'Bad luck' of random mutations plays predominant role in cancer, study shows

'Bad luck' of random mutations plays predominant role in cancer, study shows
Cancers due to bad luck and cancers due to a combination of bad luck, environmental factors, and inherited factors. Credit: Elizabeth Cook

Scientists from the Johns Hopkins Kimmel Cancer Center have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By their measure, two-thirds of adult cancer incidence across tissues can be explained primarily by "bad luck," when these random mutations occur in genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes.

"All cancers are caused by a combination of , the environment and heredity, and we've created a model that may help quantify how much of these three factors contribute to cancer development," says Bert Vogelstein, M.D., the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, co-director of the Ludwig Center at Johns Hopkins and an investigator at the Howard Hughes Medical Institute.

"Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their 'good genes,' but the truth is that most of them simply had good luck," adds Vogelstein, who cautions that poor lifestyles can add to the bad luck factor in the development of cancer.

The implications of their model range from altering public perception about factors to the funding of cancer research, they say. "If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when divide, then changing our lifestyle and habits will be a huge help in preventing certain cancers, but this may not be as effective for a variety of others," says biomathematician Cristian Tomasetti, Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. "We should focus more resources on finding ways to detect such cancers at early, curable stages," he adds.

In a report on the statistical findings, published Jan. 2 in Science, Tomasetti and Vogelstein say they came to their conclusions by searching the scientific literature for information on the cumulative total number of divisions of stem cells among 31 tissue types during an average individual's lifetime. Stem cells "self-renew," thus repopulating cells that die off in a specific organ.

It was well-known, Vogelstein notes, that cancer arises when tissue-specific stem cells make random mistakes, or mutations, when one chemical letter in DNA is incorrectly swapped for another during the replication process in cell division. The more these mutations accumulate, the higher the risk that cells will grow unchecked, a hallmark of cancer. The actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was not previously known, says Vogelstein.

To sort out the role of such in cancer risk, the Johns Hopkins scientists charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. From this so-called data scatterplot, Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to one, the more stem cell divisions and cancer risk are correlated.

"Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue," says Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.

"You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations," says Tomasetti. However, the scientists saw the opposite finding in mouse colons, which had a lower number of stem cell divisions than in their small intestines, and, in mice, is lower in the colon than in the small intestine. They say this supports the key role of the total number of stem cell divisions in the development of cancer.

Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65 percent.

Finally, the research duo classified the types of cancers they studied into two groups. They statistically calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence. They found that 22 cancer types could be largely explained by the "bad luck" factor of random DNA mutations during cell division. The other nine cancer types had incidences higher than predicted by "bad luck" and were presumably due to a combination of bad luck plus environmental or inherited factors.

"We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you'd expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes," says Vogelstein.

"This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery," adds Vogelstein.

The scientists note that some cancers, such as breast and prostate , were not included in the report because of their inability to find reliable stem cell division rates in the scientific literature. They hope that other scientists will help refine their statistical model by finding more precise stem rates.


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More information: "Variation in cancer incidence among tissues can be explained by the number of stem cell divisions," by C. Tomasetti et al. Science, www.sciencemag.org/lookup/doi/ … 1126/science.1260825
Journal information: Science

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JVK
Jan 01, 2015
They exclude the role of nutrient-dependent RNA-directed DNA methylation and RNA-mediated amino acid substitutions that differentiate cell types specific to males and females. This eliminates what is known about links between hormone-organized and hormone-activated metabolic networks and genetic networks in all species.

That eliminates effects of sensory input that link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via the bio-physically constrained chemistry of protein folding.

Having removed every aspect of what is known by serious scientists about cell type differentiation, they also eliminate its control by the physiology of reproduction that eliminates nearly all transgenerational epigenetic inheritance of mutations.

Their age-old proclamation is based on statistics: Cell type differentiation and cancer randomly occur due to mutations. Happy New Year to the evolution industry.

Jan 01, 2015
transgenerational epigenetic inheritance of mutations


Thanks for, once again, proving you don't know the difference between genetics and epigenetics. Mutations, which alter DNA base sequence, occur at the genetic level.

JVK
Jan 01, 2015
I wrote:
...control by the physiology of reproduction that eliminates nearly all transgenerational epigenetic inheritance of mutations.


What, if anything, are you trying to tell us about the role of mutations in the evolution of biodiversity. How does what you claim or avoid claiming compare to what Carl Zimmer wrote in July 2013?

