So many good comments here! It is a pleasure to read them and I can agree with most of what is said. First, let me be clear: I overall agree with the basic concept of the paper by Tomasetti and Vogelstein. Seems to make sense, does not contradict common sense and is in line with basic science. However, common sense is not equal to a scientific method or approach.

So, although I agree with the overall finding of the paper, the data the manuscript is based on are much more shaky than the authors may admit. For example, some comments in the manuscript are strange and can be disputed: “Another example is provided by melanocytes and basal epidermal cells of the skin, which are both exposed to the same carcinogen (ultraviolet light) at the identical dose, yet melanomas are much less frequent.” I doubt that melanoma is really rarer than cutaneous SCC and BCC when taking into consideration that there are far fewer melanocytes than basal keratinocytes. Furthermore, neither stem cell compartment is well defined in humans, neither the human epidermal stem cell nor the human melanoblast compartment.

So, what are these statements are based on? The authors perform a massive oversimplification stunt hidden behind fancy numbers of doubtful quality. Simple example from the Vogelstein manuscript and how they calculated stem cells for the esophagus: “The area of a squamous cell in the basal layer is ~80μm2 (69). The fraction of stem cells in the basal layer has been estimated to be 0.4% of the total basal layer cells (70), so there are a total of ~2.16·108 basal cells and 8.64·105 stem cells in the basal layer.” (70) is a mouse paper that mentions the word “human esophagus” zero times. The situation in human and mouse esophagus basically cannot be compared and the calculation is wrong. Human squamous epithelia are different from rodent equivalents since they have an extra stem cell layer. So every basal cell is basically a stem cell, plus a considerable number of parabasal cells. So, here the error is already 10 times. However, things are much more complicated if one wants to account for “stem cell proliferation”. Apparently, there is little agreement what and where the stem cells are in a given tissue and which stem cell population gives rise to the actual tumor, how often true cancer–originating stem cells divide. If you go through the supplements of the article one can probably find many such mistakes (the same mistake is made for the head and neck region in the calculations; also a squamous epithelium with a dedicated stem cell layer). Despite these limitations, I still think it is a very important paper since it puts math into cancer and stem cell biology, but I am not sure the math is correct. This has to be judged by people who are doing math and statistics for a living (http://www.statschat.org.nz/2015/01/03/cancer-isnt-just-bad-luck/)?

The paper illustrates that in general the numbers we have and the numbers the authors used could have been skewed, are shaky and don’t may not represent true conditions. Simple example: we can’t hardly figure out how many cells are in our body: http://www.smithsonianmag.com/smart-news/there-are-372-trillion-cells-in-your-body-4941473/?no-ist. Another example is the number of human villi: I could find this number for a long time. Without it, how can you determine an absolute number of stem cells and then an absolute number of stem cell divisions over a life time? The number for colon crypts or villi used in the study is 15 million. But the “references” are strange: “C. Potten personal communication” and a paper by Cheng et al. from 1984, which gives a rough estimate. These numbers could be right, could be wrong. Again, this could indicate that we have really very little ideas about the “math” of the human body. I just don’t think the numbers are there to calculate well the “stem cell divisions”. My “feeling” is that there is a lot of “bad math” in the paper. In the end I can’t judge this well. In the end, it is a math paper and I just don’t trust many of the numbers the math is based on. But that does not mean that the message of the paper is wrong. Please see related questions I had posed here on Researchgate that deal with similar issues (https://www.researchgate.net/post/What_are_the_absolute_numbers_of_villi_in_different_species; https://www.researchgate.net/post/Which_human_tissue_has_the_highest_cancer_incidence_when_normalized_to_size_of_the_organ; https://www.researchgate.net/post/What_does_Petos_paradox_really_mean_Are_mouse_tumor_studies_relevant).

When I tried to publish in this line, that the stem cell compartment of a tissue and its organization, quiescence and proliferation are key factors to understand tissue carcinogenesis rates and longevity, the reviewers just rejected it based on the fact that environmental factors are key drivers not endogenous factors such as proliferation rates within stem cell compartments. I think, the views of Tomasetti and Vogelstein are surprisingly poorly accepted in the certain parts of the cancer research community.

In regards to the claim in the paper that environment and genes cannot explain the majority of cancer: that depends on your point of view. Just using the raw numbers then there is no doubt that genotype/phenotype rubbing against the environment is the number one factor in cancer. Why? Because skin cancers are the number one cancers in the Western World. Why? Because of an unfortunate combination of phenotype/environment interactions: fair skinned people (genotype/phenotype) should not expose themselves too much to UV light (environmental factor). To be fair, this is a rather exceptional combo that does seem to reflect an extreme, and the authors acknowledge that. But it's a math paper and the majority of cancer is just by the numbers driven by the interaction of genotype/phenotype/environment (and anyways, isn’t there a thing called epigenetics that has dissolved the barriers between genotype and environment?). To give credit to the authors, it is doubtful that any other tissue shows such extreme genotype-based variation (skin type): Our colons are probably not as variable as our skins.

The issue with the “bad luck” terminology is tricky as well. I have had colon cancer when I was 35. You could call this bad luck, I prefer the term “freaky accident”. I also had “good luck” and my 50% chances to get away alive turned out to the better 50%. In the end “bad luck” is not a scientific term and “freaky accident” is neither. In private conversations I would probably use the term “bad luck”, reflecting on it scientifically, I would stick to terms (as Tomasetti and Vogelstein should have done and preferred not to do) such as likelihood or chance. My chances to develop cancer were low but not zero. Things happen, even unlikely things. The more unlikely they are, we start to call them accidents, bad luck or fate, or… Life is stochastic, isn’t it, inherently. Otherwise there would be no evolution, otherwise everything would be frozen: change is the only constant thing in life, and change does not always mean for the better, especially in life/aging from an individual’s perspective.

Gastric cancer incidence was 41.8 per 100.000 in Korea , on the other hand, 16 per 100.000 in Russia .

Are Russians luckier than Koreans?

recently role of micro RNAs as biomrkers for various cancers is being appreciated and miRNA 145 NANOPARTICLES DELIVERY SYSTEM BEING USED TO TREAT BREAST CANCER so obviously it is the immune system which fails and microRNA155 is known  tocontrol the Treg cell development  and any abnormality with development of immune system can affect the proliferation  development AND THEN RECENTLY ROLE OF bR cA 1 Hs been shown to affect not only breast cancer development but involvement in lipogenic en zymes in adipose tissue besides role of SREBP 1 c in liver so when any regulatory system goes wrong it affects development of cancer rather than simple obesity genes or breast cancer gen es  and hence the whole phsiology is more complicted than we understand.

immunosurvelliance plays significant role in preventing cancer. an example is when the body immune system is able to generate enough antibodies against  the hypoglycosylated form of mucin 1 (MUC1) it reduces prevalence of muc1 associated cancers ( breast, pancreas, lung, colon etc..). MUC1 has been reported to  be overexpressed in about 90% of all known cancers and its very promising to target them by inducing the body immune system to generate ab against cancerous hypoglycosylated forms of muc1. big biopharmaceutical industries are close to develop potential mucosal cancer vaccines ( eg stimuvax from MERCK.....) that targets muc1. This is just one example of the immune system in preventing cancer.

I think that the paper has been misinterpreted by the media. The way it is written makes it ambiguous, but what it actually says is that  variation in cancer risk AMONG TISSUES is  mainly a function of the number of cell divisions (the author say "stem  cell", which is more fashionable), a result that is not really surprising.

However, inherited gene mutations can affect many tissues, and the incidence of some very frequent cancers is strongly dependent on the environment, which lowers the authors' conclusion regarding public health implications.

In any case, whether it is due to inheritance, environment, or cell divisions, cancer is bad luck, isn't it?

luck is how we define life -if early diagnosed say some treatable like germ cell tumor which in lay mans term one would call cancer or malignancy if untreated as it does metastasize then one can have co plete treatment and then life is unpredictable death can occur in simple accident and sometimes you can have so called cnncer survivors living long as 5 year prognosis have improved considersably  as we progress with our understanding of cell division and its control and the more we go indepth of stem cell research and further management strategies the whole scenario changes. 

I find the paper controversial. There is evidence in the literature that factors such as:

- immune system e.g. immunodeficiency,

- epigenetics,

- microenvironment,

- infectious agents e.g. HPV, H. pylori,

- life style e.g. smoking, nutrition,

- microbiome,

- (in utero environment),

- genetic variability in human population

contribute to the development of cancer.

@ Jan

Concerning the immune system, people with immunodeficiency do not have a dramatic increase in cancer incidence, except for virus-induced cancers, which are not very numerous. Therefore, I don't think that taking into account the immune status would change the conclusions of this paper, which, I say it again, have been oversold.

Recent headlines that announce that “bad luck” rather than genetic and environmental factors account for most human cancers convey a rather simplistic if not misleading view of the interplay between nature and nurture in the etiology of most cancers. The work of Tomasetti and Vogelstein sought to quantify the importance of random mutations during stem cell divisions in diverse tissues in the rates of occurrence of various types of cancer in adults. However, their findings have been wrongly extrapolated to suggest that life style and heredity are less influential in the actual incidence of this disease that will afflict more than half the human adult population.

DNA polymerases are among the key enzymes involved in the faithful replication of the DNA sequences in chromosomes. The rate of genetic mutations introduced with normal DNA replication is not insignificant, with different DNA polymerases exhibiting accidental nucleotide base substitution rates in the order of 10(-7) to 10(-8) and even higher. Somatic and germ line cell mutations have certainly been linked for some time to the development of cancers as well as differences in the longevities of individual organisms [see for example, Kunkel, T.A. DNA replication fidelity. J. Biol Chem. 279, 16895-16898 (2004).]

Even with high fidelity DNA replication by DNA polymerases accompanied by very efficient proof-reading function that can produce low error rates of 10(-8), with 2.9 billion nucleotide base pairs in the human genome, typically 25 to 35 mutations are generated from each round of cell division. Considering that the adult human body has in the order of 50 trillion cells and most people can live for 70 years or more, this affords ample opportunity for oncogenic mutations to arise. What is most remarkable is that, at the cellular level, cancer is so rare. Many people never develop the disease.

In addition to defective replication of DNA, genetic mutations can also arise from exposure to radiation and chemical carcinogens during the lifetime of a person. The vast majority of these mutations, known as bystander mutations, are actually benign with little consequence to the health of a person. The critical mutations must occur in very precise locations in the DNA sequences of a relatively small subset of the 21,000 genes encoded by the human genome known as oncogenes. Moreover, these driver mutations must occur in multiple genes in a limited number of possible combinations in the same cell to result in full blown metastatic and lethal cancers. Quantification of which critical mutations emanate from defective DNA synthesis and which arise from environmental assaults will depend on individual circumstances.

