Does metabolism link beneficial mutations to cancer?

By: James V. Kohl | Published on: December 27, 2015

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Viruses steal nutrients needed by the cell. The theft deregulates protein folding, which is how viruses perturb biophysically constrained nutrient energy-dependent protein folding chemistry. The theft of nutrients by viruses links mutations to all pathology.

Nutrients are required for RNA methylation and RNA-directed DNA methylation. Cell types do not hypermethylate unless nutrient-dependent hypermethylation is required to protect organized genomes from virus-driven entropy. Simply put, viruses cause nutrient-dependent hypermethylation when hypermethylation is required to protect organized genomes from virus-driven entropy. Evolutionary theorists are so confused about biologically-based cause and effect that is has become almost impossible to untangle their misrepresentations.

For example, the role of viruses is not included in these evolutionary dynamics.

Quantitative evolutionary dynamics using high-resolution lineage tracking

Excerpt:

Our results show that in an asexually evolving population of ~108 cells, a large number of independent beneficial mutations drive adaptation.

My comment: The ridiculous idea that beneficial mutations drives adaptation can be placed into the context of what serious scientists know about how viruses cause cancer via genome unfolding.

See: Genome misfolding unearthed as new path to cancer (but first see) Gene variation promotes uncontrolled cell division

Uncontrolled cell division is linked from gene misfolding to cancer

Excerpt (with my emphasis):

The germline mutation rs351855 accounts for aggressive and rapidly growing tumors that are resistant to treatment. An effective treatment needs to be tailored to match the mutation and its biological effects.

My comment: Nutrient-dependent epigenetically-effected mutations are not fixed in the germline via the physiology of reproduction. If they were fixed in the germline, the mutations could be linked from virus-perturbed protein-folding chemistry to genomic entropy via RNA-mediated cell type differentiation in all living genera.
Instead, virus-driven entropy is typically limited because most virus-caused germline mutations are eliminated in the context of sexual reproduction in all invertebrates and vertebrates.
That fact has been somewhat concealed in the context of reports that link mutations to evolution of new species. No experimental evidence of biologically-based cause and effect suggests that mutations can be linked to the evolution of any new species.
All experimental evidence links atoms to ecosystems. An atoms to ecosystems model places RNA-mediated amino acid substitutions into the context of nutrient-dependent ecological adaptations in some populations of modern humans, but not in all populations of modern humans.
It the context of nutrient-dependent RNA-mediated receptor-mediated cell type differentiation, rs351855 is an SNP that becomes another example of an RNA-mediated theory killer linked to differences in the cell types of different populations of modern humans.
See also: Patterns and functional implications of rare germline variants across 12 cancer types
Excerpt (with my emphasis):

Dot plot shows individual missense variants where abscissa and ordinate are amino acid positions and the ratio of tumour-to-normal variant allele fraction, respectively.

Reported as: Study uncovers inherited genetic susceptibility across 12 cancer types
My comment: The dot plot is not used to link rs351855 to the variants from the amino acid positions. Thus, the nutrient-dependent amino acids that establish the stability of cell types are not linked to the inherited genetic susceptibility via the ratio of tumour-to-normal variant allele fraction in the cancer types.

See for comparison: SNPedia

Rs351855

Excerpt:

… a SNP in the fibroblast growth factor receptor 4 (FGFR4) gene, is also known as the Gly388Arg variant. The rs351855(T) allele encodes the risk (Arg) allele.

The Arg form of this SNP is likely to cause a harder to treat version of node-positive breast cancer, including reducing the efficacy of Herceptin, based on a study of 372 patients.[PMID 16822847]

A study of ~500 Japanese prostate cancer patients found that individuals with a rs351855(T;T) genotype had a 2.2- and 1.9-fold increased risk of prostate cancer and benign prostate hyperplasia (BPH), and a 1.8-fold increased risk of metastatic prostate cancer compared to the (C;C) genotype.[PMID 18756523]

A meta-analysis published in 2011, surveying a total of 2,618 cases of prostate cancer, concluded that the odds ratio per rs351855(T) allele was 1.17 (CI: 1.07 – 1.29), and that when stratified by race, Caucasians and Asians were at highest risk.[PMID 21349172OA-icon.png]

My comment: Rs351855 appears to link an energy-dependent single base pair substitution and/or one SNP to a single nutrient energy-dependent RNA-mediated amino acid substitution and undifferentiated cell types of different cancers via virus-perturbed protein folding. It also appears that pseudoscientists have not learned enough about the nutrient-dependent innate immune system to establish the link from virus-perturbed protein folding to cancer or to anything else.