"Others maintain that as random mutations arise, complexity emerges as a side effect, even without natural selection to help it along. Complexity, they say, is not purely the result of millions of years of fine-tuning through natural selection—the process that Richard Dawkins famously dubbed "the blind watchmaker." To some extent, it just happens." http://www.scient...plexity/

Do you agree with Nei? "...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world."

JVK
Jan 01, 2015
...you don't know the difference between genetics and epigenetics.


I know males and females are not differentiated by mutated genes. We established that in 1996 before I established the fact that all cell type differentiation is nutrient-dependent and pheromone-controlled by feedback loops linked to protein folding by chromatin loops.

1996 From Fertilization to Adult Sexual Behavior http://www.hawaii...ion.html
See our section on molecular epigenetics: "Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species..."

2012 Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. http://www.ncbi.n...24693349

2013 Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353

Jan 01, 2015
You continue your off topic tirades. Splicing makes multiple different mRNAs from a single gene. Splicing does not create new genes, so what you're saying here is completely irrelevant. Splicing is only a part of sexual differentiation. Also consider the differences between the X and Y chromosomes themselves.

JVK
Jan 01, 2015
Splicing is only a part of sexual differentiation.


What, if anything, are you trying to tell us about the role of mutations in the evolution of biodiversity. How does what you claim or avoid claiming compare to what Carl Zimmer wrote in July 2013?

"Others maintain that as random mutations arise, complexity emerges as a side effect, even without natural selection to help it along. Complexity, they say, is not purely the result of millions of years of fine-tuning through natural selection—the process that Richard Dawkins famously dubbed "the blind watchmaker." To some extent, it just happens." http://www.scient...plexity/

Do you agree with Nei? "...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world."

Splicing does not create new genes


What enables the de novo creation of olfactory receptor genes?

Jan 02, 2015
Mutations produce novel genotypes, which produces novel phenotypes.

http://www.scienc...2649.htm

An extension of what Zimmer's talking about:

http://sites.duke...ZFEL.pdf
http://www.biolog...t/7/1/35

What enables the de novo creation of olfactory receptor genes?


http://www.ncbi.n...1180675/
http://hmg.oxford...153.full

The gene family has expanded mainly by tandem duplications


the fact that tandem duplications have been the primary mechanism for OR family expansion


local duplications, likely mediated by unequal recombination, are the major force creating new OR genes

JVK
Jan 02, 2015
Vosshall's group is one of several to show that the odor-induced de novo creation of olfactory receptor genes is nutrient-dependent, pheromone-controlled, and perturbed by the mutations that you have been taught to believe lead to increasing organismal complexity.

Mutations produce novel genotypes, which produces novel phenotypes.


That is the most biologically uninformed statement anyone can make. It automagically links genotype and phenotype at a time when others have detailed links from metabolic networks to genetic networks.

1) Feedback loops link odor and pheromone signaling with reproduction http://www.scienc...05009815

2) Signaling Crosstalk: Integrating Nutrient Availability and Sex
http://www.ncbi.n...3932994/

3) Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. http://www.ncbi.n...24693349

JVK
Jan 02, 2015
Vosshall 1) Amino Acid Residues Contributing to Function of the Heteromeric Insect Olfactory Receptor Complex
http://www.ploson....0032372

Vosshall 2) orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET http://www.ncbi.n...3696029/

Vosshall 3)Evolution of mosquito preference for humans linked to an odorant receptor
http://dx.doi.org...ure13964
Conclusion: "Such host shifts not only impact the efficiency of mosquitoes as vectors of infectious disease, but contribute to the economic damage caused by agricultural
pests49 and play a key role in the formation of new species50."

Kohl (2012) http://www.ncbi.n...24693349 Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans (Keller et al., 2007; Kohl, 2007; Villarreal, 2009; Vosshall, Wong, & Axel, 2000).

Jan 02, 2015
That is the most biologically uninformed statement anyone can make. It automagically links genotype and phenotype at a time when others have detailed links from metabolic networks to genetic networks.


That's how nature works Kohl. If I would jump off a cliff would I 'automagically' fall down?
In your opinion all the current life forms were created non-automagically? Right....

Jan 02, 2015
Where is the research on pediatric cancers? 96% of all NCI research dollars goes towards adult cancers, only 4% goes towards pediatric cancers. The average number of years lost due to adult cancers: 15. Average number of years lost due to pediatric cancers: 71.

Our most precious resource is our children, but the NCI does not fund that way. Even a 50-50 funding formula would be a huge improvement!!

