On 2017 Jul 28, Miguel Lopez-Lazaro commented:

Cancer etiology: assumptions lead to erroneous conclusion

The authors claim that cancer is caused and driven by mutations, and that two-thirds of the mutations required for cancer are caused by unavoidable errors arising during DNA replication. The first claim is based on the somatic mutation theory. The second claim is based on a highly positive correlation between the lifetime number of stem cell divisions in a tissue and the risk of cancer in that tissue, and on their method for estimating the proportion of mutations that result from heredity (H mutations), environmental factors (E mutations) and unavoidable errors arising during DNA replication (R mutations). These claims raise several questions:

1. Sequencing studies have found zero mutations in the genes of a variable proportion of different cancer types (see, e.g., https://dx.doi.org/10.1093/jnci/dju405 and references therein). If cancer is caused by mutations in driver genes, could the authors explain what causes these cancers with zero mutations? Could the authors use their method for estimating the proportion of cancer risk that is preventable and unpreventable in people with tumors lacking driver gene mutations?

2. Environmental factors are known to affect stem cell division rates. According to IARC, drinking very hot beverages probably causes esophageal cancer (Group 2A). If you drink something hot enough to severely damage the cells lining the esophagus, the stem cells located in deeper layers have to divide to produce new cells to replace the damaged cells. These stem cell divisions, triggered by an environmental factor, will lead to mutations arising during DNA replication. However, these mutations are avoidable if you do not drink very hot beverages. Should these mutations be counted as environmental mutations (H mutations) or as unavoidable mutations arising during DNA replication (R mutations)?

3. The authors' work is based on the somatic mutation theory. This theory is primarily supported by the idea that cancer incidence increases exponentially with age. Since our cells are known to accumulate mutations throughout life, the accumulation of driver gene mutations in our cells would perfectly explain why the risk of cancer increases until death. However, it is now well established that cancer incidence does not increase exponentially with age for some cancers (acute lymphoblastic leukemia, testicular cancer, cervical cancer, Hodgkin lymphoma, thyroid cancer, bone cancer, etc). It is also well known that cancer incidence decreases late in life for many cancer types (lung cancer, breast cancer, prostate cancer, etc). For example, according to SEER cancer statistics review, 1975-2014, men in their 80s have approximately half the risk of developing prostate cancer than men in their 70s. The somatic mutation theory, which is the basis for this article, does not explain why the lifetime accumulation of driver gene mutations in the cells of many tissues is not translated into an increase in cancer incidence throughout life. Are the authors' conclusions applicable to all cancers or only to those few cancers in which incidence increases exponentially with age until death?

4. The authors estimate that 23% of the mutations required for the development of pancreatic cancer are associated with environmental and hereditary factors; the rest (77%) are mutations arising during DNA replication. However, Notta et al. recently found that 65.4% of pancreatic tumors develop catastrophic mitotic events that lead to mutations associated with massive genomic rearrangements (https://doi.org/10.1038/nature19823). In other words, Notta et al. demonstrate that cell division not only leads to mutations arising during DNA replication, but also to mutations arising during mitosis. For this cancer type, the authors could introduce a fourth source of mutations, and estimate the proportion of mutations arising during mitosis (M mutations) and re-estimate those arising during DNA replication (R mutations). Alternatively, they could reanalyze their raw data without assuming that the parameters “stem cell divisions” and ”DNA replication mutations” are interchangeable. Cell division, process by which a cell copies and separates its cellular components to finally split into two cells, can lead to mutations occurring during DNA replication, but also to other cancer-promoting errors, such as chromosome aberrations arising during mitosis, errors in the distribution of cell-fate determinants between the daughter cells, and failures to restore physical interactions with other tissue components. Would the authors' conclusions stand without assuming that the parameters “stem cell divisions” and ”DNA replication mutations” are interchangeable?

5. The authors report a striking correlation between the number of stem cell divisions in a tissue and the risk of cancer in that tissue. They do not report any correlation between the number of mutations in a tissue and the risk of cancer in that tissue; in fact, these parameters are not correlated (see. e.g., https://doi.org/10.1038/nature19768). In addition, the authors discuss that most of the mutations required for cancer are a consequence, not a cause, of the division of stem cells. So, why do the authors use their correlation to say that cancer is caused by the accumulation of mutations in driver genes instead of saying that cancer is caused by the accumulation of cell divisions in stem cells?

For references and additional information see: Comment on 'Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention' DOI: 10.13140/RG.2.2.28889.21602 https://www.researchgate.net/publication/318744904; also https://www.preprints.org/manuscript/201707.0074/v1/download

On 2017 Mar 29, Daniel Corcos commented:

The authors confuse mutation incidence with cancer incidence. Furthermore the factors are not additive. Mutations are obviously related to the number of cell divisions, which is well known, but this does not tell anything on the contribution of heredity and environment.