Excerpt:

Fibroblast growth factor 21 (FGF21) is a hormone induced by various metabolic stresses, including ketogenic and high-carbohydrate diets, that regulates energy homeostasis.

Reported as: Liver hormone reduces preference for sweets, alcohol, via brain’s reward pathway

This marks the fourth study from the Mangelsdorf-Kliewer laboratory to show that FGF21 directly affects the central nervous system. First, in two studies in Nature Medicine in 2013, they reported on FGF21’s ability to regulate metabolism, circadian (body clock) behavior, and female reproduction. In 2014, they reported in Cell Metabolism that FGF21 acts on the brain to cause weight loss.
“The finding that FGF21 acts via the brain was completely unexpected when we started down this path of investigation a dozen years ago,” Dr. Kliewer said. “These findings suggest that additional studies are warranted to assess the effects of FGF21 on sweet and alcohol preference and other reward behavior in humans.”

My comment: The links between nutrients and ligand-receptor interactions that establish classically conditioned rewards are established during life history transitions link RNA-directed DNA methylation to cell type differentiation via the physiology of reproduction in all living genera. Links from the epigenetic landscape to the physical landscape of DNA make the claims of neo-Darwinian theorists more ridiculous than ever.
For example, neo-Darwinian theorists link beneficial mutations to evolution and detrimental mutations to cancer risk in their ridiculous theories. They are caught in a trap. The trap forces theorists to explain the difference between beneficial mutations linked to evolution and mutations linked to pathology.
They avoid that trap by claiming that the beneficial mutations accumulate over millions of years. The tell people that whatever causes the mutations linked to pathology is selected against and never explain how mutations could be beneficial, or how beneficial mutations could lead to evolution.
It has become clear, however, that limiting the number of stem cell divisions limits cancer risk. But, it also limits claims about mutations and evolution.

See for example:

Variation in cancer risk among tissues can be explained by the number of stem cell divisions

My comment: In my model, variation in cancer risk is RNA-mediated. Ecological variation is linked from atoms to ecosystems via nutrient-dependent changes in the microRNA/messenger RNA balance that link DNA repair to supercoiled DNA, which protects the organized genomes of all living genera from virus-driven entropy.

Recent support for my model appeared in: Substantial contribution of extrinsic risk factors to cancer development

Excerpt:

Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.

Reported as: Cancer studies clash over mechanisms of malignancy

Excerpt:

The paper attempts to rebut an argument that arose early this year, when a report in Science concluded that differences in inherent cellular processes are the chief reason that some tissues become cancerous more frequently than others (C. Tomasetti and B. Vogelstein Science 347, 78–81; 2015).

My comment: It is not necessary to rebut any claim made that includes “inherent cellular processes” because those are the claims make no sense. The original argument that cancer resulted from “bad luck” and the “inherent cellular processes” was not placed into the context of what is currently known to serious scientists about the links from atoms to ecosystems.

Anyone who does not acknowledge the basis for claims that link ecological variation to ecological adaptations in the context of nutrient-dependent RNA-mediated cell type differentiation via amino acid substitutions is not likely to be a serious scientist. As all serious scientists know, it is a waste of time to compare arguments about biologically-based cause and effect with any biologically uninformed theorist who claims that bad luck and/or “inherent cellular processes”cause cancer, or that good luck causes one species to evolve into another.

