of being diagnosed with prostate cancer is over 2800 times higher in men over 60 years old than in men under 30. For lung cancer, the risk is over 600 times higher in people over 60 than in people under 30. Extrinsic factors do not increase cancer risk that much; for example, smoking increases lung cancer risk by approximately 20 times. Therefore, the proposal that extrinsic factors contribute more than 70-90% to the development of these and other common cancers (see e.g. Figure 3b) does not seem to be correct. The second assumption present in the Science article also seems to be present in this article (see e.g. Extended Data Table 2).

The fact that most cancer risk is unavoidable does not mean that most cancer cases are unpreventable. Preventing a small percentage of cancer risk may be sufficient to prevent a high percentage of cancer cases. For example, although age is by large the most important risk factor for lung cancer, avoiding smoking prevents a high percentage of lung cancer cases. Extrinsic factors can be seen as the “the straw that breaks the camel’s back”; they are not the major contributors in most cases, but they can be decisive [2].

[1] http://www.ncbi.nlm.nih.gov/pubmed/25554788

[2] http://www.ncbi.nlm.nih.gov/pubmed/26682276

On 2015 Dec 23, Song Wu commented:

We appreciate the thoughtful comment, which raises a very interesting point that tumor microenviroment may also affect tissue-specific cancer incidences. We agree with that. However, it is important to note that we adopted a very specific definition of intrinsic cancer risk factors as defined in this article, as well as in the previous study in Science. In this formulation intrinsic risk refers only to the internal mutation rate in those dividing cells (stem or otherwise). As such, this factor is most susceptible to randomness. In our further analyses including all our four distinct approaches, we remained agnostic as to the nature of extrinsic factors. These would include not only environmental factors but also factors in the organism that are extrinsic to the tumor including inflammatory mediators, immune responses, hormones, and tissue microenviroment. These are all potentially modifiable conditions, and should belong to the domain of extrinsic factors.

We also agree that external factors may act through avenues other than stem cell, which is the reason that we specifically did not say that external factors (or even internal factors) act exclusively through stem cells. Additionally, in some components of our analyses, such as evidence from epidemiological data and mutational signatures, the results are independent of whether external factors act through stem cells or not. In this regards, our initial approaches were primarily directed at the question of whether the strong correlation between stem cell division and cancer risk can distinguish the effects of intrinsic from extrinsic factors, and our results show that it does not.

Overall, our main message is to promote further research into the causes of cancer and how they could be prevented.

-The Authors

On 2015 Dec 20, James Degregori commented:

The article by Wu et al argues that extrinsic risk factors contribute far more to cancer risk than calculated by Tomasetti and Vogelstein (1). While I share their critique of the deficiencies in the assumptions and conclusions made by Tomasetti and Vogelstein (2), I would argue that they make a major error in solely regarding extrinsic factors as mutagens; i.e. they calculate the added risk of cancer caused by these factors (such as smoking) as solely coming from increases in mutation frequency. In fact, their modeling (see Fig 4) requires very large numbers of lifetime stem cell divisions, in part because they do not consider any selective impact of mutations. The accumulation of multiple mutations in a single cell lineage would be extremely improbable without clonal expansion (to increase the target size) following each mutation. Since Nowell (1976) (3), the cancer field has largely considered these mutational events to be inherently advantageous. Thus, most cancer models have been primarily focused on the occurrence of mutations, assuming that each oncogenic mutation immediately and inevitably leads to clonal proliferation and is thus rate-limiting for cancer progression. But this understanding of the fitness effect of mutations is discrepant with evolutionary theory, whereby the fitness value of a mutation is entirely dependent on context (genetic, environmental, etc.).

Extrinsic risk factors like smoking, as well as intrinsic risk factors like aging, will do much more than affect mutation load – they will drastically alter tissue landscapes and thus influence the selective value of mutations (4). The major driver of organismal evolution is environmental change, largely by impacting selection and drift. To give just one example, the hominid lineage leading to modern humans has undergone drastic phenotypic change in the last 5+ million years, and yet I doubt that any evolutionary biologist would argue that this was due primarily to mutation accumulation. Instead, changing environments and selective pressures drove human evolution. Our ape and chimp cousins took a different path, due to different environmental pressures, not due to differences in mutation rates. At the organismal level, it is environmental perturbations that lead to evolutionary change as organisms adapt to new environments. So why do cancer biologists so often ignore the role of altered selection driven by environmental (i.e. tissue microenvironment) changes when considering links between cancer incidence and factors such as aging, smoking, obesity, etc.?