Of equal importance to the accumulation of gain-of-function mutations in oncogenes, is the loss-of-function mutations of tumour-suppressor genes. These latter genes encode various enzymes that participate in the repair of damaged DNA as well as other regulatory proteins that inhibit the growth and spreading of cancer cells. Often, the mutations resulting in defective tumour suppressor genes may be hereditary and acquired from conception, and in such an event are present in every nucleated cell of a person's body. However, such loss of function of tumour suppressor genes may be problematic only if accompanied by subsequent mutation of oncogenes. Here again, which driver tumour suppressor gene mutations are hereditary and which are generated spontaneously in only one or a few initiating cancer cells during the lifetime of a person will vary.

Even if cancer driver mutations are generated in cells, they can be often be repaired by many of the proteins encoded by tumour suppressor genes. The lower rates of cancer in humans compared to other species such as dogs, cats and rats may be attributed to higher levels of certain repair and growth regulatory proteins such as checkpoint protein kinases. Within mutated cells, regulatory networks of these proteins carefully monitor the behaviour of these cells and can induce their suicide if their growth and reproduction are sensed to be inappropriate. Moreover, for the vast majority of early cancer cells that can evade these regulatory controls, the body’s immune system with natural killer lymphocytes and other immune cells can efficiently seek and destroy them. The health of the immune system is highly dependent on environmental factors such as the availability of nutrients, and exposure to toxic substances and other stressful conditions. Consequently, life style works at multiple levels to influence the initiation and growth of tumours and blood cancers.

Certain organs and tissues may be more prone to cancer than others for a variety of reasons besides the actual number of stem cells that they possess. Non-stem cells also undergo extensive cell divisions, as evidenced by the general shortening of telomeres with age. The skin is the largest organ of the human body, and the most exposed to radiation and noxious environmental agents. The gastrointestinal tract and the respiratory system are likewise highly exposed to the carcinogenic agents that we either consume or breathe in. The organs associated with these systems are amongst the most affected with human cancers. Prostate and breast cancer, which are the most frequent human cancers, were actually excluded from the Tomasetti and Vogelstein study. Spermatogenesis involves the presence of very active germ line cells in the testes, but testicular cancer is relatively uncommon. 

Whether driver mutations are produced in the same cell in the right combinations to transform it into a cancer cell may well be a matter of luck. However, there is little doubt from diverse epidemiology studies that life style has a profound effect on the rate that driver mutations are generated, and how the immune system can respond to a growing tumour.

@Steven, Many thanks for this excellent contribution! When it comes to cancer etiologies, there is the tendency to simplify when new data come to light which always leads to jumping to conclusions. Your summary clearly demonstrates that the complexity calls for a more humble interpretation of new data.

@Daniel, I am intrigued about the observation that people with immunodeficiency do not show dramatic increase of cancer incidence (unless virus-derived). Do I understand that this observation is based on a dedicated study on people with non-viral induced immunodeficiency?

@everyone, in the summary of the Science paper it clearly states:

" The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells."

This implies that in this case we cannot blame the sensation press from "overselling" the conclusions/interpretations. I think that the presented data in this paper are solid all right, but the conclusions drawn by the authors are premature and the peer review system clearly failed (yet again) to force the authors adding more nuance to their conclusions.

@ Jan

What is known is that immunodeficiency of many origins (including AIDS) leads to a strong increase in virus-induced cancers (mainly lymphomas and Kaposi sarcoma), but, to my knowledge, there is no important increase in the incidence of other cancers.

@Jan: It is a statement based what people have observed. It may hurt biotech companies who are developing diagnosis/prevention kits because the market becomes smaller. It may also hurt people who believe in mutagens because the factors became lesser important. But, based on the facts in the paper, people should rationally accept that most cancers are unlikely to be genetic diseases (for now). It doesn't change the fact that mutagens or other factors are influential. We just need to NOT so stick with the idea that the carcinogenesis is fully genetic. A bar code of DNA doesn't determine everything. The influence could be rare tiny. There are layers of layers before the actually spark takes place. A lot more need to be know before we really understand the tumor etiology.

The explanation in this article didn't incorporate the variation in breast and prostatic cancer. Does anybody know the number of cell divisions in this tissues?

Everybody is master of one's own luck (at least in good proportion).

We all knew that mutations in key genes are responsible of cancer onset.

Opportunities for mutations are everywhere, from cosmic rays to sun's exposure, but many mutations are in our hands through smoking, environmetal and occupational risks, nutrition poor of vegetables (antioxidants, fibers), etc. Some mutations may even go across generations and favour cancer development in families and descending individuals. What I do today in my life may develop into bad luck both for me and for my children. So, hoping in some good luck for all, I better think of my lifestyle and of my personal environment (just to prevent important consequneces).

With longer lifespans (in developed countries) this preventive attitude grows even more important. Prevention of mutagenesis is the key, in my opinion. This new study underscores with new data this basic concenpt.

I agree with Daniel that the media misrepresented the findings and the general public misunderstood the conclusions. This study shows something that was already pretty well accepted by experts in the field, mainly that tissues with higher cell division rates are more prone to developing cancer. I think there is still more work to be done to elucidate the relationship of certain environmental factors in the causation of cancers but I for one am not at all surprised by the findings in this study. As for public health implications I think that people feel slightly concerned that leading a healthy lifestyle may not protect them from cancer as much as they thought it might. However, there are other health benefits to leading a healthy lifestyle related to other health issues such as heart disease and diabetes.

I was also reminded of this recent article on healthy lifestyle and cancer risk and I'm interested in its implications related to the Science article referenced in this discussion: http://blog.aacr.org/sabcs-2014-bullet-breast-cancer-women-arent-using/?utm_source=social&utm_medium=facebook&utm_term=aacr&utm_content=guestpost&utm_campaign=meetings

The word "Bad Luck" is a bad choice of words on the media part. To most people, luck is associated with "fate"and bad luck in the case of inheriting cancer will make people stop trying to prevent it.....  We all know that cancer is an environmentally triggered "Genetic Disease" and that if we live long enough (100s of years) we will all develop cancer.  The error threshold inherited in our genetic mutations that may result in cancer development should be used as a measure to determine the amount Prevention/Intervention rather that Good/Bad Luck non-sense....

the blog pawel quotes of dr chagaal doesnt she think obese women may have visited pillar to posdt with obesity itself reaching epidemic proportions worldwide and every other day a new alternative is being looked for it to simply say the women dont take care of their diet or exercize is futile as obesity has assumed mammoth proportions and why do you think omne has to come with alternatives to bariatric surgery ,newer medicines and then endoscopic bands if it was so easy to keep a check on it..

Pawel, the paper states that tissues with higher stem cell division rates are more prone to developing cancer. That is more specific than higher cell division rates. The notion of just errors in replication causing havoc seems undermined when the observation only stands for stem cell division and not for division in general.

@tez makes a good point-if cancers can be divided into those which arise through bad luck and those where environment plays a major role (as in fig.2 of the paper) then the international variaation in Cancer incidene should be greatest in the latter type-is that the case?

In the article they do not take into account why some tissues have a higher stem cell division rate. Number of divisions is higher in epithelial tissue because these tissues have been developed to protect us from extrinsic factors. Therefore they give rise to carcinomas - which is much more frequent than cancer from mesenchymal or germinative cancers. If proliferation is increased as in chronic inflammation, smoking etc then risk of cancer is increased. Futhermore the article states 'that only a third of the variation in cancer risk among tissues is attributable to environmental factors". So the paper is not explaining the difference in absolute risk among populations.   

http://www.cancernetwork.com/review-article/chronic-inflammation-and-cancer

http://www.ncbi.nlm.nih.gov/pubmed/7977766

So many good comments here! It is a pleasure to read them and I can agree with most of what is said. First, let me be clear: I overall agree with the basic concept of the paper by Tomasetti and Vogelstein. Seems to make sense, does not contradict common sense and is in line with basic science. However, common sense is not equal to a scientific method or approach.

So, although I agree with the overall finding of the paper, the data the manuscript is based on are much more shaky than the authors may admit. For example, some comments in the manuscript are strange and can be disputed: “Another example is provided by melanocytes and basal epidermal cells of the skin, which are both exposed to the same carcinogen (ultraviolet light) at the identical dose, yet melanomas are much less frequent.” I doubt that melanoma is really rarer than cutaneous SCC and BCC when taking into consideration that there are far fewer melanocytes than basal keratinocytes. Furthermore, neither stem cell compartment is well defined in humans, neither the human epidermal stem cell nor the human melanoblast compartment.

So, what are these statements are based on? The authors perform a massive oversimplification stunt hidden behind fancy numbers of doubtful quality. Simple example from the Vogelstein manuscript and how they calculated stem cells for the esophagus: “The area of a squamous cell in the basal layer is ~80μm2 (69). The fraction of stem cells in the basal layer has been estimated to be 0.4% of the total basal layer cells (70), so there are a total of ~2.16·108 basal cells and 8.64·105 stem cells in the basal layer.” (70) is a mouse paper that mentions the word “human esophagus” zero times. The situation in human and mouse esophagus basically cannot be compared and the calculation is wrong. Human squamous epithelia are different from rodent equivalents since they have an extra stem cell layer. So every basal cell is basically a stem cell, plus a considerable number of parabasal cells. So, here the error is already 10 times. However, things are much more complicated if one wants to account for “stem cell proliferation”. Apparently, there is little agreement what and where the stem cells are in a given tissue and which stem cell population gives rise to the actual tumor, how often true cancer–originating stem cells divide. If you go through the supplements of the article one can probably find many such mistakes (the same mistake is made for the head and neck region in the calculations; also a squamous epithelium with a dedicated stem cell layer). Despite these limitations, I still think it is a very important paper since it puts math into cancer and stem cell biology, but I am not sure the math is correct. This has to be judged by people who are doing math and statistics for a living (http://www.statschat.org.nz/2015/01/03/cancer-isnt-just-bad-luck/)?