However, the controversy that was reported in “Cancer studies clash over mechanisms of malignancy,” was reported with no resolve. The researchers still seem to be unable to report their claims in the terms that link experimental evidence of biologically-based cause and effect to cell type differentiation via nutrient-dependent changes in the microRNA/messenger RNA balance.
The changes link nutrients to healthy longevity and viruses to all pathology. Viruses prevent fixation of RNA-mediated amino acid substitutions in organized genomes via the physiology of reproduction. The accumulation of viral microRNAs, which is associated with nutrient theft by viruses to support their replication, links stolen amino acids to viral replication instead of linking the nutrient-dependent microRNAs to DNA repair.

If serious scientists are not going to link atoms to ecosystems across generations, they are not likely to help find effective treatments or help to prevent the uncontrolled cell type differentiation that is driven by viruses in all cell types of all individuals of all living genera.

See for example:

Noncoding RNA –NORAD– Regulates Genomic Stability by Sequestering PUMILIO Proteins

Reported as:

Scientists discover a new role for RNA in safeguarding human chromosome number

Excerpt:

NORAD produces a long noncoding RNA, a type of molecule that was not previously known to be important in chromosome maintenance, the researchers report in the journal Cell.

My comment: Nutrient dependent microRNAs appear to link all non-coding RNA to genomic stability. As more serious scientists become aware of the need to link ecological variation from the availability of nutrients to speciation via chromosomal rearrangements that limit hybridization, theories about mutations and evolution of new species may disappear. There are too many examples of how chromosomal rearrangements are linked from the nutrient-dependent pheromone-controlled physiology of reproduction by chromosomal rearrangements for any intelligent person to keep making claims about mutations and evolution.

But wait. Why are other researchers (see below) still reporting results outside the context of metabolic networks and genetic networks that link RNA-mediated cell type differentiation in species from microbes to humans?

Brain Cancers Reveal Novel Genetic Disruption in DNA

Excerpt:

It was really surprising,” Dr. Bernstein said. “Why would a metabolism gene cause cancer?”

My comment: Genes don’t cause cancer. This “metabolism gene” obviously links the theft of energy by viruses to perturbed cycles of protein biosynthesis and degradation that are typically biophysically constrained.

The biophysical constraints link nutrient-dependent microRNAs from adhesion proteins to supercoiled DNA, which protects organized genomes from virus-driven entropy. How can cancer researchers not know anything about how cell type differentiation is biophysically constrained by RNA-mediated protein folding chemistry?

Genome misfolding unearthed as new path to cancer

Excerpt:

By creating these loops — roughly 10,000 of them in total — the genome harnesses form to regulate function. “It has become increasingly clear that the functional unit of the genome is not a chromosome or even a gene, but rather these loop domains, which are physically separated — and thereby insulated — from neighboring loop domains,” said Bernstein.

My comment: The question arises: Is Bernstein trying to tell us that the genome harnesses form by automagically creating these loops that regulate the function of the genome?

Serious scientists know how nutritional epigenetics links metabolism and virus-perturbed thermodynamic cycles of protein biosynthesis and degradation to failed DNA repair. The serious scientists placed the conserved molecular mechanisms of RNA-mediated cell type differentiation into the context of the RNA-mediated cell type differentiation we detailed in the molecular epigenetics section of our 1996 review.

See: From Fertilization to Adult Sexual Behavior

What has been known about the molecular epigenetics of RNA-mediated cell type differentiation since 1996 seems to have escaped the notice of cancer researchers for nearly two decades.

The entirety of what is known about cellular intelligence has since been linked from the innate immune system of microbes to antibiotic resistance in humans via what is known about sensing, secreting, and signaling molecules in all living genera.

But, see: Shouldn’t Be Over Here

Excerpt 1)

Mutations in the housekeeping gene IDH may mediate the development of brain tumors by increasing methylation throughout the genome and disrupting usual DNA folding patterns, a Broad Institute-led team of researchers reports in Nature.

My comment: Viruses cause the mutations.

Excerpt 2)

In particular, the Broad’s Bradley Bernstein and his colleagues found that gain-of-function mutations in IDH lead to genome-wide hypermethylation of CTCF binding sites and the deregulation of boundary elements that divide different topological domains. The elimination of a boundary near PDGFRA, a glioma oncogene, enables an enhancer then to swing by and activate it.

