Cancer causes: circa 67% are Replication error

[jim mcnamara]

New article, abstract:

http://science.sciencemag.org/content/355/6331/1330
abstract:

Most textbooks attribute cancer-causing mutations to two major sources: inherited and environmental factors. A recent study highlighted the prominent role in cancer of replicative (R) mutations that arise from a third source: unavoidable errors associated with DNA replication. Tomasetti et al. developed a method for determining the proportions of cancer-causing mutations that result from inherited, environmental, and replicative factors (see the Perspective by Nowak and Waclaw). They found that a substantial fraction of cancer driver gene mutations are indeed due to replicative factors. The results are consistent with epidemiological estimates of the fraction of preventable cancers.

 

[Greg Bernhardt]

But do those replicative factors have causes or are they pure chance?

 

[jim mcnamara]

@Ygggdrasil is closer to the subject than I am. I do not know positively. My take is that replication errors appear to be random. Which raises the question- why are:
smoking cessation,
plant based diets,
weight control,
regular exercise
indicators for cancer prevention/reduction?

Back a few years ago, models supported a higher proportion of cancers being related to the environment than other causes. The physicians I know still buy that model or something very similar.

There is and associated perspective article, I cannot get to it.

 

[atyy]

New article, abstract:

http://science.sciencemag.org/content/355/6331/1330
abstract:

But do those replicative factors have causes or are they pure chance?

This group had a previous paper http://science.sciencemag.org/content/347/6217/78.

That paper was widely reported in the news as showing that cancer was due to bad luck. The original paper was critiqued by Romain Brette: http://romainbrette.fr/is-cancer-due-to-bad-luck/.

A comment in Brette's post mentions http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html.

 

[Ygggdrasil]

This has been an active topic of research for the past few years. It began with the 2015 Science paper mentioned by @atyy http://science.sciencemag.org/content/347/6217/78, which we discussed previously on Physics Forum: https://www.physicsforums.com/threads/bad-luck-is-primary-cause-of-most-cancer.790125/

A paper was subsequently published in Nature, challenging the conclusions of the Science paper: http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html. I wrote an Insight article discussing this paper: https://www.physicsforums.com/insights/causes-cancer-bad-luck-bad-lifestyles/

In late 2016, researchers published an analysis of mutation rates in a few tumor types testing some of the assumptions of the above studies: http://www.nature.com/nature/journal/v538/n7624/full/nature19768.html

I haven't had the opportunity yest to read the latest study in detail yet, but here's a summary of what to think about the study from a news piece in Science:

Martin Nowak, who studies mathematics and biology at Harvard University, praises the authors for pushing the question of how much of cancer is due to random “bad luck” mutations, and for using statistics to probe the disease. But Nowak thinks we’re a long way from having the solution in hand, and worries about putting too much stock in the numbers being advanced right now. “It will take many years to settle” what proportion of cancer-causing mutations are random, he says. Not to mention what to do about them.

http://www.sciencemag.org/news/2017/03/debate-reignites-over-contributions-bad-luck-mutations-cancer

Nowak co-wrote a piece to accompany the Science article, providing some additional mathematical modeling of cancer initiation and progression:
http://science.sciencemag.org/content/355/6331/1266

Could be a topic that would interest the physics and math side of PF.

 

[Ygggdrasil]

@Ygggdrasil is closer to the subject than I am. I do not know positively. My take is that replication errors appear to be random. Which raises the question- why are:
smoking cessation,
plant based diets,
weight control,
regular exercise
indicators for cancer prevention/reduction?

Back a few years ago, models supported a higher proportion of cancers being related to the environment than other causes. The physicians I know still buy that model or something very similar.

There is and associated perspective article, I cannot get to it.

All parties seem to agree with epidememiological research compiled by Cancer Research UK that says that ~40% of cancer cases can be prevented by lifestyle changes:

In the UK, more than 1 in 2 people will develop cancer at some point in their lives. Every year, more than 350,000 people are diagnosed with the disease. But experts estimate that more than 4 in 10 cancer cases could be prevented, largely through lifestyle changes, such as:

• not smoking
• keeping a healthy bodyweight
• eating a healthy, balanced diet
• cutting back on alcohol
• enjoying the sun safely
• keeping active
• doing what you can to avoid certain infections (such as HPV or hepatitis)
• being safe at work (see cancer risks in the workplace)

http://www.cancerresearchuk.org/about-cancer/causes-of-cancer/can-cancer-be-prevented

The recent Tomasetti et al. paper suggests that 40% is close to the upper limit for prevention. Others (such as the http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html from late 2015) suggest that there might be additional environmental or genetic factors that could increase the fraction of preventable cancers.