The paper illustrates that in general the numbers we have and the numbers the authors used could have been skewed, are shaky and don’t may not represent true conditions. Simple example: we can’t hardly figure out how many cells are in our body: http://www.smithsonianmag.com/smart-news/there-are-372-trillion-cells-in-your-body-4941473/?no-ist. Another example is the number of human villi: I could find this number for a long time. Without it, how can you determine an absolute number of stem cells and then an absolute number of stem cell divisions over a life time? The number for colon crypts or villi used in the study is 15 million. But the “references” are strange: “C. Potten personal communication” and a paper by Cheng et al. from 1984, which gives a rough estimate. These numbers could be right, could be wrong. Again, this could indicate that we have really very little ideas about the “math” of the human body. I just don’t think the numbers are there to calculate well the “stem cell divisions”. My “feeling” is that there is a lot of “bad math” in the paper. In the end I can’t judge this well. In the end, it is a math paper and I just don’t trust many of the numbers the math is based on. But that does not mean that the message of the paper is wrong. Please see related questions I had posed here on Researchgate that deal with similar issues (https://www.researchgate.net/post/What_are_the_absolute_numbers_of_villi_in_different_species; https://www.researchgate.net/post/Which_human_tissue_has_the_highest_cancer_incidence_when_normalized_to_size_of_the_organ; https://www.researchgate.net/post/What_does_Petos_paradox_really_mean_Are_mouse_tumor_studies_relevant).

When I tried to publish in this line, that the stem cell compartment of a tissue and its organization, quiescence and proliferation are key factors to understand tissue carcinogenesis rates and longevity, the reviewers just rejected it based on the fact that environmental factors are key drivers not endogenous factors such as proliferation rates within stem cell compartments. I think, the views of Tomasetti and Vogelstein are surprisingly poorly accepted in the certain parts of the cancer research community.

In regards to the claim in the paper that environment and genes cannot explain the majority of cancer: that depends on your point of view. Just using the raw numbers then there is no doubt that genotype/phenotype rubbing against the environment is the number one factor in cancer. Why? Because skin cancers are the number one cancers in the Western World. Why? Because of an unfortunate combination of phenotype/environment interactions: fair skinned people (genotype/phenotype) should not expose themselves too much to UV light (environmental factor). To be fair, this is a rather exceptional combo that does seem to reflect an extreme, and the authors acknowledge that. But it's a math paper and the majority of cancer is just by the numbers driven by the interaction of genotype/phenotype/environment (and anyways, isn’t there a thing called epigenetics that has dissolved the barriers between genotype and environment?). To give credit to the authors, it is doubtful that any other tissue shows such extreme genotype-based variation (skin type): Our colons are probably not as variable as our skins.

The issue with the “bad luck” terminology is tricky as well. I have had colon cancer when I was 35. You could call this bad luck, I prefer the term “freaky accident”. I also had “good luck” and my 50% chances to get away alive turned out to the better 50%. In the end “bad luck” is not a scientific term and “freaky accident” is neither. In private conversations I would probably use the term “bad luck”, reflecting on it scientifically, I would stick to terms (as Tomasetti and Vogelstein should have done and preferred not to do) such as likelihood or chance. My chances to develop cancer were low but not zero. Things happen, even unlikely things. The more unlikely they are, we start to call them accidents, bad luck or fate, or… Life is stochastic, isn’t it, inherently. Otherwise there would be no evolution, otherwise everything would be frozen: change is the only constant thing in life, and change does not always mean for the better, especially in life/aging from an individual’s perspective.

I think our genetic make up and food habits plays a important role in cancer initiation in our body. 

i liked the concept cited by Thomas Andl that ultraviolet light is shared by melanocytes as well as keratinocytes yet the frequency of ca differs in the 2 having the same stimulant  and then as far as the word luck is used regarding having ca WHAT WOULD BE BETTER IF somebody just gets quadriplegic when some standing truck is hit by some stupid drunken driver at uncontrollable speed and some poor fellow sitting in the stationary car develops quadriplegia/[araplegia as i know of some case -where would one say spending life be more difficult having a treatable ca or some debilitating condition where one can nor choose  and i agree one should not use the word bad luck  but as suggested freaky accident of nature in case of these cancerous changes in stem cells etc.

I think there is no place for luck in the development of cancer.some drivers are well known by those who got some types of cancer such as smoking in lung and bladder.many voluntarily choose the answer although aware of risks and consequences.yet others got itinherently .many due to the life they choose.others socially or economically .but in all itis genes that say yes or no

Hello

The two-thirds figure comes from the correlation coefficient between stem cell divisions and cancer incidence. While it is the case that the former explains 65% of the variation in cancer incidence between tissues, this does not translate to a percentage of cancer cases. This data is plotted on a log-log axis, and so distance along the plot is not linear. As the cancers with clear environmental factors are more common,I am sorry if I disappoint you , but the basis of Vogelstein is that cancer is caused by mutations, but if something is based on

5% of cases, it already reveals, that this cannot be true. The major problem is that the reality is not looked at: 5-10% by mutation ,15% by infection ANDsome 80% of cases are still (since 85y) sporadic, meaning unknown cause

Second, while this correlation might explain variation between tissues, it does not suggest the source of mutagenesis. Any factor that had similar effects throughout all tissues would vary this plot on the y-axis but have no effect on the correlation. Notably, as the data is plotted on a log axis, even for tissue-specific toxins many fold changes in the incidences of these cancers would still have no effect on the conclusions of this study.

Additional failures of interpretation in this study suggest little understanding of the data analysis involved. For example, k-means clustering a single variable lends little insight, and with outliers on either end is sure to form two groups with separation near the center of the range. This provides no evidence of there being two "classes" of cancer.

Although in agreement with many of the answers given, I have great confidence in the quantitative approach in biomedicine. The analysis made by Tomasetti and Vogelstein is premature simply because the analyzed data are not complete. Only now we are realizing something more about cancer and our knowledge is still limited. The parameters to be analyzed are numerous and probably many are still unknown. Any quantitative analysis, performed on a data system not adequate, can say everything and its opposite. We will probably have to wait to get a more complete picture to be analyzed, so that we will not speak of good or bad luck, but of statistically significant numbers that make sense because the data to be analyzed are complete in every respect. Certainly we will be constantly amazed in the future by new discoveries that we are not yet able to predict. Common sense should avoid this type of analysis that however is still a good attempt to make the medicine quantitative, but only as a demonstrative exercise.

Thanks Mesut for citing Hippocrates: of course his statement stands through all times. Surely we can speak of bad luck as long as we lack thorough knowledge on the matter. Indeed the key here is the lack of adequate knowledge on ~80% of all cancers and I call on everyone to read the BMC Cancer paper by Brucher and Jamall that was attached by Saleh. Thanks Saleh for your valuable contribution!

I do not dismiss the data from the Tomasetti and Vogelstein paper, but I do dismiss the jumping to conclusions that I allege these authors (and the Science editors and their peer reviewers) being guilty of. The paradigm described by the Brucher and Jamal paper seems much more plausible and all data (including the data from this Science report) fit nicely into it.

Any thoughts on dividing stem cells vs dividing non-stem cells?

There is another important error, which is not obvious at first sight, concerning the percentage of cancers related to genetic inheritance. The authors say that it is low, according to their data, but this is true only if genetic inheritance leads to a specific type of cancer, which is generally not the case.

The truth is that, depending on genetic inheritance, the likelihood of having a cancer can somehow vary. Then, estimating the percentage of cancers related to genetic inheritance is simply impossible.

As an example, if a minority of individuals are protected by their genetic constitution (for instance, they have a three times less probability of cancer), then one could rightly say that the majority of cancers are related to genetic inheritance. Pure speculation?

Then have a look: http://www.ncbi.nlm.nih.gov/pubmed/10506723

In conclusion, the Science paper is right and original, but the part that is right is not original, and the one that is original is not right.

Virtually everything about life is dynamic, so are the processes that define us as humans. While as scientists we claim to 'know so much', it is this same 'wealth of knowledge' that exposes our 'dearth of idea' of what indeed is the truth, so we strive to want to know more... in the name of research!

'Luck' as a factor in the development of certain disease conditions would only be true if we all are born the same (in terms of genetic and phenotypic characteristics), grow in the same place, subjected to same treatment (nutritional, environmental, educational, etc) and make same choices in life. Because such a state is impossible, we would forever continue to look for answers to those things that seem to defy our reasoning as humans. All seem to be a matter of chance, and if this is what is meant by luck, so be it. 

Among many cogent observations is a necessary distinction between the origins and ultimate manifestation of cancer. The implications for both early detection and treatment of the manifest disease are obvious and profound. The paper is published in science, which is - at least to me - not automatically synonym of excellence. Someone may remind us that the paper (unortunately) did not take care about reality.

Reality is the following, Cancer is triggered in

1) 5-10% by mutation

2) 15% by infection AND

3) 80% are (since 85y) sporadic, meaning unknown cause

This means, the starting point of the paper took 5% of cancer cases as its basis into account; therefore the results or conclusions cannot reflect truth.

Why is not someone asking: what about the mass of cancers, the 95%?

It is a major difference if mutations are found in

-advanced tumors or if they trigger

-carcinogenesis.

Everyone finds mutations in advanced tumors as carcinogenesis already occurred.

It makes very much sense, that mutations being the cause triggering carcinogenesis are increasingly questioned [Rosenfeld S, Cancer Inform 2013, 12:221–229; Versteeg R, Nature 2014, 506 (7489): 438–439].

You may be interested reading the following:

http://www.biomedcentral.com/content/pdf/1471-2407-14-331.pdf

And some more deeper explanations:

http://www.karger.com/Article/Pdf/362978

Further it is quite interesting, that since this week one significant step of the newly proposed sequences in carcinogenesis had been proven:

Nature 2015:

http://www.nature.com/leu/journal/v29/n1/full/leu2014260a.html?WT.ec_id=LEU-201501

From the abtract, "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 predisposition" Now, if one is not a careful reader one might infer causal information from this description. There could be a factor X so that every cancer case occurs in somebody with exposure to factor X. It could further be true that there is 100-percent correlation between number of cell divisions in a tissue and the lifetime cancer incidence (an aggregate measure). In this case all of the variation in cancer incidence is attributable to variation in cell division, but that does not preclude factor X as a cause.

It is well established that micronutrient deficiencies can mimic radiation or chemical damage to DNA that is commonly associated with malignancy. Moreover, it is amply demonstrated that nutrition has a strong preventative role in cancer and our studies showed that it even has curative effect in some cases.

One might say that it is a bad luck not to have proper nutrition but this argument cannot be considered with any seriousness.

Article Cancer: A single disease with a multitude of manisfestions?