My comment: The claim that mutations cause the genome-wide hypermethylation is a foolish claim. Viruses cause nutrient-dependent hypermethylation when hypermethylation is required to protect organized genomes from virus-driven entropy. Viruses that deregulate biophysically constrained nutrient-dependent protein folding chemistry by stealing nutrients needed by the cell cause perturbed protein folding that is linked to mutations and pathology. Simply put, cell types do not hypermethylate their genomes unless nutrient-dependent hypermethylation is required to protect organized genomes from virus-driven entropy.

Excerpt 3)

Bernstein tells the New York Times that this way of becoming cancerous likely isn’t limited to brain tumors.

My comment: He also claimed that he doesn’t know why a metabolism gene would cause cancer. Alll serious scientists have begun to link metabolic networks and genetic networks via the nutrient-dependent microRNA/messenger RNA balance, which is perturbed by viruses. Did Bernstein really tell someone that the way cells types become cancerous is not known? Did he claim that what is not known about the link from metabolic networks to genetic networks is not known, but it probably is not limited to brain tumors?

Excerpt 4)

Such excessive methylation also suggests a possible treatment, he notes. As he and his colleagues report in Nature, they found that treating patient-derived IDH mutant gliomaspheres with a demethylating agent like the first-generation chemotherapy drug 5-azacytidine partially restored insulator function and downregulated PDGFRA.

My comment: Excessive methylation suggests that the researchers should explain what causes it before treating patients with anything that surprised them via a link to a metabolism gene. Treating excessive methylation caused by one virus with a demethylating that promotes replication of a different virus by altering the stability of an organized genome will most likely lead to a treatment resistant virus-driven cancer in another cell type or tissue.

Excerpt 5)

But first, Bernstein tells the Times, there needs to be a way to detect an overabundance of methyl tags and the breakdown of DNA topological domains.

My comment: No, first you need to detect the virus and link it from its viral microRNAs the cause of the nutrient-dependent overabundance of methyl tags and unrepaired DNA damage that is typical repaired in the context of nutrient-dependent RNA-mediated cell type differentiation via microRNAs linked from amino acid substitutions to adhesion proteins and supercoiled DNA that protect organized genomes from virus-driven entropy.

Excerpt 6)

“I am biased, obviously,” Bernstein says before adding that he is “really optimistic about the potential of this information.”

My comment: Of course he is biased, and other people like him are biased. They are paid to be biased. If they weren’t biased by ridiculous theories about mutations and evolution, they would be examining biologically-based cause and effect. Instead, these researchers are being paid to report “gain of function” mutations as if the gains were beneficial. If they can’t find a way to treat the mutations that they claim cause a “gain of function,” their research is less likely to be funded.

The potential loss of funding is a threat to their career and that threat requires them to present their findings in the context of ridiculous theories about mutation-driven evolution. They can earn a good living without ever learning the difference between an amino acid substitution and de Vries definition of “mutation.” The difference became clear in the early 1990s.

The late Robert L. Moss, with colleagues from UT Southwestern, explained the role of odors in gene activation. Food odors and social odors, called pheromones alter the “inherent cellular processes” which Bernstein and his colleagues have ignored despite the fact that hypermethylation is nutrient-dependent. The epigenetic effects of odors and pheromones must be included the reports that Bernstein claims link mutations to cancer because the link to cancer must start with epigenetically-effected metabolism and gene activation, not with mutations.

Dr. Moss and others told me to start with gene activation before they gave me the green light to proceed with confidence to explain my model to others. Will the role of viruses in pathology continue to escape pseudoscientists for another two decades, or will someone step forward and stop this nonsense about surprises. Serious scientists have presented the first evidence of what is known about the links between metabolic networks and genetic networks in all living genera during the past two decades. The links are nutrient dependent, RNA-mediated and controlled by the physiology of reproduction until ecological insults enable the accumulation of viruses to alter transgenerational epigenetic inheritance of organized genomes and cause pathology in the next two, or more, generations of humans.

Ignoring that fact will not make it go away. Ignoring this fact will make that fact worse. “The entire evolution of the microbial world and the virus world, and the interaction between microbes and viruses and other life forms have been left out of the Modern Synthesis…”