Jan 02, 2015
I wonder how much of the "bad luck" only section has cancers that have genetic cues that we haven't discovered yet?

@jjanes34 You're comparing an aspect, average of years lost. I get that, now tell me how much of the population is affected in each demographic? Are adults considered 18+? If 33% of the adult population dies from cancer (made up number, I'm requesting this to be properply provided) while only 1% of children are affected by cancer, then the proportions make more sense. Of course what affects most of humanity doesn't necessarily get the appropriate funding either.

cjn
Jan 02, 2015
transgenerational epigenetic inheritance of mutations


Thanks for, once again, proving you don't know the difference between genetics and epigenetics. Mutations, which alter DNA base sequence, occur at the genetic level.


My head just exploded.....

Why the feedback loop of stupid, when you already acknowledge that a) mutations can be inherited, and b) mutations have to be in the DNA to be inherited?


Jan 02, 2015
Vosshall's group is one of several to show that the odor-induced de novo creation of olfactory receptor genes is nutrient-dependent, pheromone-controlled, and perturbed by the mutations that you have been taught to believe lead to increasing organismal complexity.


Duplication is a type of mutation, Kohl. If you read the last link I posted, you would know that

These highly similar sequence blocks of OR genes in distant genomic locations can in fact be disadvantageous, since they can mediate genomic rearrangements. For example, two widely separated copies of a block containing OR7E pseudogenes on human chromosome 8 occasionally recombine to cause chromosomal abnormalities with associated mental handicap


Duplications, as with all other mutation types, can be advantageous and detrimental. It all depends on what the resulting phenotype is.


Jan 02, 2015
I read through the Vosshall papers. I saw no indication that they confirmed creation as nutrient-dependent/pheromone-controlled. That's because that's not what those papers were about. They were about, respectively, what amino acids are conserved in the receptors, how behavior is influenced by receptor mutants, and how AaegOr4 affects human odor specificity. None of them concerned how the receptors came to be and they certainly did not confirm your claim.

Jan 02, 2015
Cancer was rare 100 years ago. So "bad luck" is cop out particularly for scientists who MUST know better

JVK
Jan 02, 2015
None of them concerned how the receptors came to be and they certainly did not confirm your claim.


All experimental evidence of biologically-based cause and effect confirms my claims, and more of it is published each week. Here's the latest:

Defying textbook science, study finds new role for proteins
http://www.scienc...2314.htm

Science idiots can't understand it, but they've never understood anything except evolution for dummies taught to them by dummies who believe in beneficial mutations.

See for contrast: Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
http://www.ncbi.n...24693353

During the past decade serious scientists have learned that RNA-mediated cell type differentiation occurs via amino acid substitutions that stabilize protein folding and that mutations perturb protein folding, which is why anyone who claims there are beneficial mutations is a science idiot.

JVK
Jan 02, 2015
"bad luck" is cop out particularly for scientists who MUST know better


Read their published work. They use population genetics to support their claims after eliminating all aspects of nutrient-dependent pheromone-controlled cell type differentiation. They exclude breast, ovarian, cervical, and prostrate cancer from their analysis and support the evolution industry as they were told to do.

It's not their fault. They were taught to believe in theories by others who were taught to believe in ridiculous theories. It will never end until everyone realizes this:

"[W]hat Haldane, Fisher, Sewell Wright, Hardy, Weinberg et al. did was invent.... Evolution was defined as "changes in gene frequencies in natural populations." The accumulation of genetic mutations was touted to be enough to change one species to another.... Assumptions, made but not verified, were taught as fact." http://www.huffin...211.html

Jan 02, 2015
@jvk

"During the past decade serious scientists have learned that RNA-mediated cell type differentiation occurs via amino acid substitutions that stabilize protein folding and that mutations perturb protein folding, which is why anyone who claims there are beneficial mutations is a science idiot."

Mutations aren't necessary for protein misfolding.

http://www.fasebj...115.full


JVK
Jan 03, 2015
Mutations aren't necessary for protein misfolding.


Great link! Do you think that they showed mutations are beneficial in their 2008 review of "...protein misfolding and disease."?

Excerpt: "The common element of proteins is the peptide backbone formed by peptide bonds that link the amino acids."

Did you see: "Table 2.
Summary of protein misfolding diseases and the related proteins and peptides in human."?

Table 2 includes sickle cell disease, which many science idiots attribute to a beneficial mutation.

See also:
http://phys.org/n...firstCmt

Conclusion: "The anonymous fools and idiot minions of biology teachers like PZ Myers continue to ignore everything known about the bio-physically chemistry of protein folding and tout pseudoscientific nonsense about mutations."