Excellent question and responses throughout this great blog. I need to interject that the studies that say cancer is by chance are using the wrong baseline for what would qualify as "optimal health". Indeed in a world fraught with radiation, toxicities, the dramatic disappearance of essential micronutrients optimal is the only way for one to avoid secondary diseases like cancer. Cancer does NOT happen in a vacuum, of course, and while there are some wild cards in genetics, we have to ask what caused the wild card damage to DNA--for sure, understanding the human body as we do today ("we" being those who rise above the norm of the lowly allopathic view) know that the best doctor in the house is that organelle of foreign origin, Mitochondria, which has to have a genetic code translator called RNA to even be able to read out DNA. So exacting is MItochondria's work that if you file off the fingerprint from your index finger being careful not to get it infected you will see...your fingerprint restored in immaculate form within about 72 hours...compliments of your MItochondria and its energy byproduct called ATP. To say cancer occurs in a vacuum, on its own without provocation, or other primary detriment to the body exposes a profound ignorance of how the body maintains itself and how cancer sneaks into the hinterlands where there are no phones, electricity, no civilization for miles around and grows quietly, often slowy and insidiously, until it becomes a threat to its host entity and is discovered.   

here i agree with max chartrand that our environment is fll of so many carcinogens and with industries throwing chemicals directly into water how does one prevent cancer even if diet is taken care of  for eg people working with lead or other chemical factories get exposed to lead,people in ceramics,road building to strontium,and so on and so forth and then genetic and epigenetic alterations which go by it is bad luck since the person was involved in that job.

Very interesting discussion here. Many good thoughts on the topic. To be fair Dr. Brucher the effect of the source of IL-6 in our studies (Leukemia article referenced in your comment) was examined in the presence of manipulated genetics in the B cells that became plasma cell neoplasms. Mutations thus played a key role in the development of the mouse neoplasms. Certainly the microenvironment played a key role too – dramatically altering the kinetics for mice developing tumors.

My apologies for only taking a quick perusal of your BMC and Cellular Physiology and Biochemistry papers. Based on what I saw though, I think your ideas have merit. I specifically like the idea of how the altered state of incipient cancer cells (such as residing in an inflammatory environment) can promote tumorigenesis. Further, I like the call to better understand these circumstances in light of prevention. Dr. Brucher, I am curious why you juxtapose “sporadic” cancers with ones with mutations. Am I missing something because I don’t think that sporadic means that the cancer is not associated with mutations?

As many in this discussion have eluded, cellular life in a physiological context is so dynamic and little understood that couldn’t it be that mutations (drivers OR combinations of passengers that alter the state of the drivers at any moment of time – backseat drivers perhaps) in incipient cancer cells are induced or primed or even just have their effects amplified by what is happening in the microenvironment at any moment of time? I think it is most likely that all of the above can and do occur.

The article by Drs. Tomasetti and Vogelstein is provocative, makes some sense, and is a useful new way to look at cancer. However, I think it is an oversimplification of reality (discussed well by Dr. Pelech and again by Dr. Brucher among others here) and appears, to me, as a bit overzealous in the interpretation of the extra risk score (ERS) results. This ERS is perhaps a bit incestuous – based only on the lifetime risk and total number of stem cell divisions. Perhaps this may be a way to rank the potential influence of stem cell division as it relates to lifetime cancer risk by tissue type, but it does not necessarily relate to the influence of other causative factors. Seems like the inclusion of some value from studies that measured the influence of other causative factors would yield a more reliable factor, perhaps as a subset analysis (not sure what this would be off the top of my head - perhaps including a subset of lung cancer in smokers and/or geographic distribution of those with basal cell carcinoma, stratified by number of sun-days or self-reported sun-exposure??).

Couldn’t the number of stem cells and the number of times they divide also be influenced by other factors (environment)? Isn’t it also possible that the stem cells themselves could act as a type of “environmental” factor – setting up an environment that enables the outgrowth of cancerous cells that have not necessarily arisen directly from the stem cell compartment? In this light, and in agreement with Dr. Brucher’s work, I do not agree with Drs. Tomasetti and Vogelstein when they mention “For R-tumors, primary prevention measures are not likely to be very effective…” We simply don’t know enough yet.

I concur with Van's tumor/inflammation connection and other comments.

Very good points by @Max and @Van

I agree, that inflammation initiated by a biological or chemical stimulus as one sequence reflects a significant trigger, but inflammation is not inflammation, therefore chronic inflamation is needed as recently proven some days ago in the above mentioned Nature paper, and it is of importance that consecutive remodeling of the extracelular matrix with stimulation of fibrosis plays also an significant sequence for further sequences:

http://www.biomedcentral.com/content/pdf/1471-2407-14-331.pdf

Further here some deeper explanations:

http://www.karger.com/Article/FullText/362978

We could say that prolonged stress and inadequate nutrition are the two major causal factors in the genesis cancer. Genetics is tertiary although presently overemphasized in significance. Life-style factors work together with genetics in determining the expression of specific genetic traits and tendencies for disease.

It is indeed a bad luck living next to a toxic dump site, drinking contaminated water, breathing polluted air, eating chemical laced, nutrition deprived food produced in a mineral exhausted soil. So I congratulate the authors to add bad luck to this already well-recognized other risk factors for cancer.

Peter hit a lot of nails on their proverbial head. I might add that the absence of micronutrients as they occur in nature are immensely more contributive to oxidative stress and inflammation than the macro nutrient deficiencies.

Bjorn raised the chronic vs acute manifestation of inflammation, which when we look at the proinflammatory vs anti--inflammatory cytokine effects, chronic inflammation that inspires long-term proinflammatory cytokines is the most damaging in terms of cell abnormalities.  

Mesut, this would be a very untrue explanation...

Yes, just because we do not investigate a patient's case enough to come up with a clear answer does not mean it was just dumb luck. I think that Mesut was saying that in jest. But I do want to remind all that it is our duty to find out why patients get cancer and how they can reverse it. If we start with the basics (dehydration, acidosis, polypharmacy, high caffeine, micronutrient deficiencies, heavy metals, unhealed injuries, subclinical infections, lack of sleep, smoking, food additives, environmental toxins) we will likely find an answer, and by having an answer, a solution.  

Most of the above comments agree with the spirit of a recent research on the topic, carried out to give a biological explanation why some tissues are more likely to transform themselves in cancer tissue than others. The methodological approach can be considered correct and interesting. But the conclusions open space to criticism. So that the conclusions could be syntesized as in the Hamlet: “To be (lucky) or not to be (lucky)? That’s a question”. Strong genes alone don’t answer the question as well as the number of divisions. Cancer is still a complicated condition in which a lot of different substances and circumstances can act alone or in various combination with a pathogenetic role (lifestyle, occupational conditions and risk factors, genetic and inherited factors, etc.). So that, instead of classifying people (or tissues?) into “Lucky” and “Unlucky”, it should have been better to talk of  lucky or unlucky combination of factors in the lifetime. Among the environmental (co)factors there are no informations about occupation and risk factors (agents, time of exposure, etc.) in the paper.

I can refer of nine pulmonologists (7 males) daily exposed to ionizing radiations. Seven different cancers in different organs were diagnosed to five of them (two with two different type of cancer). The subjects were comparable for age, lifestyle, diet, years of exposure, absorbed radiation dose. Only three (males) out of nine were smokers. Also comparable with no difference was the time interval between the end of the exposure to ionizing radiations and cancer diagnosis.

What to state? Were these subjects preselected as “unlucky” when they started working in the Department? Or were they lucky initially before starting working there and that specific risk was a misfortune for most of them?

Reading reports in journals not specifically devoted to Occupational Disease, very often the occupational risk is underestimated or not evaluated at all. It is misleading in most of the conclusions.

The authors of the paper tell us “how” a number of people is “lucky” but not “why”. Recalling the brief history of the five “unlucky” pulmonologists I have just reported above, the answer is simple: they had their film-badge on their white coat, but they hadn’t the red horn (good luck amulet) in their pocket, to reject the Misfortune. As the Neapolitans well know.

The moment I heard of this study and its conclusions I thought there was something fundamentally wrong with the interpretations many people (including the authors) were putting on it.

I have been writing, for many years, about the whole process of tissue homeostasis (or morphostasis) and immunity.  These ideas can be easily found on the web. 

One of the earliest observations that my musings on cancer led to was this prevalence of malignancy in tissues that had a high cell turnover. That is, the probability that cancer will occur in tissues is heightened by an increased mitotic activity. But that never tempted me to reach the same conclusions as the authors of (and many commentators on) this paper.

The first observation to make is that the paper seems to assume that the old prevailing explanation of cancer is right. It is a disease CAUSED by cumulative genetic mutations; once the right set of mutations has occurred within the same cell, the cancer is initiated and becomes unstoppable; end of story. A recent editorial in Cancer Research critiques this (doi: 10.1158/0008-5472.CAN-14-3532).

There is little doubt that genetic mutations are generally NECESSARY for the seeding of cancer but this does not, in any way, make it SUFFICIENT. The authors of the paper talk of tissue homeostasis but do not, to my mind, follow this through. It is around this that I think that they are extrapolating wrongly with the information that they have gathered. I believe that the vast majority of potentially malignant cells are dealt with efficiently by a tissue homeostatic system (by immune cells and inflammation). Only a small percentage of these “break out” into clinical cancers (CIN in cervical cancer is one example). The circumstances that allow this to occur are increasingly being attributed to non-resolving inflammation and the two edged sword of the immune system; this can both attack and protect cancerous cells (miscreant stem cells). The protection of stem cells by immune tolerance is a crucial necessity during the regeneration of tissues.

What the study DOES support is that the supposition that those tissues most prone to high mitotic turnover are, indeed, the tissue most at risk of seeding clinical cancers. It says nothing whatsoever about the origin of this accelerated tissue turnover. Indeed, it seems to leave this floating in the air and without comment. There are two factors that would affect this turnover. The first factor is a reactive response to tissue damage (due to various noxiae), with its consequent auto-rejection of miscreant cells that is then followed by cell replacement via stem cells. This will be influenced by many factors including genetic predisposition, environmental agents, infections, repetitive trauma and other modulators. The second factor is the likelihood that a pre-emptive shedding of epithelial tissues has emerged as a useful evolutionary strategy to slough off damage prone tissues.  But this would have developed in response to a high exposure to environmental noxiae throughout aeons of animal evolution.