When the dynamic evolutionary concept of fitness is incorporated into our understanding of cancer, then cancer progression, as a type of somatic evolution, can primarily be understood as a microenvironment-dependent process. While the natural selection driven maintenance of tissues through periods of likely reproduction promote stabilizing selection in stem and progenitor cell pools (limiting somatic evolution), alterations in tissue landscapes (whether from aging, smoking or other insults) will change adaptive landscapes, promoting selection for mutations that are adaptive to this new microenvironment. Some of these mutations can be oncogenic, and thus contexts that promote tissue change like aging promote selection for adaptive oncogenic mutations. Of course, mutations are still necessary (and thus cell divisions are necessary), but mutations without the other evolutionary forces of selection and drift would be insufficient to account for increased rates of cancer in old age, in smokers, and for other cancer-promoting contexts. Hopefully, the impact of etiologic factors on cancer risk will be more frequently considered in terms of how they impact tissue microenvironments and selection, in addition to how they impact mutation frequency.

This comment was also posted on the Nature website linked to this same paper.

James DeGregori Department of Biochemistry and Molecular Genetics University of Colorado School of Medicine james.degregori@ucdenver.edu

1 Tomasetti, C. & Vogelstein, B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81, doi:10.1126/science.1260825 (2015).

2 Rozhok, A. I., Wahl, G. M. & DeGregori, J. A Critical Examination of the “Bad Luck” Explanation of Cancer Risk. Cancer Prevention Research 8, 762-764, doi:10.1158/1940-6207.capr-15-0229 (2015).

3 Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23-28 (1976).

4 Rozhok, A. I. & DeGregori, J. Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proceedings of the National Academy of Sciences of the United States of America 112, 8914-8921, doi:10.1073/pnas.1501713112 (2015).

On 2015 Dec 20, James Degregori commented:

The article by Wu et al argues that extrinsic risk factors contribute far more to cancer risk than calculated by Tomasetti and Vogelstein (1). While I share their critique of the deficiencies in the assumptions and conclusions made by Tomasetti and Vogelstein (2), I would argue that they make a major error in solely regarding extrinsic factors as mutagens; i.e. they calculate the added risk of cancer caused by these factors (such as smoking) as solely coming from increases in mutation frequency. In fact, their modeling (see Fig 4) requires very large numbers of lifetime stem cell divisions, in part because they do not consider any selective impact of mutations. The accumulation of multiple mutations in a single cell lineage would be extremely improbable without clonal expansion (to increase the target size) following each mutation. Since Nowell (1976) (3), the cancer field has largely considered these mutational events to be inherently advantageous. Thus, most cancer models have been primarily focused on the occurrence of mutations, assuming that each oncogenic mutation immediately and inevitably leads to clonal proliferation and is thus rate-limiting for cancer progression. But this understanding of the fitness effect of mutations is discrepant with evolutionary theory, whereby the fitness value of a mutation is entirely dependent on context (genetic, environmental, etc.).

Extrinsic risk factors like smoking, as well as intrinsic risk factors like aging, will do much more than affect mutation load – they will drastically alter tissue landscapes and thus influence the selective value of mutations (4). The major driver of organismal evolution is environmental change, largely by impacting selection and drift. To give just one example, the hominid lineage leading to modern humans has undergone drastic phenotypic change in the last 5+ million years, and yet I doubt that any evolutionary biologist would argue that this was due primarily to mutation accumulation. Instead, changing environments and selective pressures drove human evolution. Our ape and chimp cousins took a different path, due to different environmental pressures, not due to differences in mutation rates. At the organismal level, it is environmental perturbations that lead to evolutionary change as organisms adapt to new environments. So why do cancer biologists so often ignore the role of altered selection driven by environmental (i.e. tissue microenvironment) changes when considering links between cancer incidence and factors such as aging, smoking, obesity, etc.?

When the dynamic evolutionary concept of fitness is incorporated into our understanding of cancer, then cancer progression, as a type of somatic evolution, can primarily be understood as a microenvironment-dependent process. While the natural selection driven maintenance of tissues through periods of likely reproduction promote stabilizing selection in stem and progenitor cell pools (limiting somatic evolution), alterations in tissue landscapes (whether from aging, smoking or other insults) will change adaptive landscapes, promoting selection for mutations that are adaptive to this new microenvironment. Some of these mutations can be oncogenic, and thus contexts that promote tissue change like aging promote selection for adaptive oncogenic mutations. Of course, mutations are still necessary (and thus cell divisions are necessary), but mutations without the other evolutionary forces of selection and drift would be insufficient to account for increased rates of cancer in old age, in smokers, and for other cancer-promoting contexts. Hopefully, the impact of etiologic factors on cancer risk will be more frequently considered in terms of how they impact tissue microenvironments and selection, in addition to how they impact mutation frequency.