On 2017 Mar 29, Atanas G. Atanasov commented:

Compliments to the authors for this so interesting work, I have featured it at: http://healthandscienceportal.blogspot.com/2017/03/new-study-points-that-two-thirds-of.html

On 2017 Mar 29, Atanas G. Atanasov commented:

Compliments to the authors for this so interesting work, I have featured it at: http://healthandscienceportal.blogspot.com/2017/03/new-study-points-that-two-thirds-of.html

On 2017 Mar 29, Daniel Corcos commented:

The authors confuse mutation incidence with cancer incidence. Furthermore the factors are not additive. Mutations are obviously related to the number of cell divisions, which is well known, but this does not tell anything on the contribution of heredity and environment.

On 2017 Jul 28, Miguel Lopez-Lazaro commented:

Cancer etiology: assumptions lead to erroneous conclusion

The authors claim that cancer is caused and driven by mutations, and that two-thirds of the mutations required for cancer are caused by unavoidable errors arising during DNA replication. The first claim is based on the somatic mutation theory. The second claim is based on a highly positive correlation between the lifetime number of stem cell divisions in a tissue and the risk of cancer in that tissue, and on their method for estimating the proportion of mutations that result from heredity (H mutations), environmental factors (E mutations) and unavoidable errors arising during DNA replication (R mutations). These claims raise several questions:

1. Sequencing studies have found zero mutations in the genes of a variable proportion of different cancer types (see, e.g., https://dx.doi.org/10.1093/jnci/dju405 and references therein). If cancer is caused by mutations in driver genes, could the authors explain what causes these cancers with zero mutations? Could the authors use their method for estimating the proportion of cancer risk that is preventable and unpreventable in people with tumors lacking driver gene mutations?

2. Environmental factors are known to affect stem cell division rates. According to IARC, drinking very hot beverages probably causes esophageal cancer (Group 2A). If you drink something hot enough to severely damage the cells lining the esophagus, the stem cells located in deeper layers have to divide to produce new cells to replace the damaged cells. These stem cell divisions, triggered by an environmental factor, will lead to mutations arising during DNA replication. However, these mutations are avoidable if you do not drink very hot beverages. Should these mutations be counted as environmental mutations (H mutations) or as unavoidable mutations arising during DNA replication (R mutations)?

3. The authors' work is based on the somatic mutation theory. This theory is primarily supported by the idea that cancer incidence increases exponentially with age. Since our cells are known to accumulate mutations throughout life, the accumulation of driver gene mutations in our cells would perfectly explain why the risk of cancer increases until death. However, it is now well established that cancer incidence does not increase exponentially with age for some cancers (acute lymphoblastic leukemia, testicular cancer, cervical cancer, Hodgkin lymphoma, thyroid cancer, bone cancer, etc). It is also well known that cancer incidence decreases late in life for many cancer types (lung cancer, breast cancer, prostate cancer, etc). For example, according to SEER cancer statistics review, 1975-2014, men in their 80s have approximately half the risk of developing prostate cancer than men in their 70s. The somatic mutation theory, which is the basis for this article, does not explain why the lifetime accumulation of driver gene mutations in the cells of many tissues is not translated into an increase in cancer incidence throughout life. Are the authors' conclusions applicable to all cancers or only to those few cancers in which incidence increases exponentially with age until death?

4. The authors estimate that 23% of the mutations required for the development of pancreatic cancer are associated with environmental and hereditary factors; the rest (77%) are mutations arising during DNA replication. However, Notta et al. recently found that 65.4% of pancreatic tumors develop catastrophic mitotic events that lead to mutations associated with massive genomic rearrangements (https://doi.org/10.1038/nature19823). In other words, Notta et al. demonstrate that cell division not only leads to mutations arising during DNA replication, but also to mutations arising during mitosis. For this cancer type, the authors could introduce a fourth source of mutations, and estimate the proportion of mutations arising during mitosis (M mutations) and re-estimate those arising during DNA replication (R mutations). Alternatively, they could reanalyze their raw data without assuming that the parameters “stem cell divisions” and ”DNA replication mutations” are interchangeable. Cell division, process by which a cell copies and separates its cellular components to finally split into two cells, can lead to mutations occurring during DNA replication, but also to other cancer-promoting errors, such as chromosome aberrations arising during mitosis, errors in the distribution of cell-fate determinants between the daughter cells, and failures to restore physical interactions with other tissue components. Would the authors' conclusions stand without assuming that the parameters “stem cell divisions” and ”DNA replication mutations” are interchangeable?

5. The authors report a striking correlation between the number of stem cell divisions in a tissue and the risk of cancer in that tissue. They do not report any correlation between the number of mutations in a tissue and the risk of cancer in that tissue; in fact, these parameters are not correlated (see. e.g., https://doi.org/10.1038/nature19768). In addition, the authors discuss that most of the mutations required for cancer are a consequence, not a cause, of the division of stem cells. So, why do the authors use their correlation to say that cancer is caused by the accumulation of mutations in driver genes instead of saying that cancer is caused by the accumulation of cell divisions in stem cells?

For references and additional information see: Comment on 'Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention' DOI: 10.13140/RG.2.2.28889.21602 https://www.researchgate.net/publication/318744904; also https://www.preprints.org/manuscript/201707.0074/v1/download