The critical point is this. What proportion of malignantly transformed cells go on to seed clinical cancers? If they all do, as the old paradigm might suggest, then the extrapolations into simple “bad-luck” (really just a metaphorical roll of the dice) might indeed be a warranted conclusion. However, if a majority are dealt with and disposed of by physiological tissue homeostasis then the final emergence of clinical cancer is overlaid by a plethora of circumstances that are not solely influenced by a suitable cascade of chance genetic mutations. The latter may be necessary but they are not sufficient.

The emergence of chronic inflammation, as a pretty much universal precipitant of clinical cancer, strongly supports the failure of effective tissue homeostasis as the final arbiter in the onset of this form of disease. This failure is not necessarily (or even probably) the result of genetic mutation.

That’s my two-penn’orth. There is a little more in Unpublished/Other thoughts at my web site.

Andrey brought out the mind/body component, which is absolutely a critical factor to bring into any coherent discussion as to causes of abnormal cell divisions. We see the inverse of that manifested in those who, with a more positive frame of mind, go into remission. 

One thing is certain; the paper by Tomasetti & Voglestein has challenged our thoughts re possible origins of cancer and stimulated many comments. Thanks Jan.

Considering that we are a dynamic, mega-cellular system, it is impossible for me to contemplate that we would be alive and able to have this discussion if any aspect of our internal biochemistry and genetic expression was based on chance and luck; any more than a modern airplane could depend on luck and still be a reliable way to travel!

As noted by others, it is not surprising that the incidence of cancer increases with a greater number of stem cell divisions since the number of divisions increase as we grow older and there is an undeniable age factor in the incidence of cancer. While I don’t see that the “Variations in cancer risk among tissues can be explained by the number of stem cell divisions” I recognize that cell division most likely plays an unrecognized important role in cancer initiation, i.e. recent research in the fast growing field of inquiry into asymmetrical cell division is showing that stem cells are asymmetrically proportioning faulty organelles and misfolded protein conglomerates into the daughter cells This leads to one daughter cell with the ‘garbage’ and the other with more functional organelles and proteins.

http://www.ncbi.nlm.nih.gov/pubmed/23681659.

In considering the known factors affecting glycolysis as shown in table 1 of Harguindey’s 2013 paper

http://www.impactjournals.com/oncoscience/files/papers/1/109/109.pdf,

we can easily recognize many factors that in spite of considerable homeostatic control, are shown to be out of norm in many diseased states. We recognize that many of these factors change with age, nutrition and psychological stress inputs. For instance, cancer cells have been shown to be deficient in Mg, K and Se along with increased levels of Na and Cl. These ionic influences, along with known and measured vitamin deficiencies, physical, toxic chemical insults, etc. can lead to major cell challenges, not even taking into account the effects of Bruce Ames’ triage theory or the response of our cells to the constantly varying levels of all cellular metabolites.

http://www.anaboliclabs.com/User/Document/Nutritional%20Foundation%20Articles/Ames,%20triage,%202006.pdf ,

In addition, we are now recognizing that there are endogenous bioelectrical networks that provide non-genetic patterning information during development and regeneration of our cells.

http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.271940/pdf

If we consider the collective possibilities of just the above interdependent actions along with simple Michaelis-Menten biochemical kinetics, the different membrane potential that we find among tissues and the inflammation that has been observed in cancer, I do not think it too hard to imagine that there is much that is under appreciated with respect to variations in cancer risk among tissues.

So while it is difficult to come up with a simple scenario that could explain cancer and its phenotypic expression, there appear to be many clues that will eventually lead us to understand that cancer is quite likely to form in 'a given cell' or group of cells in a distinct tissue such as the breast or prostate that are being overstressed, possibly due to substantial fluctuations in normal hormonal levels.

In considering the many possible biochemical insults that our cells are subjected to on a daily basis, I only envision resolution or an altered genetic expression and/or alternative pathway activation, leading to the cell's 'most appropriate' feedback control to meet the challenge. This ‘unfortunately’ can lead to cancer or other non-communicable diseases.

 There are many methodological issues with the paper, but I will focus on inclusion of points into the dataset. There are 31 “types” of cancer presented in Figure 1. “Type” is not a well-defined unit of analysis. It is striking that osteosarcoma is presented as if it were 5 different “types” when in fact the authors simply assume that all bone is the same (i.e. the number of stem cells is proportional to bone size and they all divide at the same rate). Thus, by the same logic one could divide leg osteosarcomas into femur, tibia, and fibula sarcomas (the data is provided). Also why not left leg osteosarcoma vs. right leg osteosarcoma? It is also curious that there is a separate point for osteosarcoma (not differentiated by site). Likewise it is curious that lung cancer is presented as two different “types”, one that occurs in smokers and one that occurs in non-smokers. Presumably, this is to account for the fact that smoking is highly associated with lung cancer. But again, having divided lung cancer into two “types” why not five depending on the total pack-years? And having divided lung cancer into the smoking and non-smoking type, then why not divide other cancers the same way? The authors seem to believe there is a threshold of important environment or genetic effects that matter and presented them as separate types (no matter their population frequency) while at the same time they lump all cancer incidence occurring in a different tissue. This separation of important environmental/genetic causes is striking because at the end of all of their analysis they identify 9 types of cancer that are environment or gene linked, and 6 of the 9 were a priori different and had excess risk at the beginning of the analysis. The authors conduct a correlation analysis and regression analysis using these 31 separate cancer “types”. Clearly, the analysis depends on two very non-random choices in selecting cancer “types”. One of the choices (i.e. to separate out osteosarcoma as five different entities) will inflate the correlation because of double counting and will strongly anchor the left end of the line. The other choices, made by separating out important environment/genetic causes, give the illusion of accounting for all environmental/genetic sources while in fact making sure that other non-included environment and gene exposures would only contribute when they have tissue-specific, not global effects, and that these effects are not off-set by measurement error. One cannot quantify the amount of variation attributable to X if it has not been measured and included in the analysis. Summary estimates (as the authors have used) will miss other sources of variation, thus one cannot use the residual variation as the upper bound for amount of total variation due to X. Thus, while the authors make claims differentiating model-based variation (attributable to cell division and random mutation) and gene/environment variation this estimate is seriously limited by the information they put in the model and choices they made constructing the model, and should not be considered as an informative answer. Figure 1 does however present a rather nice descriptive picture of the general relationship between cell division and cancer incidence, but inference should be limited.

Many thanks to Jamie Cunliffe with his great contribution. This IS the big question: Is the majority of malignancy been cleared in a healthy system, and do we only get clinical outcome when there is something wrong with the homeostasis? If so, the bad-luck paradigm is a mere prerequisite. I like to think so, because it brings all contributions and theories together, and it makes the disputable figure 2 of the Science paper of less importance. Homeostasis is known to be heavily influenced by the environment and by mental state. this is where stress, pollution and nutrition come in to play. It also explains why traditional chemotherapy needs to be banned (sorry to bring this up, need to get it off my chest (pun not intended)), as it destroys the very system that may cause a patient to go into remission. Then, rather targeting cell division, it would make more sense to interfere into the system that fails to clear the malignancy and fix that. This requires much more fundamental science than currently takes place. A shift in funds will be necessary to shift the emphasis from wasteful trials to fundamental research into systemic biology and into homeostasis and immunology at molecular level.

Indeed Andrey, in fact most contributors together bring us to this point. Let me take this opportunity to express my deepest appreciation to all who contributed thus far. So many have pointed out very interesting points of view, and they all contribute to a better understanding of where we are in our fight to our greatest enemy, cancer.

I look forward to more contributions, it is also a great way to meet more interesting scientists and specialists and new fresh points of view. Sometimes we need to say things that not everyone likes to hear, but it brings us forward.

The notion that somatic mutations are a causal event in the transformation of a normal cell to a cancer cell is fatally flawed. Please see Prof. Brucher and my paper from May 2014 for details on our view:

http://www.biomedcentral.com/1471-2407/14/331

If one goes back and examines the cancer data from Hiroshima and Nagsaki, they too, do not show mutations as being pivotal to cancer.

A very interesting discourse. Thumb up for everyone who has contributed. I wish you all 'good' luck!

a very good point @Mesut:

if someone stays honest and critica, he would ask the question: if the incidence of gastric cancer rates in Korea are 4-times fold higher than in Russia, why should be mutations the reasons? 

It is a difference if

1) we find an observation and how someone consecutively produces conclusions:

"An apple found in a car is not synonym of prove, apples grow in cars"

Saying so means: if we have an observation it is also not synonym of prove, it is the cause of something and this exactly happened during the last 4 decades in regard to mutations and declaring tem as "the" reasons causing cancer. Take the molecular findings of the 90ies. If we find an increased expression of TS, TP or DPD in tissue of squamous cell cancers, than this means at first: the expression rates are increased in a proportion of tissue samples. It would be wrong declaring: squamous cell cancers are triggered by increased TS, TP or DPD expressions.

One major reasons may be, that our knowledge explodes and by this an increasing number of scientists read receptively only, because they try getingas much information as possible, but unfortunately do not think about the content.

2) If we find an increased rate of mutations of this or that protein / molecule in advanced cancer tissue, than this means at first: in advanced cancer tissues an increased mutation rate of this or that molecule is increased.

It would be - as it is done since some decades - wrong, making the conclusion that such mutations cause cancer, because at first it is an observation and not a synonym of prove mutations cause cancer. 

3) If we know or assume, that this or that molecule results in this or that effect.

Professor Vladimir Matveev recently bloged at the web group of the Theodor-Billroth-Academy a blog of a molecule, that destroys apoptopic cells BUT which also repairs damaged axons. It supports the findings in embryology, when a protein changes its function during embryogenesis to an opposite function (by only adding a little molecule). This means, it opens opens a complete new book: the multifunctional habit of molecules, which for sure had been completely underestimated within the last decades.

4) Carcinogenesis is completely different from investigation in cancer - both are different and by this: findings in cancer tissues are observations primarily and do not automatically attribute to carcinogenesis.

5) As Dr. Ijaz Jamall recently pointed correctly out: if someone attributes cancer to bad luck may promote a more lax attitude to environmental/lifestyle factors that increase cancer risk such as smoking, sun exposure, tanning beds, etc.

6) Just because Vogelstein does not have the explanation of carcinogenesis, I do not see, why his view "bad luck" should be logical - maybe this is my bias, but this makes no sense. If a view is based in general on some 5% of cancer causes, it is wrong overtaking this view onto the mass of cancers. 

7) Take BRCA mutations and breast cancer: only some 8% of breast cancers are triggered by such mutations, what about the 92% of breast cancers? The rate of mutations causing colorectal cancers are between 3 and 5% and in gastric cancers the rate is even below 1%. This means: 90% of cancer funding is invested into some 5% of cancers.

