Saturday, April 08, 2017

Somatic cell mutation rate in humans

A few years ago, Tomasetti and Vogelstein (2015) published a paper where they noted a correlation between rates of cancer and the number of cell divisions. They concluded that a lot of cancers could be attributed to bad luck. This conclusion didn't sit well with most people for two reasons. (1) There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation), and (2) there's a widespread belief that you can significantly reduce your chances of getting cancer by "healthy living" (whatever that is). The first objection is based on solid scientific evidence but the second one is not as scientific.

Some of the objections to the original Tomasetti and Vogelstein paper were based on the mathematical models they used to reach their conclusions. The authors have now followed up on their original study with more data. The paper appears in the March 24, 2017 issue of Science (Tomasetti and Vogelstein, 2017). If you're interested in the debate over "bad luck" you should read the accompanying review by Nowak and Waclaw (2017). They conclude that the math is sound and many cancer-causing mutations are, in fact, due to chance mutations in somatic cells. They point out something that should be obvious but bears repeating.
An understanding of cancer risk that did not take bad luck into account would be as inappropriate as one that did not take environmental or hereditary factors into account...

Cancer is a by-product of the fact that we are made of cells that are individual replicators. Mutations destroy their cooperative program and elicit unwanted replication (defection). Mutants arise whenever cells divide. These normal mutations are due to "bad luck."
This brings me to the topic for today. What is the somatic cell mutation rate?

I did a series of posts on the human mutation rate a few years ago. I calculated the average number of mutations per generation using a standard error rate of DNA replication of 10-10 per base. This means approximately 0.32 mutations every time the haploid genome is replicated (genome size = 3.2 × 109 bp). Given the number of germline cell divisions between generations this equates to 138 mutations per generation [Estimating the Human Mutation Rate: Biochemical Method]. This value is roughly consistent with the estimates from phylogeny [Estimating the Human Mutation Rate: Phylogenetic Method]. The estimates from direct sequencing of parent and child genomes tend to be a bit lower [Estimating the Human Mutation Rate: Direct Method].

There's a lot of debate about which estimates are correct but keep in mind that we're dealing with only a two-fold effect (Ségurel et al., 2014) [see also Human mutation rates; Human mutation rates - what's the right number?]. The consensus seems to be around 100 new mutations per generation. This corresponds to about 0.25 mutations per genome replication and a mutation rate of 0.8 × 10-10 per base pair per replication.

If that rate is the same in somatic cells then there should be about 0.5 (2 × 0.25) new mutations for every cell division.

Tomasetti and Vogelstein disagree with this estimate in their latest paper. They say,
It has been extensively documented that approximately three mutations occur every time a normal human stem cell divides (Lynch, 2010; Tomasetti et al., 2013).
That's six times the expected mutation rate based on germline cell divisions. Why should there be a difference in DNA replication error rates in somatic cells compared to germline cells?

The first reference they give is to a paper by Michael Lynch in 2010. He claims the germline mutation rate is about 0.6 × 10-10 per bp per replication, which is close to the value I calculated above (0.8 × 10-10) (Lynch, 2010; Lynch et al., 2016). His estimate is based on the mutation rate determined from frequencies of disease-causing mutations.

Lynch (2010) also looked at mutations in somatic cells and estimated that the mutation rate in somatic cells is higher than the rate in germline cells. He figures it might be 4-25 times higher. His best estimate of the rate is 7.7 × 10-10 per bp per replication. That's about ten times higher than the germline mutation rate. It corresponds to about 5 mutations every time a cell divides. That's what Tomasetti and Vogelstein are referring to in their 2017 paper.

Lynch thinks this somatic cell mutational load must be enormous. So large, in fact, that there's little hope we can survive much past current life expectancies in industrialized nations. As an example, he notes that the intestinal epithelial cells of an average 60 year-old will each harbor thousands of mutations (4,000 - 40,000) and if you take all these cells into account the tissue will contain more than one million independent mutations.1

The second reference in the Tomasetti and Vogelstein paper is Tomasetti et al. (2013). They looked at whole genome sequences of various cancers and estimated that the somatic cell mutation rate is 6.4 × 10-10 per bp per replication. This is similar to Lynch's value and almost ten times higher than the germline mutation rate.

