Hi Robert,

Cancer IS a genetic disease. Even when the cancer is caused by infections (H. pylori, human papiloma virus, etc), the infection produces chronic inflammation and excesive cell proliferation/renewal which, in turn, causes genetic errors in some of the daughter cells. So, at the end, you need a number of genetic mutations to initiate the cancer. If you do not have these, you may have some kind of hyperplasia but never a malignant tumor.

I hope this helps!

Best regards,

Alfredo 

Thanks, Alfredo, for supporting the mutations as the widely accepted view, which is supported by clear experiments since decades (incl. mine on point mutations in low-grade tumors; or gene transfer models in animals). But what if we look for the very first tumor or metastatic cell, which will develop into the tumor? For sure, we can induce tumors by increasing mutations by chemicals or radiation. And inflammation, as you mentioned, leads to cell proliferation... and so on. So, how can one be sure the mutations are always first, and the changes in methylation only the later events ?

Hi Robert,

I agree that epigenetic changes may precede mutation, as inflammation would precede mistakes of the replication machinery. But you need to fix the changes into the genome if you want those changes passed to the next generation of cells. Otherwise you may end up with a very angry cell but that´s all.

Basically, the generation of a cancer cell is based on a Darwinian iteration of chance mutations and very stringent selection over a very long period of time (sometimes more than 20 years for lung cancer and such), that ultimately allows the cell to acquire a number of genetic competences needed for self-regulation of growth, survival, migration, angiogenesis, etc.

I guess what you propose is a Lamarckian theory of cancer cell generation but you will have the same problems that the followers of this theory encountered in the past: if you cannot fix the acquired changes into the genome they will not be passed into the next generation. Example: you can attend the gym and become one of the strongest men in the world but you will not pass this trait to your children. The only way to pass this trait is if you had a “gene” for the drive to go to the gym in which case some of your children will share your propensity for visiting sweaty places.

So, in conclusion, epigenetic changes may happen before mutation but without mutations and natural selection there will be no cancer.

Hi Alfredo,

I agree with your views, that any cancer has evolved by mutations and selection; but what if the initial event before the first mutation in such a tumor stem cell is just a change in epigenetics, changing the expression level of tumor suppressor genes (but without classical point mutations) - driving the cell into less controled growth and cell division... and then increasing the chances to aquire the first "real" mutation? This doesn't seem to contradict all the research on mutations over the last decades, but may add some windows for preventive strategies.

I agree with this view, but this seems to contradict your initial hypothesis: "tumor stem cells could evolve ... only by changes in methylation, or similar, due to some outside changes". Again, I don´t see a problem in epigenetic changes preceding and even favouring mutation acquisition, but until the cell has acquired not one but several mutations that allow it to behave as a tumor cell, we cannot talk about a cancer cell.

sorry about my "german"-english; I think I share your view.

 Hi Rohan,

Very interesting work.

Nevertheless, you have to admit that integration of large pieces of DNA in the genome is an extreme case of "mutation". Something similar seems to occur with exosomes. In any case, these are not examples of epigenetic changes.

Best regards,

Alfredo

Cancer had been correctly associated with mutations, but that should not be seen or taken as synonymous of prove carcinogenesis in the majority of Cancers is caused my mutations:

Cancer had been proven being cause in

(1) 5-10 % by mutations

(2) 15 % by infections and

(3) 80% are sporadic, meaning unknown cause.

An apple found in a car is not synonymous of prove apples grow in cars.

We recommend read non-receptiovely in detail the attached web links.

Article Epistemology of the origin of cancer: A new paradigm

Article Somatic Mutation Theory - Why it's Wrong for Most Cancers

Article Cell-Cell Communication in the Tumor Microenvironment, Carci...

Article Genomics, microRNA, epigenetics, and proteomics for future d...

 Dear Björn,

You are right when you say that only 5-10% of cancers are hereditary (passed from parents to children, therefore suggesting a mutation in the germline, not a somatic mutation). That does not mean that the rest of tumors lack genetic changes. These genetic changes are acquired during the life of the cell and are therefore  sporadic (your 80%). Infection, as discussed above, induces mutations through rapid proliferation of the cells and replication mistakes. 

As I said before, I can see how epigenetic changes can happen prior to the mutations and that this could offer new therapeutic opportunities, but a cell without driver mutations is NOT a cancer cell.

All the new technologies on massive sequencing of cancer genomes show the huge number of mutations collected by these cells. Since they are random mutations, some of them are needed for the carcinogenesis process (driver mutations) whereas others are just "passengers" with no real physiological relevance.  

Dear Alfredo,

thanks, again I recommend - if I may - reading the papers in Detail, not just the Abstracts only.