By this, mutations being the cause triggering carcinogenesis are increasingly questioned [Rosenfeld S, Cancer Inform 2013, 12:221–229; Versteeg R, Nature 2014, 506 (7489): 438–439]. This reflects as it was pointed outaboe: Vogelstein's views do not reflectthe view of the scientific community.

--------------

Lets think about two things:

I. Observation: anti-inflammatory drugs increasingly show an anti-cancer effect. So, if the mutation theory would be (for the mass of cancers) correct, why would be anti-inflammatory drugs effective?

II. There are many cell types (e.g., skin and gastrointestinal epithelial cells) that multiply faster and undergo more cell divisions than your average cancer cell but do not go on to necessarily develop cancer - Why?

To me it seems more important that we may stop reading receptively, and increase our critical and blinker-free thinking and exchange, instead of overtaking opinions, although such mutated to dogmas within the last some 50 years. If someone sends someoe a link or a PDF the result is (by now) that the abstract is read and the people think, they know something of the scientific content of this paper. THis maybe rght for some 40% of papers, but not the rest. It is not enough anymore to read the asbtract and by this to overread the paper, people need increasingly thinking about the content of papers again.

@ Björn: While I agree with most of the points raised I would add some more points.

Is it possible that, environment aside, Russians and Koreans have different haplotype in the population which give them a greater risk to develop one type of cancer over another? In which case, the population on average may  be inheriting a set of SNPs which predispose them to one type of cancer more than to another and might be considered "bad luck".  Also, is the overall cancer rate among Russians and Koreans the same? What is the environmental factor that causes Koreans to get gastric cancer at a rate that is 4X higher than Russians? If Russians moved to Korea, and Koreans moved to Russia, would the gastric cancer rates of these immigrant populations mimic that of their ethnic group back at home or of their adoptive country?

1. I agree with you here but, if you did not know apple trees existed and found an apple in every single car you looked inside, you might think apples and cars are somehow linked :)

2. True. Some mutations in late stage cancers are related to tumour maintenance rather than tumour formation. One could always test the transformative ability of said mutated protein rather than assuming it is cancer causing.

5. Living a healthy lifestyle also impacts on non-cancer related diseases like heart disease and diabetes so information about the benefits of leading a healthy lifestyle do not need to be focused on cancer regardless if you believe a majority are caused by "bad luck" or not. People who have a lax attitude will always look for excuses anyway and those that are committed to living healthy won't suddenly drop what they are doing.

7. Perhaps a portion of the remaining 90-95% (minus the viral infection related) of cancers have non-coding DNA alterations which we cannot yet determine to be cancer causing? I think in a lot of sequencing studies which look at cancer genomes, we ignore for the most part, non-coding DNA because we do not have as good of an understanding about the effects of non-coding DNA variations in cancer as we do for oncogenes and tumour suppressors. The non-coding DNA field is still maturing.

thanks @Pawel, good insights and also @Mesut thanks for answering. As Mesut stated correctly, we are aware of the findings, after Japanese citizens moved to the US and their risk changed. 

An apple is an apple and we had it too long, that too many declared observations with wrong conclusions, and what made me sad, when I found out about this: this is contraproductive for patients and their relatives. I do not say, that having research in terms of mutations is not necessary for understanding biology, but we should not act as Pinguins anymore (one jumps - all others follow).

ad 5): yeap, that is also quite interesting. I read last week the following paper - we may both imagine, what this could mean, although of course it (at first) needs being reproducible: 

http://link.springer.com/article/10.1007%2Fs00213-014-3810-0#page-1

ad 7: you may read te section we write in both papers in terms of mutations / polymorphism and genomics

I forgot: everyone is heartly welcome joining he web group of the Theodor-Billroth-Academy at Linkedin, here you find more blinker-free and open minded discussions about science and research of any subject incl.biology / biotechnology/ health care, surgery,surg.oncol, oncology, radiation, etc etc as well as ethics, leadership - or send me your mail to [email protected] and I add you and send you the mail from linkedin

thanks again to everyone - highly appreciated

So today I stumbled upon an article (http://www.thestar.com/life/2015/01/13/black_women_more_likely_to_die_of_breast_cancer_study_says.html)  which I think might be interesting to those following this question. As you know there have been some examples and discussions about cancer rates in Russians/Koreans (who is luckier) related to where they live (environment) and some additional examples were given related to Japanese risk to cancer when living in Japan versus those in Western countries...and of gastric cancer rates of Polish and Portuguese living in the US (see some of the previous comments/discussion).

So this new article from JAMA (http://jama.jamanetwork.com/article.aspx?articleid=2089353) looks at cancer survival rates of women diagnosed with breast cancer in the US based on race and suggests that race plays a role in a patients risk of succumbing to the disease when controlled for things like early diagnosis. Even early detection of stage I beast cancer showed a difference in survival based on race. Does "bad luck" play a role in terms of some sort of underlying biology that makes certain cancers in one race more deadly than in another - because in this case the environment would have been more-or-less the same (living in the US). I don't know if there is a difference in the rate of breast cancer in the different races living in the US, but another interesting article to add to the discussion on "bad luck" vs environment.

@Mesut: "Gastric cancer incidence was 41.8 per 100.000 in Korea , on the other hand, 16 per 100.000 in Russia. Are Russians luckier than Koreans?"

No, but we do know that alcohol in high doses can act to promote or facilitate cancers (http://www.ncbi.nlm.nih.gov/pubmed/9751943). I would assume that South Koreans drink more alcohol than the Russians and, if that were true (http://www.dailymail.co.uk/news/article-2551059/South-Koreans-drink-TWICE-Russians-five-times-Brits.html), it might explain some of the discrepancy in gastric cancer rates between the two populations . 

Pawel, there is certainly an ethnic aspect to the risk of cancer, in particular with breast cancer (for example BRCA1/2 carriers). However, the way statistics are carried out to assess leaves some room for criticism, see http://www.ncbi.nlm.nih.gov/pubmed/21358336

Breast cancer is one of the most complicated types of all cancers, because there are so many different kinds of breast cancer (see http://everestbiotech.com/overview-breast-cancer/ for a "simplified" overview). We simply cannot put all breast cancers together and address risk factors. Probably the same is true for other tissue-types.

BRCA1/2 carriers do run an increased risk of obtaining breast cancer. Before we knew this, one could speak of bad luck when you were in that risk group. Now, we can take measures to prevent cancer for this group of patients. Lucky when you opt for breast amputation after being identified to be a carrier???

I agree with you Jan that its complicated with many subtypes - and yes many cancer are complicated in this manner. Lets not include BRCA1/2 carriers which for sure are enriched in some ethnic groups. If they constitute 5% of breast cancers then lets look at the rest. If the remaining sporadic cases are different based on race (http://www.cdc.gov/cancer/breast/statistics/race.htm) and all of the individuals live in the same environment (again the US), then the differences in their risk for developing breast cancer might be explained by a genetic predisposition based on SNPs (haplotype) they are more likely to carry based on race. If one assumes an equal underlying mutation rate it breast tissue based on race (which seems reasonable) - then seeing a predisposition to one type of breast cancer more so in one ethnic group than another suggests a non-environmental factor to explain those differences. Even if you look at the data from the link you provided based on subtype: "The triple-negative (TN) subtype (defined as ER−, PR− and HER2−) comprises 10–30% of all invasive breast cancers. However, this estimation varies dramatically depending on race/ethnicity". So if it varies based on race/ethnicity but in a population that lives in the same environment, it looks like the difference in the risk is based on "what your momma gave you" and if that isn't based on "luck" then I don't know what is (again I define "luck" as something intrinsic to the biology of the individual and not an external environmental carcinogen).

Interesting discussion, please allow me 2 questions:

(Q 1)

Is the observation that BRCA mutations are found in some (advanced !) 8% of breast cancers synonym of prove, that such mutations caused the cancer?

(Q 2)

Should we concentrate on 8 or 92 % of cancers for making a difference in the future?

Bjorn L bRUCHER GAVE A LOT OF FOOD FOF THOUGHT regarding if only 5%mutations for a particularly cancer are implicated in causing that cancer then we are wasting our resources for looking for the same mutations in rest 92%cancers say in breast cancers ,and yes we dont give a thought regqrding how rapidly proliferating cells in verious gonads which are constantly entering the G and S phase do not enter the malignancies say for follicular development or spermatogenesis or the endmetrium which undergoes cyclical proliferation and shedding as tumor suppressor genes are there to protect and hence one has to give importance to the basic immune system and of course importance to the entry of known viruses like HPV etc which are known to cause a transformation in the genome and stimulate malignant transformation but just goin g by a very small number of known mutations in a given populaTION ONE CANT GENERALZE it as the iportant cause for that cacer asc2%cancers dont show them and just by concentrating on them one would be missing these 92%population etc

Valuable comment, thanks @Kulvinder, because of your insights, allow myself another 'small' question, in terms of infection triggered cancers:

Do such (e.g.HPV infection) initiate

(1) a transformation in the genome "after" carcinogenesis occured

(and we just measure it - but in reality it is just an observation or makes the tumor later on aggressive)

(2) or before a cancer is established

This is one major question, as this reflects: epiphenomena and secondary mutations or primary cause.I know the answer is disappointing, and believe me, Ijaz ad myself had a very hard time, realizing, that observations had been declared as being the prove within the last some 30 years by the majority of papers.

And if you, what Ijaz and I did, review crticially the last 250 years of cancer literature in detail, you will not find a prove that such mutations caused cancer, but of course you will find mutations in advanced cancers, as they occur in te mass o cancers "AFTER" carcinogenesis.

Here it is extremely important to differentiate an observation per se versus a prove, that something causes something.

"An apple found in a car is not synonym of prove, apples grow in cars"

But many did so, measured and found mutations and falsely they had ben declared being the cause and this is the major differentiation which has to be done: the differentiation between measuring an observation in an advanced cancer or during carcinogenesis.

well i cant for sure say whether thev genome change occurs before carcinogenesis as there are some ahpv INFECTIONS STRAINS WHICH HAVE NO EFFECT ANDget resolved and although a vaccine has been discovered i am more scared to uzse the vaccine as i have seena death dfolowing the anaphylaxis after the vaccine just to prevent cervical cancer although a correlation is seen between cervical cancer and HPV infection although allof them dont go on to develop CA DONT KNOW WHETHER THE APPLE CAME FIRST OR THE mystery of lifes story regarding adam AND EVE but i agree reading abstracts and presuming so much of aetiopathogenesis of cancer may not be fair and unnecessary wasting of resources..