There are a lot of assumptions and estimates in the Lynch (2010) and the Tomasetti et al. (2013) paper but they seem reasonable to me. However, it doesn't make sense to me that the DNA replication error rate would be ten times higher in typical somatic cells compared to typical germline cells.

The issue gets even more confusing with a paper in one of the latest (March 30, 2017) issues of Nature. In that issue, Ju et al. (2017) looked at whole genome sequences of blood samples from 279 individuals. They were looking for sites where there were multiple variants and one of the variants (alleles) was in the frequency range of 10% to 35%. These are likely due to mutations that occurred early on in embrygenesis so that a substantial fraction of the descendants inherit the mutation. For example, if a mutation occurs at the first cell division of the zygote then half the somatic cells of the adult will carry the mutations and half will have the original allele. Since the cells are diploid, this means that the overall frequency of the mutant allele will be 25%.

Using this technique, the authors calculate that the somatic cell mutation rate during early embryogenesis is about three (2.8) mutations per cell division. This works out to a DNA replication mutation rate of 5 × 10-10 and that's similar to the estimates above for somatic cells. The difference is that this rate is estimated for early embryogenesis creating an awkward situation were germline cells in the same embryo are replicating DNA with an error rate ten time lower (fewer mutations) than the rate in somatic cells. I can't imagine how this happens. How can the embryo "know" which cells are destined to become the germline, especially in the first few divisions?

(Ju et al. don't think there's a problem since they believe the germline mutation rate may be as high as 2 × 10-10. This is not consistent with most studies.)

There's a problem here. I'm skeptical of the somatic cell mutation rates, especially when extrapolated back to embryos. The literature is confusing but most papers conclude that the somatic cell mutation rate is, indeed, higher. In some cases, it could be due to an increase in oxidative damage in some tissues. In other cases, it may be due to increases in methylation that have consequences in repair. I'm not sure these effects are very important in real somatic tissues.


1. Most of Lynch's paper is devoted to concerns about the average germline mutation rate and the genetic load on the species. He is not optimistic about our chances for long-term survival as a species.

Lynch, M. (2010) Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. (USA), 107:961-968. [doi: 10.1073/pnas.0912629107]

Lynch, M. (2016) Mutation and Human Exceptionalism: Our Future Genetic Load. Genetics, 202:869-875. [doi: 10.1534/genetics.115.180471]

Ju, Y. S., Martincorena, I., Gerstung, M., Petljak, M., Alexandrov, L. B., Rahbari, R., Wedge, D. C., Davies, H. R., Ramakrishna, M., and Fullam, A. (2017) Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543:714-718. [doi: 10.1038/nature21703]

Nowak, M. A., and Waclaw, B. (2017) Genes, environment, and “bad luck”. Science, 355:1266-1267. [doi: 10.1126/science.aam9746 ]

Tomasetti, C., and Vogelstein, B. (2015) Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science, 347:78-81. [doi: 10.1126/science.1260825 ]

Tomasetti, C., Li, L., and Vogelstein, B. (2017) Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science, 355:1330-1334. [doi: 10.1126/science.aaf9011]

Tomasetti, C., Vogelstein, B., and Parmigiani, G. (2013) Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc. Natl. Acad. Sci. (USA) 110:1999-2004. [doi: 10.1073/pnas.1221068110 ]

Ségurel, L., Wyman, M.J., and Przeworski, M. (2014) Determinants of mutation rate variation in the human germline. Ann. Rev. Genomics and Human Genetics, 15:47-70. [doi: 10.1146/annurev-genom-031714-125740]

78 comments :

  1. What about selection at the level of the gamete/early embryo? The direct method is looking at comparisons between adults, and is going to underestimate the mutation rate if there is a large amount of selection at that level.

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    Replies
    1. Since 90% of the genome is junk this isn't going to have much effect. The only mutations that will be missed are those in the functional parts of the genome that are heterozygous lethals. The best estimates I've seen say that this will account for much less than 1% of all new mutations.