This might be of relevance

thanks b

If we can all agree that a cancer cell is defined by its recruited mutations as a result of epigenetic events, I can live with that. But, as I see it, the question is not how to define cancer cells, but how to define carcinogenesis. Once we have the answer, we will soon have a cure. The so-called driver mutations have all been targeted in clinical trials in the past decade(s) without much avail.  This should tell us that carcinogenesis cannot be defined by simply looking at the cells and their mutations involved. 

Dear Robert,

I feel that the cautious way you have stated your question tells volumes about the model that you question.  Something that is proven beyond doubt is not usually intimidating. 

Please also see two papers attached.

Thanks.

Yuri

I think it is much more complicated than mutation issue!I remember a patient (pancreatic cancer) without any single mutation found by NGS out of hundreds of cancer-related genes. In this case, epigenetics only is to be blamed!? I do not know. So, it may be either or its combination. Or none of them but just a kind of chromosomal chaotic situation?.... not a single/simple answer i am afraid.

Yuri comes with an extremely refreshing look in his NRC comment. Perhaps it is time to dismiss a tumour as synonymous to cancer and just call it what it actually is. Cancer is a disease that we do not understand and a tumour is likely a symptom.

Dear Robert

A pertinent question since it leads to a review of knowledge on a topic, in this instance carcinogenesis. I am surprised that no one mentioned Otto Heinrich Warburg who had first proposed that mutation is the result of cancer and not. His hypothesis that cancer is related to alterations in cellular respiration caused by insult to mitochondria. But now it is not taken seriously, but who really is sure about these things?

Personally I think that damage to the centrioles, the pericentriolar matrix, may be even the cell membrane, could be the cause leading to alterations in mitotic divisions, DNA and mutations. After all, cancer is a disease of cellular proliferation, isn't it and it seems logical that the kinetic apparatus of the cell should be related to the cause. This concept is an off shoot of my findings in Radiobiology. Radiotherapy is presumed to be effective in cell killing because of effect on DNA, but my clinical research suggests that cell kill is very well correlated with markers abnormal PCM, nuclear membrane and cell membrane damage, apparent as micro- and multinucleation. Relevant papers are indicated in myRG profile.

Narayanan

Dear Dr. Eibl:

I would like to add the following in connection with your intriguing and thought provoking question.

The following article published in the Proceedings of the National Academy of Sciences argues against the widely considered “accumulation of mutations" model of oncogenesis in favor of a model that relies on evolutionary pressures exerted on populations of cells.  

Andrii I. Rozhok, James DeGregori. Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proceedings of the National Academy of Sciences, 2015; 201501713 DOI: 10.1073/pnas.1501713112

The authors state:

“The recognition of cancer as a somatic evolutionary process requiring multiple rounds of selection for adaptive oncogenic mutations has armed cancer modeling with parametric approaches and led to the foundation of the current multistage model of carcinogenesis operating with mutation fitness effects as the pivotal element of the theory. This common incidence pattern is characteristic of cancers requiring different numbers of oncogenic mutations, and it scales to very divergent life spans of mammalian species. Also, bigger mammals with larger underlying stem cell pools are not proportionally more prone to cancer, an observation known as Peto’s paradox. Here, we present a number of factors beyond the occurrence of oncogenic mutations that are unaccounted for in the current model of cancer development but should have significant impacts on cancer incidence. Furthermore, we propose a revision of the current understanding for how oncogenic and other functional somatic mutations affect cellular fitness.”

“If the described effect of SC pool architecture is operative in affecting cancer odds, the different ratios of the HSC pool size to the epithelial SC pool size between small and large mammals could explain the relative rarity of carcinomas in small mammals like mice (with a greater frequency of hematopoietic malignancies), which contrasts with the prevalence of carcinomas in humans (and perhaps other large animals having much larger total epithelial surfaces).” End of quotation... HSC - hematopoietic stem cell (HSC). SC –stem cell.

The model proposed could help in answering an ongoing question prevalent in cancer science termed as “Peto's Paradox”.  If cancer development owes to random activating mutations, larger animals with greater number of cells should be at an elevated risk of developing cancer early on in their lives. Why is that mammals of vastly different sizes and lifespans all seem to have a propensity to develop cancer mostly during relatively late stages in life?

The authors reason and argue that evolution, not just mutation, drives the development of cancer.

Dear Dr. Ulukaya:

Your statement concerning  a patient with pancreatic cancer without any single mutation (found by NGS out of hundreds of cancer-related genes) is fascinating.

The following paper suggests that cancer-causing gene alone does not trigger pancreatic cancer.

Christine M. Ardito et al. EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis. Cancer Cell, 2012; 22 (3): 304 DOI: 10.1016/j.ccr.2012.07.024

Thank you...

Dear all:

The following paper could be of interest.

Certain cancer mutations slow down or halt tumor growth.

C. D. McFarland et al. Impact of deleterious passenger mutations on cancer progression PNAS 2013 110 (8) 2910-2915;  doi:10.1073/pnas.1213968110

http://www.pnas.org/content/110/8/2910.full