Ljaz gave a nice example of how a drinking culture can be an environmental factor. One could imagine that heavy drinking will have some adverse effects on the immune system (prove anyone?). As Kulvinder rightly commented, viral DNA gets integrated in the host's DNA. But only when this happens in gametes, this integration potentially becomes genomic in the offspring. However, as we know for HPV, local integration can be sufficient to cause malignancy right there at some point in time. The question then is what would trigger the malignancy? A general biological rule is that viral outbreak is triggered by cellular stress. Could this be environmentally  induced, for example by overexposure to toxins, alcohol, lack of sleep, mental stress, etc? And what about non-viral cancers? Are certain mutations (like BRCA1/2) the prerequisite, but is there an environmental trigger? Will DNA replication errors in dividing stem cells be a stochastic prerequisite for "spontaneous" malignancies, but other events may also create such prerequisites?

Interesting, the International Agency for Research on Cancer (IARC) strongly disagrees with the conclusion of Cristian Tomasetti and Dr Bert Vogelstein.

“The remaining knowledge gaps on cancer etiology should not be simply ascribed to ‘bad luck’,” says IARC Director Dr Christopher Wild

http://www.iarc.fr/en/media-centre/pr/2015/pdfs/pr231_E.pdf

Thank you @Andrey. Usually the IARC is "the" organization, which declares since some two decades, that mutations cause cancer. However, we should see this in a differentiated manner and not in a political one. 

Please let me allow clarifying shortly why:

Despite bad chosen semantic, oversimplification of conclusion, without explaining differences in absolute risk, as well as misunderstanding by the media as well as by some readers, it should be pointed out clearly why this paper lacks in general and this is not due to bad chosen semantics – agai, this is just one 'small and overestimated point.

Cristian Tomasetti and Bert Vogelstein basic methods:

1) Mutations trigger carcinogenesis,

2) The risk of mutations are relatively constant for a given cell division

3) Stochastic process.

Realits is, that Cancer is triggered in

1) 5-10% by mutation

2) 15% by infection and

3) 80% are sporadic, unknown cause.

Tomasetti ad Vogelstein took the 80% of sporadic cancers and declared such as mutation triggered cancers for having the majority of cancers, that their model works.

5 % of cancers only had been proven being triggered by carcinogenesis, an by this, the stochastic model as well as its results and as a Domino effect the conclusions are also wrongly approached to the majority of cancers.

My view may be biased, but this means, we do not have a need talking about cell division rates of any kind of cells in regard to the discussion of the content of the paper. The methods already lack and that – unfortunately – is enough. If you or I would submit such a paper – although in general the approach reads itself interesting (but the paper is complicated written) – every reviewer would reject it immediately. 

The findings of Tomasetti & Vogelstein are interesting. It is perhaps worth mentioning that Bob Weinberg (in the Biology of Cancer, 2014) cites J. Peto (Nature 411:390-395, 2001) with supporting epidemiological data to state that “the great majority of commonly occurring cancers are caused by factors or agents that are external to the body”. The argument is buttressed by the significant differences in the occurrence rate of prostate, colon, stomach and breast cancers between Japanese, Hawaiian Japanese and Hawaiian Caucasian respectively. Off course Weinberg clearly conveys the appreciation of cancer risk associated with stochastic events subverting cellular mechanisms such as, I assume DNA replication, given the estimated 10 million cell turnover events per second.

It occurred to me, on reading the IARC statement Referenced above) that what many commentators are doing in reporting this paper is analogous to the following (I don’t think that the authors are totally “innocent” in this).

An analysis of traffic related fatalities shows a strong correlation with the form of transport used. From motorbikes and sports cars to ships and airliners there is an extremely high correlation between the frequency of deaths and the form of transport employed. This correlation is so strong that it eclipses other factors in the causation of fatal  accidents. Thus the chance of dying when travelling by motor cycle is massively higher than the risk encountered when travelling by airline or ship. The type of transport used far exceeds the strength of other factors in the prevalence of deaths.

Therefore, we might as well ignore environmental/behavioural factors as an important cause of fatal accidents  because they are eclipsed.

I think that this is a valid analogy. It is only when we compare the incidence of like with like (motor cycle fatalities grouped together; airliner fatalities grouped together) that we discern the other, potentially avertable, environmental factors that modulate the prevalence of fatalities. Indeed, in looking at cancer prevention – by behaviour modification – we concentrate strongly on the sites that demonstrate the higher incidences of cancer (skin, breast, lung, bowel).  I do not hear much public health advice on how to avoid rhabdomyosarcomas.

In my first contribution to this discussion, I guess that I have glossed over some of what other people have said. I have not always read the (many) contributions carefully enough. I apologise for failing to acknowledge these.

Thanks to Ijaz (Jamall) for making me question the absolute necessity for upstream genetic mutation in the origin of cancer. It has been known for a long time that the dominant cell population of some forms of cancer (eg, teratomas) are not necessarily clonally mutated (individual teratoma nuclei can be used to clone normal embryos). Mutation does not appear to be inevitably necessary for "cancer" to emerge. Nevertheless, the cancer favouring niche (part of the wound that never heals) does, at least, seem to favour an opportunistic runaway re-population by clonally mutated cells. My opinion (currently – and as follows) favours cancer as a stem cell generated disease; it is the outcome of a distorted inflammation/regeneration. Stem cells need to be invasive during the repopulation of a focus of cellular damage.  Macrophages first clear the debris (inflammation), then they convert to a tolerant and immunosuppressive phenotype to allow tissue invasion and the repopulation by stem cells. This phase then switches off (presumably following contact inhibition and the re-establishment of normal  junctional communication).  It is under the cover of this physiological immunosuppressive phase that the cancer niche establishes itself and becomes uncontrollable.

The mitosis of occasional adjacent differentiated cells probably does not result in invasive behaviour, as contact inhibition may be restored much more rapidly (my response to a point raised earlier). The “monstrous” and chromosomally abnormal cells that are a histological accompaniment to cancer also occur during rapid repair “tissue filling” in the restitution phase of normal tissue regeneration (I can’t find the reference at the moment) and this points towards the failure of surveillance for substandard/miscreant cells in the restitution phase.

Thank you @Jamie for your valuable comment and the example with bikes, and @Andrey for your great sense of humor.

An apple found in a car is not synonym of prove apples grow in cars – although finding many apples in many cars would implicate us the assumption (if we calculate it), that a strong correlation reveals a higher correlation score. At first it still would be an observation - nothing else. Consecutively, the conclusions are human made, although an analysis can be performed these days automatically by a machine.

That is one reason why Ijaz and myself made it happen, writing the ‘Epistemology…’ and the following paper in Cell Physiol Biochem providing evn more depth knowledge and critical thinking, as we both always ask ourselves – what I call - the Sesamstreet principle: asking the whys instead of overtaking opinions only.

One major question – at least to me and Ijaz – is the following in regard what we measure in tumor tissue: mutations had not been proven for the majority of cancers, only for a minority, some 5% - since its first proposal in 1928. We both have the opinion, that 85 years are enough of a dogma, which did not work for the majority of cancers. 

It is our duty for patients and their relatives, asking ourselves the following question: why? AND should we continue measuring it, as some still telling us since some three decades? If mutations are not “the” cause, why can we observe them in cancer tissue?

What, if mutations are epiphenomena? What, if they occur later during carcinogenesis, and are primarily not responsible for the majority of causing cancer?

Does this reflect the truth or is it not just an observation, although not primarily necessarily evolved in carcinogenesis?

Independent if we look at motorcycles or apples, a motorcycle should be seen as one as well as an apple, but the conclusion makes a difference, although this may be my and Ijaz' biased view.

Björn,

My (new!!) current belief is this: mutations in cancer are epiphenomena; they do occur later (downstream) during carcinogenesis and are analogous to opportunistic infections.

I should had qualified that: mutated stem cells "infect" the developing cancer-prone-site as a downstream event. They may arise years before but generally cause no problems. They are more likely to be opportunists "awaiting" the right "soil" to seed. It is the focal immunosuppression and the subsequent failure to switch off the regenerative phase that creates the necessary soil. And, if you are right, mutations are not necessary for the development of all cancers. This, latter point, may have been one of those convenient blinkered assumptions that has, for a long time, stopped us reaching the correct inferences.

Thanks @Jamie, honestly it was at first a shock for us, when we realized, that an opinion mutated to a dogma, but asking the necessary questions helped getting on the necessary way, and sometimes it is not easy recognizing that we had a on-helpful view and we stay honest, it is because some told us and we overtook their opinions. 

@Andrey, interesting, thank you sharing that ! Please send me the paper when you can, as Ijaz and myself are interested in very much.

I allow myself citing a sentence on page 2 from our paradigm paper, as we integrated many aspects...

"The Watson and Crick discovery, aided by Rosalyn Franklin’s X-ray diffraction study of DNA [7], achieved in large measure by “theoretical conversation…little experimental activity” [8],"

I this quite interesting that both did not perform an experiment in regard to the double helix, it was an intense intellecutual and critical thinking & discussion. But the key experiments had been performed by Rosalyn Franklin and she together with Maurice Wilkins should have received the Nobel award these days and that was som decades ago also declared by Watson.

If I will (hopefully) make it getting to your beautiful country, we together have a look at the museum's in your country and we get Vladimir Matveev from St.Petersburg and Ijaz with us - this will be fun for sure.

Formation of cancer is a multifactorial issue which needs Initiation, promotion and progression and many genetic and transcriptional factors , and a person should be very unlucky if he or she gets cancer considering cancer is bad luck

Let’s put all factors systematically in place.

Internal, physiological factors that contribute (or thought to contribute) to cancer:

1. Hereditary alleles (e.g. BRCA1/2, APC, VHL, etc)

2. Viral-derived malignancy (e.g. HPV, EBV, HCV, etc)

3. Replication errors leading to malignant mutations (multiple mutations in tumors)

4. Epigenetics (e.g. DNA hemimethylation, histone methylation, microRNAs, etc.)

5. Stressed immune system (no adequate clearance of malignant cells)

6. Mental state (e.g. fobia, depression, traumatic history, etc)

External long-term factors that contribute (or thought to contribute) to cancer:

1. Exposure to toxins (e.g. work environment, weak makers from plastics, smog/waste from coal-fired power stations, etc)

2. Life style (e.g. use of creative drugs incl. tobacco, lack of exercise, unbalanced diet, etc)

3. Prescribed drugs (e.g. immune-suppressors, opiates, chemotherapy, etc.)

4. Excessive radiation (e.g. fall-out from nuclear plants, UV, X-ray)

If I overlooked something, please let me know. I do not believe that un-related diseases will lead to cancer, but prescribed medications to battle such diseases can do.