      Delete
    2. Since 90% of the genome is junk this isn't going to have much effect. The only mutations that will be missed are those in the functional parts of the genome that are heterozygous lethals. The best estimates I've seen say that this will account for much less than 1% of all new mutations."

      Well, it's easy then...

      BTW: I'm just curious how this personal view of yours Larry would change if the human genome were 100% functional or nearly 100%? I mean you have got to take into consideration some people you may find to be ... whatever think of people who worked for ENCODE and supported it...

      To me personally Larry, I don't care one way or the other... but it would be nice to leave a nice legacy behind no Darwinist will spit on when you are I are no longer here to argue these things...Don't you think?

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    3. Jass,

      You do yourself too much credit. You aren't arguing these things. You're just making often incomprehensible snide comments with bad punctuation.

      Delete
    4. Jass,
      If the genome were 100% functional, then, newborns 100 to 200 new mutations would disable many of those "functions." Now think about that going on for generations. How do you think that would be sustainable for our species?

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    5. Jass,

      Even ENCODE is backing off of their higher estimates for functionality in the human genome. They started out at 80%, and have now backed down to 20% functional as supported by sequence conservation data. Given the divergence rates within different parts of the genome, there is nearly 0% chance that the human genome is 100% functional with respect to sequence specific function. You might as well be asking geologists to take into account the possibility that the Earth is square.

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    6. If the human genome were nearly 100% functional (as it is in pufferfish and some bladderworts) we'd have fun researching the mechanisms that remove the non-functional parts!

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    7. "we'd have fun researching the mechanisms that remove the non-functional parts!"

      Certainly!

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    8. Nature has already done the experiments for removing the non-functional parts. It's called genetic drift which causes about 90% of the human genome to diverge at a different rate than the 10% that is functional.

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  2. Are Ju et al assuming that all the early embryonic cells contribute equally to the final organism?

    If so, I think that's an unsafe assumption. There's some brainbow-type work in early embryos to show not all blastomeres contribute equally to the ICM. That means lineages contributing 1:4 of the eventual organism could be 1:8 or less of the original embryo.

    I suspect this would give a systematic upward bias to their estimates.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543519/#!po=33.0882

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    1. Yes, they make that assumption even though they're aware of its limitations. They don't think it's a significant problem but, remember, they also don't think the somatic cell mutation rate is much different than the germline mutation rate!

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  3. Larry
    "A few years ago, Tomasetti and Vogelstein (2015) published a paper where they noted a correlation between rates of cancer and the number of cell divisions. They concluded that a lot of cancers could be attributed to bad luck. This conclusion didn't sit well with most people for two reasons. (1) There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation), and (2) there's a widespread belief that you can significantly reduce your chances of getting cancer by "healthy living" (whatever that is). The first objection is based on solid scientific evidence but the second one is not as scientific."

    If you include getting sunlight as healthy living then I would say that the second claim is indeed true. There is a significant correlation between blood vitamin d levels and several cancer types like colon and breast.


    Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study
    Sharon L. McDonnell , Carole Baggerly, Christine B. French, Leo L. Baggerly, Cedric F. Garland, Edward D. Gorham, Joan M. Lappe, Robert P. Heaney
    Published: April 6, 2016http://dx.doi.org/10.1371/journal.pone.0152441

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    1. If you include getting sunlight as healthy living then I would say that the second claim is indeed true.

      And I guess skin cancer doesn't exist in the fantasy land you seem to inhabit.

      Delete
    2. And I guess skin cancer doesn't exist in the fantasy land you seem to inhabit.

      Your solution is no sunlight, low vitamin d levels and risk of pancreatic, prostate, kidney, liver, lung and other cancers that low vitamin d levels can cause.

      The other choice is vitamin d supplements if your pigment is not compatible with safe sun exposure.

      Delete
    3. Your solution is no sunlight, low vitamin d levels and risk of pancreatic, prostate, kidney, liver, lung and other cancers that low vitamin d levels can cause.

      Once again, Bill Cole proves he is better acquainted with the things he imagines than with the things that actually exist. Unless someone else can point out where I wrote what he claims I wrote.

      Still working on a method to delineate quotes in your posts, I see, Bill. Need some more help with that?