This comment was also posted on the Nature website linked to this same paper.

James DeGregori Department of Biochemistry and Molecular Genetics University of Colorado School of Medicine james.degregori@ucdenver.edu

1 Tomasetti, C. & Vogelstein, B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81, doi:10.1126/science.1260825 (2015).

2 Rozhok, A. I., Wahl, G. M. & DeGregori, J. A Critical Examination of the “Bad Luck” Explanation of Cancer Risk. Cancer Prevention Research 8, 762-764, doi:10.1158/1940-6207.capr-15-0229 (2015).

3 Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23-28 (1976).

4 Rozhok, A. I. & DeGregori, J. Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proceedings of the National Academy of Sciences of the United States of America 112, 8914-8921, doi:10.1073/pnas.1501713112 (2015).

On 2015 Dec 23, Song Wu commented:

We appreciate the thoughtful comment, which raises a very interesting point that tumor microenviroment may also affect tissue-specific cancer incidences. We agree with that. However, it is important to note that we adopted a very specific definition of intrinsic cancer risk factors as defined in this article, as well as in the previous study in Science. In this formulation intrinsic risk refers only to the internal mutation rate in those dividing cells (stem or otherwise). As such, this factor is most susceptible to randomness. In our further analyses including all our four distinct approaches, we remained agnostic as to the nature of extrinsic factors. These would include not only environmental factors but also factors in the organism that are extrinsic to the tumor including inflammatory mediators, immune responses, hormones, and tissue microenviroment. These are all potentially modifiable conditions, and should belong to the domain of extrinsic factors.

We also agree that external factors may act through avenues other than stem cell, which is the reason that we specifically did not say that external factors (or even internal factors) act exclusively through stem cells. Additionally, in some components of our analyses, such as evidence from epidemiological data and mutational signatures, the results are independent of whether external factors act through stem cells or not. In this regards, our initial approaches were primarily directed at the question of whether the strong correlation between stem cell division and cancer risk can distinguish the effects of intrinsic from extrinsic factors, and our results show that it does not.

Overall, our main message is to promote further research into the causes of cancer and how they could be prevented.

-The Authors

On 2015 Dec 26, Miguel Lopez-Lazaro commented:

Most cancer risk is unavoidable, but most cancer cases are preventable.

Tomasetti and Vogelstein recently reported in Science a highly positive correlation between the lifetime number of stem cell divisions in a tissue and the risk of cancer in that tissue. Based on this correlation, they proposed that most cancers are unpreventable ('the bad luck of cancer'), and that early detection may be more effective than prevention to reduce cancer mortality [1]. Fortunately, 'the bad luck hypothesis' does not seem to be correct. It was based on the assumption that the parameters 'stem cell divisions' and 'DNA replication mutations' are interchangeable. These parameters cannot be interchanged, mainly because the mutations arising during DNA replication are random and unavoidable, while the division of stem cells is not a random and unavoidable process (the division of stem cells is highly influenced by external factors and physiological signals that can be controlled). A second important reason is that the parameters 'cancer risk' and 'cancer incidence' cannot be interchanged either [2].

In this Nature article, Wu et al. use several modeling approaches to propose that most cancer risk is avoidable. They conclude that unavoidable intrinsic factors contribute only less than 10-30% of the lifetime cancer risk. However, cancer statistics make this conclusion very difficult to accept. Age (an 'unavoidable' intrinsic factor) is by large the most important risk factor for the development of most cancers. For example, according to SEER Cancer Statistics Review 1975–2012, the risk of being diagnosed with prostate cancer is over 2800 times higher in men over 60 years old than in men under 30. For lung cancer, the risk is over 600 times higher in people over 60 than in people under 30. Extrinsic factors do not increase cancer risk that much; for example, smoking increases lung cancer risk by approximately 20 times. Therefore, the proposal that extrinsic factors contribute more than 70-90% to the development of these and other common cancers (see e.g. Figure 3b) does not seem to be correct. The second assumption present in the Science article also seems to be present in this article (see e.g. Extended Data Table 2).

The fact that most cancer risk is unavoidable does not mean that most cancer cases are unpreventable. Preventing a small percentage of cancer risk may be sufficient to prevent a high percentage of cancer cases. For example, although age is by large the most important risk factor for lung cancer, avoiding smoking prevents a high percentage of lung cancer cases. Extrinsic factors can be seen as the “the straw that breaks the camel’s back”; they are not the major contributors in most cases, but they can be decisive [2].

[1] http://www.ncbi.nlm.nih.gov/pubmed/25554788

[2] http://www.ncbi.nlm.nih.gov/pubmed/26682276