To move on from the new hypothesis introduced by Bjorn and Ljaz, I would like to put the above factors into consideration. Each one on their own would not b e enough to cause cancer, including the inherited alleles. Carriers of such alleles suffer from increased risk, and this is true for each one of the above factors on their own. However, when a few of these factors are combined, the risk to develop cancer is dramatically increased. From this it follows that chances of remission are increased when the majority of the relevant factors are removed after cancer have been diagnosed.

I also like to propose that tumours including their secondary mutations are symptomatic, not the cause of cancer. Evidence for this would be recurrence of tumours after removal of the original one. Hence any therapy directed to killing/removal of a tumour is not going to cure the patient from the disease. Removal of as many contributing factor s as possible would be required to keep the disease at bay. It is worth noting that (likely all of) the contributing factors directly influence the immune system, mental state including. I like to think that the failure of clearance of malignancy is the primary cause of cancer. And this is where the new hypothesis of Bjorn and Ljaz starts to kick in.

A recent article by Stuart G. Baker looks very relevant. It was found in the Huffington Post in a comment on the "bad luck" article in Science(http://www.huffingtonpost.com/susan-m-love/bad-luck-and-stem-cells_b_6466306.html).

Title: "A Cancer Theory Kerfuffle Can Lead to New Lines of Research."

JNCI J Natl Cancer Inst (2015) 107 (2):dju405 

doi: 10.1093/jnci/dju405

Abstract: The standard viewpoint that cancer is a genetic disease is often stated as a fact rather than a theory. By not acknowledging that it is a theory, namely the Somatic Mutation Theory (SMT), researchers are limiting their progress. An attractive alternative to SMT is the tissue organization field theory (TOFT), which is summarized as “development gone awry.” To initiate a kerfuffle, I discuss the interpretation of various results under both TOFT and SMT, including recurrent mutations, hereditary cancers, induction of tumors in transgenic experiments, remission of tumors following the inhibition of enzymes activated by mutated genes, nongenotoxic carcinogens, denervation experiments, foreign-body carcinogenesis, transplantation experiments, and tumors with zero mutations. Thinking in terms of TOFT can spur new lines of research; examples are given related to the early detection of cancer.

I have now had longer to peruse Tomasetti and Vogelstein's paper.

“The variation in cancer incidence (they say risk) among tissues is strongly correlated to the number of life time cell divisions in the respective tissues.” I believe that that is all this paper can claim. “Risk” may be an accepted term but it adds a bit of emotion.

Bad-luck is a highly subjective and emotive phrase that, for me, has no place in a scientific paper. Its use was inflammatory.

They state, “Although this has been has recognised for more than a century, it has never been explained.” This paper brings us no closer to an explanation beyond what we have already intuitively suspected; tissues with a high turnover of cells are more prone to cancer. It does help to emphasise that those tumours the authors term “R-tumors” tend to follow a simple stochastic pattern where more divisions lead to more tumours; there is a finite chance that every regenerative event will pervert into a cancer seeding outcome; exogenous agents have relatively little influence in these tissues.

The D-tumours, that they admit do show a higher influence of exogenous influences, are those tissues that are exposed to the higher cell turnovers (and, notably, to a higher attention by public health advisors). Presumably, there is a relatively accelerated auto-rejection in these tissues leading to accelerated tissue regeneration. The auto-rejection can include apoptosis, deliberate sequestration of older cells (as with keratinocytes and bowel epithelia) and an increased exposure to pathogenic stimuli that lead to heightened inflammatory responses; these augment tissue turnover. The deliberate sequestration of epithelia has probably arisen as a pre-emptive strategy to dampen the adverse outcome due to this high exposure to pathogenic stimuli.

The authors freely admit that they assume that this increased tissue turnover leads to (cancer causing) mutations. Now that is a funny one; on the one hand they sweep away the importance of mutagens by their conclusions – particularly with R-tumors. But, on the other hand they substitute a new (probably correct) assertion that increased tissue turnover increases, stochastically, the incidence of genetic damage. However, they ignore the possibility that the prevalence of genetically altered cells in cancer may be epiphenomena and that such cells only populate the tumour niche after chance disruptions of the normal aggressive-suppressive-regenerative-restitutional sequence of the inflammatory response. Now, if this is important and the vast majority of genetically damaged cells are normally cleared by an effective inflammatory/tissue-homeostatic response (I suspect that they are), then we have a very different view of the stochastic accumulation of the “risk” (incidence) incurred. Exogenous pathogenic stimuli now become important modulators of the inflammatory response, ramping up the rejection/regeneration process.

The latter is fairly clear in sunburn when large patches of keratin are shed in the healing phase. In inflammatory bowel disease there is an increased mucosal turnover; and I think that this principle will prove true of many of the D-tumor types.

The authors do state, “In formal terms, our analyses show only that there is some stochastic factor related to stem cell division that seems to play a major role in cancer risk .” The validity of this statement sharpens if “risk” is replaced by “incidence”. That conclusion would be commendable on its own; and that is as far as they should have gone, in my opinion. However, they have hoisted up their belief petard in the next few sentences when they conclude, “we interpret the stochastic factor underlying the importance of stem cell divisions to be somatic mutations.” They commit, lock stock and barrel, to the “somatic mutation theory (SMT)” as the cause of cancer.  If that theory is wrong, their extrapolated inferences are similarly wrong. In a time when the SMT is coming under increasing suspicion, this polarisation seems somewhat unwary.

The worst part of this whole event is that it has seeded a welter of distorted interpretation that the Science editor's comments have fuelled.

as we move down the line watson and crick model has been challenged for DNA as the dr from russia said he is soon coming with the new DNA structure similarly these theories keep getting challenged but i find it so stupid that as dr Bjorn burcell puts it whether the apple is in the car and how much significance one should give to thesxe mutations ytet famous personalities like angelina jolie are szetting up examples by grtting prophylactic nastectomgr a positive BRCA1 gene and on social media this is becoming a faSHION IS THIS A PREVENTIVE MEDICINE that for 5%causaton you get rid of the structure and what is the mortality of surgery per se and anaesthesia etc .

The public may have been misinformed about the real impact of observed / measured mutations / genetics due to wrongly mixing up observations and conclusions.

If I may be allowed, reminding us: it nearly seems that this had been in a comparable way, as cholesterol and heart disease were for decades wrongly be connected, and as we already had been thought by the primary results of the Framingham Heart Study, which to date is the longest-running and most comprehensive study on heart disease, it was clearly demonstrated that cholesterol intake in the diet had no correlation with heart disease. Interestingly, those scientists who reminded colleagues about the possibility abou a wrong direction were - before the results came up - ignored.

However, as above mentioned by this, some generations of scientists may have been misleaded into the wrong direction.

Contrary to the popular opinion, mutations and the majority of findings in cancer genetics so far reported are either late events or epiphenomena that occurs after the appearance of the pre-cancerous niche.

Does anyone have access to the full paper JNCI J Natl Cancer Inst (2015) 107 (2):dju405 that Jamie mentioned? PDF greatly appreciated.

No - I wish I did

Jan I had it, but I dont find it right now, I send you Stuart Bakers email for requiring the PDF, please be so kind forwarding it to Ijaz, myself and Jamie, thanks best björn

Got it, Jamie, if you send me a message to [email protected], I can forward you the access links. Forwarded already to Bjorn and Ljaz.

Jan

Thanks!! However, I now have it straight from Stuart Baker and was waiting to see if he would allow me to send you all the link. Thanks anyway. More to read.

Thanks Jan for the paper of Stuart which we received.

In my view Stuart's paper shows overwhelming evidence against the SMT (Somatic Mutation Theory), and based on this paper it may have to be discarded as dogma. Nonetheless, we cannot simply discard the few hereditary factors that we know.The arguments used in this paper are not satisfactory regarding this inheritance as the famous ones, like BRCA1/2, APC, VHL alleles,etc., are not discussed. This aside, the majority of cancer is NOT inherited, so the main message stands that the various mutations found in tumors must be secondary. I would like to take one step further and postulate that tumors themselves are also secondary: take a tumor away and do not do anything else, then the tumor will reoccur since the cause has not been removed with the tumor. I invite others to come with evidence from the literature.

Stuart's paper introduces the TOFT (Tissue Organization Field Theory) as an alternative to the SMT dogma. It is based on the postulation of signals involved in homeostasis (morphostats) that when disturbed will cause cancer. The paper describes compelling arguments to support this new theory. It is likely the inspiration we need to better understand the early cues to malignancy. However, the way these disruptions of postulated morphostat signalling pathways take place in each cancer case remains still elusive. 

I hope that my contribution of separating malignancy from the actual disease gets some "resonance". The idea that in a healthy body malignancies are being cleared by the immune system remains valid, both in the SMT and in the TOFT. And both theories allows cancer to evolve by failure of malignancy clearance.

rrecently besides the discussions above the prokineticins and kisspeptins have been associated with various cancers with infact ispeptin initially discovered as the metastasis suppressor gene and their receptors have shown a lot of pro ise and building nalogs of these have been tried in prostatic cancer ,and are being tried for other metastaic cansers with kp agonists and antagonists developed which further exemplifies the complexieties of aetiopathogensis wit EG-VEGF beng another factor found in certain testicular tumours where it affects the vascular proliferation and dont know if any knon mutTION IS KNOWN FOR SUCH CANCERS .l

I second the opinion by Chris Wild, Director of IARC, in that  “Concluding that ‘bad luck’ is the major cause of cancer would be misleading and may detract from efforts to identify the causes of the disease and effectively prevent it.”According to current knowledge, nearly half of all cancer cases worldwide [that are related to livestyle] can be prevented.

See: http://www.euro.who.int/en/health-topics/noncommunicable-diseases/cancer/news/news/2015/01/most-types-of-cancer-not-due-to-bad-luck

Many thanks Bas (may I call you this?) for this excellent input. Here is a better link for our audience: http://www.iarc.fr/en/media-centre/pr/2015/pdfs/pr231_E.pdf

Please note the second reference in there (Stuart and Wild). Anyone has access?

One final note, who says that the rate of cell division of stem cells is not also influenced by modifiable lifestyle factors?