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    4. Here's the most recent review I could find of the evidence supporting the preventative effects of vitamin D supplementation for cancer, courtesy of the Cochrane group (the first source you should check when evaluating the strength of any medical claim):

      http://www.cochrane.org/CD007469/ENDOC_vitamin-d-supplementation-for-prevention-of-cancer-in-adults_

      As usual, Bill's beliefs are running a bit ahead of the evidence to support them.

      Delete
    5. More on point to Bill, a vitamin D deficiency clearly falls into category 1, environmental factors.

      Delete
  4. Dear Dr.,

    May I ask a basic question. When I read that in cancer, recurrent genomic mutation happen. What does that mean. Does it mean inside one individual, there are the same mutation at particular position repeated in all of his cancerous cells. Or it means that among populations, that is the scenario. Or it means that inside one cancerous cell, it change its mutation by time at single position. Also, would you please explain what does it means that mutation rate obey stochastic behavior. And what is opposite to stochastic, is it organized mutation mechanism.

    Thanks in advance.
    Mohamed

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    1. Mohamed, "recurrent mutation" in this case means that there's a mutation in one cell, then the cell divides (and divides) and later there's another mutation in one of the descendant cells. Therefore, some of the cells show two mutations. This can happen again and again, so some cancer cells have many mutations that make them different from normal cells.

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  5. LS
    "As usual, Bill's beliefs are running a bit ahead of the evidence to support them." Vitamin d deficiency was first identified by Dr Garland and his brother in 1980 which correlated colorectal cancer with proximity to the equator. The data showed elevated levels with distance to the equator with high correlation. Since then there are 8000 papers on pubmed that show experimental evidence that low vitamin d levels are implicated in most cancer types. Dr Garland is part of the 2016 paper I cited showing that a 40 ng per ml reduces overall cancer risk by 65%. In addition there are hundreds of papers that show that vitamin d is a down regulator of cell division and blood vessel construction (metastasis). This path is now well understood as part of the WNT beta catenin pathway. The paper you cited show inconclusive results but they did not measure blood levels and correlate that to cancer risk. Vitamin d measurement has become a standard part of blood tests and it is now standard treatment for breast cancer.

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    1. Bill,

      as per default, you seem to confuse many things here.
      1) "There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation)," sun light = enviromental, UV radiation...
      2) Catching rays =! 'living healthy', thus your claim "If you include getting sunlight as healthy living then I would say that the second claim is indeed true." = false.
      3) All evidence you seem to think you're collecting to support your claim, is in fact evidence in support of 1), not 2). 2 being your claim.

      Capiche?

      Delete
    2. The paper you cited show inconclusive results but they did not measure blood levels and correlate that to cancer risk.

      Bill Cole does not understand what a meta-analysis is. The depth and breadth of his ignorance truly defies comprehension.

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    3. Vitamin D...is now standard treatment for breast cancer.

      That is simply, utterly, completely false.

      OK, so Bill is a victim of "crank magnetism," i.e., folks who have no idea how to evaluate things scientifically fall victim to any number of crank ideas, from evolution denialism to climate denialism to homeopathy to, in Bill's case, those concerning cancer, "healthy living," and vitamin D. Of course this doesn't mean particular environmental and particular "lifestyle" factors, including diet, don't affect risk of specific types of cancer. What it absolutely does mean is that a protective effect of vitamin D regarding breast cancer is still not proved, and is very definitely *not* standard treatment for breast cancer. Whether it may be in the future is an open question that will eventually be resolved by science/medicine.

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    4. LS
      Do you agree that blood level testing is important?

      Delete
    5. Ed
      "as per default, you seem to confuse many things here.
      1) "There are many well-known environmental effects that increase cancer rates (e.g. smoking, radiation)," sun light = enviromental, UV radiation...
      2) Catching rays =! 'living healthy', thus your claim "If you include getting sunlight as healthy living then I would say that the second claim is indeed true." = false.
      3) All evidence you seem to think you're collecting to support your claim, is in fact evidence in support of 1), not 2). 2 being your claim.

      Capiche?"