 

[atyy]

This group had a previous paper http://science.sciencemag.org/content/347/6217/78.

That paper was widely reported in the news as showing that cancer was due to bad luck. The original paper was critiqued by Romain Brette: http://romainbrette.fr/is-cancer-due-to-bad-luck/.

A comment in Brette's post mentions http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html.

This has been an active topic of research for the past few years. It began with the 2015 Science paper mentioned by @atyy http://science.sciencemag.org/content/347/6217/78, which we discussed previously on Physics Forum: https://www.physicsforums.com/threads/bad-luck-is-primary-cause-of-most-cancer.790125/

A paper was subsequently published in Nature, challenging the conclusions of the Science paper: http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html. I wrote an Insight article discussing this paper: https://www.physicsforums.com/insights/causes-cancer-bad-luck-bad-lifestyles/

The first paper seems to be based on wrong reasoning, as both the Brette critique and the Nature paper you comment on say.

Although there may be an interesting discussion to be had, it seems unfortunate that the discussion started from erroneous statistical interpretation.

 

[Buzz Bloom]

I have not read all of all the articles, but I think I got the gist, and I am puzzled. There is a lot to read, so I am hoping someone will help me with a short cut to get past my confusion. The gist I get has three parts.
1. It is known that there are environmental causes of cell DNA mutations that after some accumulation (of usually more than one mutation) cancer results.
2. Inherited DNA can also cause some of these mutations which make some individuals in some families more likely to develop cancer.
3. Some kinds of cells in the body are more likely than others to develop these mutations that lead to cancer.

(3) seems to be the point of the first cited article in post #1.

My confusion is that I don't get how the concept of bad-luck fits into any model that can calculate what fraction of cancer can be attributed to bad-luck.

ADDED
I have just read the summary

http://wtkr.com/2017/03/25/bad-luck-mutations-increase-cancer-risk-more-than-behavior-study-says/.​

This clarified my confusion. I suppose that if I had read the entire original linked article I would have come to the same clarity, but I think it would have been more difficult.

 

[PaulCallaghan]

This has been an active topic of research for the past few years. It began with the 2015 Science paper mentioned by @atyy http://science.sciencemag.org/content/347/6217/78, which we discussed previously on Physics Forum: https://www.physicsforums.com/threads/bad-luck-is-primary-cause-of-most-cancer.790125/

A paper was subsequently published in Nature, challenging the conclusions of the Science paper: http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html. I wrote an Insight article discussing this paper: https://www.physicsforums.com/insights/causes-cancer-bad-luck-bad-lifestyles/

In late 2016, researchers published an analysis of mutation rates in a few tumor types testing some of the assumptions of the above studies: http://www.nature.com/nature/journal/v538/n7624/full/nature19768.html

I haven't had the opportunity yest to read the latest study in detail yet, but here's a summary of what to think about the study from a news piece in Science:

http://www.sciencemag.org/news/2017/03/debate-reignites-over-contributions-bad-luck-mutations-cancer

Nowak co-wrote a piece to accompany the Science article, providing some additional mathematical modeling of cancer initiation and progression:
http://science.sciencemag.org/content/355/6331/1266

Could be a topic that would interest the physics and math side of PF.

in re McNamara's question why such large commentary on cancer by smoking, diet, lifestyle, if random effects so large? I thought from school days that DNA replication error rates were related to stress level on the DNA copying system, like stressed dirty hot photocopier's produce more errors than with cleaned 'less-stressed' photo-copy machine. So an improved diet/lifestyle improves biomechanical efficiency of the copier. So bad luck is inheriting a bad copier system, so you need new body or DNA upgrade. Perfect opportunity for 'Crispr Cas-9' based DNA upgrade 'epi-pen' to come to market via Pennsylvania University study later this year, or China's very own human cancer sufferer test subject last year. I am just surprised its not in the Financial Venture market media as well as the Maths & Bio science community. Or crowdfunding Immortality Inc. via Facebook. I would invest a £100. times 100 mill people = £10billion.should be easy.