Attempting to discuss facts on phys.org is futile.

Jan 03, 2015
Do you think that they showed mutations are beneficial in their 2008 review of "...protein misfolding and disease."?

Why would they? Their focus was on protein misfolding in relation to disease.
Excerpt: "The common element of proteins is the peptide backbone formed by peptide bonds that link the amino acids."

Why are you quoting secondary school knowledge? Who do you think you're talking to at phys.org?
Table 2 includes sickle cell disease, which many science idiots attribute to a beneficial mutation.

This assertion proves that you don't have a basic understanding of genetics. The sickle gene mutation is of course nonadvantageous for patients who are homozygous for the sickle gene (SS) since they suffer from sickle cell anaemia but is beneficial for healthy heterozygotes (carriers, AS) who are protected against the danger of dying of malaria, as was firmly established through a number of clinical field studies from different parts of Africa.

Dug
Jan 05, 2015
"Bad luck" and coincidence do not exist, but are the by-products of the ignorance of and or failure to observe causation.

JVK
Jan 05, 2015
Finally, a sign of intelligent life on phys.org

Thanks Dug.

...the by-products of the ignorance of and or failure to observe causation.


"...the only worthwhile biology is molecular biology. All else is "bird watching" or "butterfly collecting." Bird watching and butterfly collecting are occupations manifestly unworthy of serious scientists!" http://icb.oxford...citation

"...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla." http://www.jstor..../4444260

"If you learnt evolutionary biology and genetics a decade or more ago you need to be aware that those debates have moved on very considerably, as has the experimental and field work on which they are based." (p 1014) http://jp.physoc....007.full

JVK
Jan 05, 2015
...as was firmly established through a number of clinical field studies from different parts of Africa.


Nothing about biologically based cause and effect has been firmly established by starting from a ridiculous theory about beneficial mutations, collecting data, and meaningfully interpreting it as if it made sense in the context of what is known about physics, chemistry, and molecular biology. Meaningful interpretations of meaningless data make sense only to pseudoscientists.

How can anyone not know that? https://www.youtu...X_0jDsrw

Jan 05, 2015
I wonder if the 'bad luck ' is not being in a society that sets profit above health? Chlorine in our tap water, flouride based drugs to cross the blood brain barrier, perfumes and preservatives in our rancid cooking oils............

cjn
Jan 06, 2015
katesisco
I wonder if the 'bad luck ' is not being in a society that sets profit above health? Chlorine in our tap water, flouride based drugs to cross the blood brain barrier, perfumes and preservatives in our rancid cooking oils............


No argument that we accept risk to offset initial cost of things, but FTA:
" "You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations," says Tomasetti. However, the scientists saw the opposite finding in mouse colons, which had a lower number of stem cell divisions than in their small intestines, and, in mice, cancer incidence is lower in the colon than in the small intestine. They say this supports the key role of the total number of stem cell divisions in the development of cancer."

JVK
Jan 06, 2015
http://www.ncbi.n...3960065/

The recently detailed mouse model (Li et al., 2013) builds on what is known about olfactory/pheromonal communication in species from microbes to man and incorporates works from mammals that elucidate the molecular mechanisms that are clearly involved.

The result of this synergy is (1) a liver enzyme that oxidizes trimethylamine to (2) an odor that causes (3) species-specific behaviors. Thus, the complex systems that biology required to get from nutrient acquisition and nutrient metabolism to species-specific odor-controlled behavior is exemplified by adaptive evolution of an attractive odor to mice that repels rats (see for review Li et al., 2013).

This synergy requires at least two things to happen simultaneously: for example, (1) natural selection for nutrient chemicals and (2) sexual selection for odor production.

JVK
Jan 06, 2015
http://www.ncbi.n...3960065/

Cont:

Sexual selection for nutrient-dependent odor production is not likely to be achieved via one mutation involved in nutrient acquisition and another mutation that is involved in odor production because two mutations are not likely to simultaneously occur.
-----------------------------------------
However, feed the mice foods that have been chemically processed or feed them excess amounts and their gut bacteria will cause links between metabolic networks and genetic networks manifested as mutations linked to cancer via amino acid substitutions that typically differentiate cell types linked to health until perturbed metabolism leads from perturbed RNA-mediated protein folding to pathology (not typically seen in mice or other animals).

Call that "bad luck" and fix the problem with a pill. Support extension of the evolution industry to evolutionary medicine, or die trying.

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