      I think it fits both categories. We have a choice how much time we spend in the sun. We also have a choice to monitor our levels and supplement when needed. I was 33ng/ml and according to the AMA standards of 30ng/ml I was ok. But the 2016 paper I cited showed strong evidence that I would lower my cancer risk if I got my levels above 40 ng/ml so I decided to take supplements of 2000iu.

      Delete
    6. Bill, you're confused about having LOW vitamin D levels, as in a vitamin D deficiency, with vitamin D being somehow a "treatment" or "cure" for a host of ailments.

      It is true that many people have vitamin D deficiencies, either because they don't get enough sunlight, or because of some metabolic syndrome that prevents the body from producing it naturally, or from a reduction in effective uptake of vitamin D from your diet.

      Yes, people who have a DEFICIENCY of vitamin D, will benefit from getting more vitamin D. That doesn't mean people who already have a healthy vitamin D level will benefit from even MORE of it. This is an important distinction.

      If you lack important vitamins and minerals for an extended period of time, you will get sick and vulnerable to all sorts of other ailments. None of this is news. If you eat a balanced diet and get some daylight on exposed skin every day, then most people aren't going to get vitamin D issues.

      But don't think somehow stuffing your face with vitamin D (overdosing on vitamin D can be very dangerous actually), or wasting hours in the sun, is somehow going to prevent or treat cancers. It isn't. Every minute spent in direct sunlight to get vitamin D production in the skin up, is also going to increase your chance of skin-cancer. You don't need more than 20 minutes of daylight on your skin a day if you're a normal healthy person. Getting more than this is wasted because your body actually prevents you from making too much of it by itself.

      Delete
    7. LS
      Do you agree that blood level testing is important?


      No, not for your claim, which was that exposing oneself to lots of sunlight reduced the risk of cancer.

      Delete
    8. Perhaps an analogy would help. If your car engine is low on oil it can cause a whole host of problems. However, jamming your engine with 2 gallons more oil than it needs will also lead to problems. More isn't always better.

      Delete
  6. Judmarc
    From breast cancer.org
    "

    Low Vitamin D Levels


    Vitamin D helps the body absorb calcium, which is essential for good bone health. Vitamin D also helps the immune, muscle, and nervous systems function properly. Most vitamin D is made when an inactive form of the nutrient is activated in your skin when it's exposed to sunlight. Smaller amounts of vitamin D are in fortified milk and other foods, fatty fish, and eggs. As more and more people spend most of their time out of direct sunlight or wearing sunscreen when they are in the sun, vitamin D production from sun exposure is limited.

    Research suggests that women with low levels of vitamin D have a higher risk of breast cancer. Vitamin D may play a role in controlling normal breast cell growth and may be able to stop breast cancer cells from growing.

    Steps you can take
    The two most reliable ways to boost your vitamin D level: get more direct sunlight exposure and take vitamin D3 supplements. Eating foods rich in vitamin D can help, but is less effective."

    The paper I originally cited shows correlation with most cancers. We now know the biochemical pathway that causes run away cell division when the down regulator of the WNT beta catenin pathway DKK transcription is controlled by the VDR protein which is active when the active form of vitamin d binds to it.

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    1. Bill,
      once again you claim something which isn't supported by evidence --> "Vitamin D...is now standard treatment for breast cancer." when the source you quote says "Vitamin D may play a role in controlling normal breast cell growth and may be able to stop breast cancer cells from growing."

      Your claim "Vitamin D...is now standard treatment for breast cancer." is clearly a false claim.

      And you move the goalposts away from the other false claim you made:
      Catching rays =! 'living healthy', thus your claim "If you include getting sunlight as healthy living then I would say that the second claim is indeed true." = false.

      Strike 2!

      Delete
    2. Bill has confused people having a vitamin D DEFICIENCY obviously being in need of more vitamin D, with perfectly healthy people who already have enough vitamin D somehow being able to benefit from even more of it.

      You can actually overdose on vitamin D, which can be very dangerous, so don't stuff your face with it. Eat your balanced diet with some fatty fish and maybe some eggs, then get some daylight on your skin every day. Don't go buying supplements unless you doctor directly recommends it due to you having an actual deficiency. Don't just assume you're deficient, get that checked first before doing anything.