 

[Ygggdrasil]

In graduate school, a wise colleague once told me that, if you want to figure out if a paper is trustworthy or not, don't look at the data—look at the methods. With that in mind, here's an example of how the Tomasetti paper estimates the fraction of mutations resulting from replicative errors:

There is a lot more complicated math involved in other cases, but this description is much shorter, easier to understand, and illustrates the flaws and limitations of the study. The study relies on existing epidemiological data to craft their estimates of the fraction of mutations due to replication error. As one can see above, most of their "calculations" are back-of-the-envelope estimates based on those data. Thus, the starting point for most of their calculations is the premise that ~40% of cancers can be prevented by lifestyle changes. Next, they assume that the other 60% of cancers cases must all be unpreventable, essentially making the assumption that that all causes of cancer are currently known and accounted for. Finally, they make the assumption that all cancer cases not from known environmental or known genetic sources are due solely to replicative error. From these starting points and assumptions, they estimate that 66% of all cancer-promoting mutations are due to replicative error.

Thus, a better way to phrase the conclusion of the paper would be: if ~60% of cancers cannot be prevented, then ~70% of cancer-promoting mutations are due to replicative error (the fraction of unpreventable mutations will always be higher than the fraction unpreventable cancers because most cancers require more than one mutation to arise). The article does not really add much new data to understand the fraction of preventable cancers, but rather just takes already published estimates, plugs those into a couple of equations, and comes out with a rough estimate of the fraction of mutations from replicative error. Therefore, I would echo the sentiment from Martin Nowak I posted previously, and say that the numbers from this paper are very rough estimates that are nowhere close to being set in stone. For example, the http://www.nature.com/nature/journal/v529/n7584/full/nature16166.html paper from Nature used a very different method for estimating the fraction of mutations due to replicative error (based on studying the pattern of mutations from DNA sequencing data) and came up with very different estimates. The study also does not rule out the possibility that other factors contributing to cancer could be recognized and increase the fraction of preventable cancers.

It's also worth noting that some of the actual data collected by the authors of the study suggests the fraction of preventable cancers might be somewhat higher. The authors collected data on cancer incidence rates in many different countries and found that cancer incidence in a particular organ correlates well with number stem cell divisions in that particular organ. However, other researchers have looked at that data and noted that the differences in cancer rates among the countries supports a high contribution of supposed environmental factors (this argument was also made in the Wu et al. paper referenced above). This paper will certainly not be the last we hear of this debate.

 

[DrDu]

In this context, I would like to mention several stochastic models of carcinogenesis, like the TSCE (Two stage clonal expansion model of Moolgavkar), which, due to their strong mathematical content, are a playground for physicists. These models have been fit data from many cohorts of men and animals to see how carcinogens effect carcinogenesis. All these methods have in ocmmon, that there is a baseline mutation rate, which may be increased by some toxic agent. However, the adequacy of other model assumptions is often dubious, as for example the number of rate limiting steps. Nevertheless I got the impression from these models, that the human body is quite robust against deterious external influences and that most of the cancer is due to chance. http://www.math.lsa.umich.edu/~millerpd/docs/501_Fall12/RafaelMezaAIMFacultyPortrait.pdf

 

[jim meyer]

Rather than say this is random chance why not say "we don't why it happens". That would be more accurate would it not? And then we can look for a reason. I have an opinion on why it seems to be random and yet is not random at all. The idea I have is the four letters used to construct DNA are made of atoms that are not all the same-there are two atoms(potassium and calcium) with three stable isotopes each. These elements are common components of the cells and it could be some odd combination of isotopes in one or more letters leads a cell to act in odd ways. The isotopes must have some effect on how a cell develops and might even be a factor in evolution of mutations leading to many strange details existing in evolutionary processes.

 

[mfb]

Hydrogen has 2 stable isotopes, oxygen has 3, carbon has 2 plus one with a long lifetime, nitrogen has 2 stable isotopes. The chemical effects of different isotopes have been studied, and in general the difference is negligible. If you have a peer-reviewed study showing that it could have a relevance in DNA replication, we can discuss it, otherwise it is just personal speculation and not allowed here.