      This is the same as with all the other vitamins the body needs. If you're chronically low on them, you will get sick. But you probably aren't if you eat normal food.

      Delete
    3. Bill - You are now into territory where you may actually be putting people's lives and health at risk with bad advice, so be careful.

      The Susan G. Komen Foundation has a couple of excellent pages on the inconclusive research into vitamin D, including an examination of some of the strengths and weaknesses of different types of studies. Read all of this(!) - it will give you some context that may hopefully get you to see what the possible problems are with spouting falsehoods like "Vitamin D is standard treatment for breast cancer," especially if there are people around you who have risk factors and may foolishly believe you know what you are talking about.

      http://ww5.komen.org/KomenPerspectives/Vitamin-D-%E2%80%93-How-much-is-enough-.html

      http://ww5.komen.org/BreastCancer/Table20VitaminDandbreastcancerrisk.html

      Delete
    4. Rumraket
      "Bill has confused people having a vitamin D DEFICIENCY obviously being in need of more vitamin D, with perfectly healthy people who already have enough vitamin D somehow being able to benefit from even more of it. "



      This is correct, however about half the population is vitamin D Deficient. You are also correct that with oral supplements you can reach a toxic level, however this is difficult. The range quoted by Stanford medical is 25 to 80 ng/ml. Based on Dr Garlands latest paper the level to maintain is around 50 ng/ml.

      "This is the same as with all the other vitamins the body needs. If you're chronically low on them, you will get sick. But you probably aren't if you eat normal food."

      Vitamin D is naturally obtained mostly from the sun. It is difficult to get enough from food. Supplements are the alternative to maintain adequate blood levels. Vitamin D is not just another vitamin. It regulates the cell cycle and also regulates immune responses.

      Delete
    5. This is correct, however about half the population is vitamin D Deficient.

      41.6%, to be exact. Which means your advice would actually increase the risk of cancer for about 60% of the population. Murderer!

      Vitamin D is not just another vitamin. It regulates the cell cycle and also regulates immune responses.

      IOW, it's just another vitamin.

      Delete
    6. LS
      "41.6%, to be exact. Which means your advice would actually increase the risk of cancer for about 60% of the population. Murderer!" :-)

      This number depends on the definition of deficiency. Stanford defines it as 30 ng/ml. The paper I cited shows reduced cancer risk if blood levels are around 40 ng/ml so the benefit appears to be greater then the 41% you cited. I was at 33 and my goal is to get to 50 ng/ml. My brother was at 17 (high risk) so the test may have saved his life. He now takes supplements 2x the dose I take.

      Do you know of another vitamin that directly regulates the cell cycle?

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    7. "Do you know of another vitamin that directly regulates the cell cycle?"

      Does this somehow make vitamin D into not-another-vitamin?

      Delete
    8. Do you know of another vitamin that directly regulates the cell cycle?

      Folate and B12 are involved in cell division.

      Delete
    9. I guess Bill Cole, with his extensive medical expertise, thinks folate and B12 deficiency causes no problems, 'cuz they're "just another vitamin."

      Delete
  7. It would seem to me that the recent cancer papers are a great opening salvo. Off the top of my head, there would seem to be a lot of possible follow up studies that could delve farther into the subject using in vitro cell culture techniques since there are many cell types that can be easily induced to divide in culture (e.g. B-cells, epithelial cells). The hard part would be correlating in vitro rates to in vivo rates, but limiting sequences to a short stretch of DNA may allow for massive parallel workflows.

    Overall, I am skeptical that all tissues experience the same mutational load, as Larry mentioned. The correlation between melanin and skin cancer rates is well known and an obvious indication that environmental exposure to risk factors does still play a role.

    ReplyDelete
  8. JM
    "Bill - You are now into territory where you may actually be putting people's lives and health at risk with bad advice, so be careful."

    I respect your concern here. Since vitamin d is a natural vitamin, maintaining adequate amounts in the blood is not risky. If you want to do research here I suggest you start with pubmed for experimental evidence.
    Search results

    Items: 1 to 20 of 9398<< First< PrevPage of 470Next >Last >>

    Here is the result of the search on pubmed for vitamin d and cancer. This is up from around 8000 the last time I did the search around 6 months ago.

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    1. We've now apparently moved from "It's standard care..." (no) to "It's an interesting topic with a lot of articles about it..." (yes) and vitamin D is "natural." It is; so are many poisons, and you can overdose on vitamin D itself (as someone might do in a misguided attempt to stave off cancer). Or as I pointed out earlier, someone with risk factors or early stages of the disease might dose themselves with vitamin D rather than getting the diagnostic work or effective treatment they need. (There are proven effective treatments for breast cancer, so it would be an absolute sin for someone to be misled into foregoing these.)

      For those wondering about vitamin D as a preventative, as mentioned before the studies are so far inconclusive. (Bill, you cited a big number; I pointed to specific information about how to evaluate these studies. Which do you think is more important - that there are a lot of them, or how to know what the good ones are?)

      Delete
    2. JM
      "
      For those wondering about vitamin D as a preventative, as mentioned before the studies are so far inconclusive. (Bill, you cited a big number; I pointed to specific information about how to evaluate these studies. Which do you think is more important - that there are a lot of them, or how to know what the good ones are?)"

      I suggest you do more homework. There are many epidemiological studies here but the propensity of the evidence shows strong correlation. There is also lots of molecular experimental evidence that supports the epidemiological studies. This is not a cancer cure but a way to prevent cancer and reduce the risk of metastasis. Again, managing your blood levels to 50ng/ml is not risky.

      Delete
    3. but the propensity of the evidence shows strong correlation

      No. (BTW, it's "preponderance" of the evidence, not "propensity.") Bill, you continue to show you have rendered yourself ill equipped to critically evaluate scientific topics.

      Why exactly do you think the Susan G. Komen foundation calls the studies "inconclusive"? Do you think they have a strong interest in *not* having millions of women utilize a treatment modality for which a preponderance of the evidence shows strong correlation with a preventative effect?

      Delete
  9. It's worth pointing out that even if people with higher blood vitamin D levels really do have lower cancer risk, that does NOT necessarily mean that taking supplements will help.

    Getting back to the actual topic, it seems like one could (in principle) sequence cells taken from different tissues or locations in the body and look for mutations unique to each sample. Ideally, most of the cells in each individual sample would be within a few generations of a common precursor, while the different samples are separated by many generations. Maybe take samples that trace back to early endoderm vs. mesoderm vs. ectoderm?

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    1. Q
      "It's worth pointing out that even if people with higher blood vitamin D levels really do have lower cancer risk, that does NOT necessarily mean that taking supplements will help. "

      Would you agree that it helps if supplements are shown to raise blood levels?

      Delete
    2. I think what he's getting at is correlation does not equal causation. If, for instance, darker skinned people were at higher risk of certain cancers for reasons completely unrelated to Vit D (e.g. certain cancer causing alleles being more common in people of African descent), that may result in a spurious correlation. Not to say that was not considered in the research you have cited.

      The best way to settle the question is thru placebo controlled trials of Vit D supplements. Hey, wouldn't you know it? Such a study was released just a few weeks ago. Guess what it found:

      http://jamanetwork.com/journals/jama/article-abstract/2613159

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    3. LS
      Thanks for citing this.
      "Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention."

      The results were slightly better for the supplemented group. The gap here is narrow based on the blood levels. The paper I cited goes below 20 ng/ml to 50g/ml.

      Delete
    4. LS JM
      Here are some additional findings from UCSD.

      After adjustment for age, BMI, smoking status, and calcium supplementation, the age-adjusted cancer incidence was 1020 cases per 100,000 person-years in the Lappe cohort and 722 per 100,000 person-years in the GrassrootsHealth cohort.
      Cancer incidence declined with increased 25(OH)D. Women with 25(OH)D concentrations of at least 40 ng/mL had a 67% lower risk for cancer than women with levels of 20 ng/mL or less (hazard ratio, 0.33; 95% confidence interval, 0.12 - 0.90).
      Other studies have shown similar reductions in risk for individual cancers, Dr Garland noted.
      In one hospital-based case–control study, women with serum concentrations above 60 ng/mL had an 83% reduction in breast cancer risk, compared with women with concentrations below 20 ng/mL (P < .001) (Eur J Cancer. 2005;41:1164-1169).
      In another study, women with 25(OH)D concentrations of at least 30 ng/mL had a 63% lower risk for breast cancer than women with concentrations below 20 ng/mL (PLoS One. 2011;6:e17251). And for postmenopausal women, the risk was 71% lower.
      More recently, a nested case–control study showed that women with 25(OH)D concentrations of at least 29 ng/mL had a 55% lower risk for colorectal cancer than women with concentrations below 18 ng/mL (Cancer Prev Res [Phila]. 2015;8:675-682).

      Delete
    5. The results were slightly better for the supplemented group.

      Not to a statistically significant level. Do you need me to explain what that means?

      Your 2nd post only suggests cancer incidence may be negatively correlated with serum Vit D levels. It has already been explained to you why that does not confirm the claim you are making.

      Delete
    6. There's an interesting trend here, if you look back at what Bill wrote in the past week.
      It starts with the claim that (according to him) living healthy == getting sunlight on your skin. And is followed by many other claims unsupported by evidence. All because Bill can, by his own choice, manage his own vitamin D levels. Which according to claims of Bill (unsupported by any evidence) prevents cancer. Because, hey, he's the living proof high vitamin D == no cancer.

      Problem is Bill, n=1 doesn't hack it.

      If you look back you see the exact same behavior when it comes to other topics in the realm of science. Bill is in favor of ID, because Bill is in favor of ID, n=1, thus ID. He will try to quote papers and come up with all kinds of interesting sciencey lingo, but none of these papers support his claims. As we've seen in the past week, everything he tries to quote in support of his claims, actually has a conclusion 180 degrees opposite of what Bill claims. But still Bill digs on and on, because hey, Bill == n=1, so he's always right.

      Delete
    7. Oops, last bit dropped off.

      And when Bill is shown his errors, he'll pick up the goalposts and move them with general questions, which seem to be related to the topic at hand, but aren't, like:
      "Would you agree that it helps if supplements are shown to raise blood levels?"
      and
      "Do you know of another vitamin that directly regulates the cell cycle?"

      Most alarmingly Bill also comes up with:
      "Vitamin D...is now standard treatment for breast cancer."

      Delete
  10. JM
    I looked at the 4 papers that Komen listed in the meta analysis studies. 3 were blood level tests. All 3 supported the hypothesis that higher blood levels of vitamin d reduced the risk for breast cancer. Again, the epidemical studies are the first layer of the onion. The mechanism of how vitamin d prevents cancer and metastasis is now understood. The Mohr paper in the Komen group is from University of California SD. This is the same group that provided the 2016 paper I cited that does a broad cancer study. Dr Garland who is the leader of this group was the one who discovered this relationship when he was a grad student at John's hopkins in 1980. The original study was for colorectal cancer based on location proximity to the equator. The data showed a steady increase in the populations further away from the equator.

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    Replies
    1. I looked at the 4 papers that Komen listed in the meta analysis studies. 3 were blood level tests. All 3 supported the hypothesis that higher blood levels of vitamin d reduced the risk for breast cancer.

      Yes, Bill, the Susan G. Komen foundation is part of the big conspiracy to keep the good news that vitamin D cures cancer hidden, and they're so effective at it that you managed to penetrate their obfuscation by reading studies *they cited publicly on the Web*.

      Right down the rabbit hole, same as with evolution.

      Delete
  11. I haven't followed much of the somatic mutation rate literature, or the larger debate on how it ties into different tissue types having different cancer risks, but this article by Ed Yong is really informative:

    https://www.theatlantic.com/science/archive/2017/03/no-cancer-isnt-mostly-bad-luck/521049/?utm_source=twb

    ReplyDelete
    Replies
    1. Ed Yong is an excellent science writer. I don't know why he is so opposed to the idea that many cancers are just due to bad luck. Why does that idea upset so many people?

      Do they want to drop into their local children's hospital and tell all the cancer patients that they could have avoided having cancer if they had been more careful? It's their fault (or their parents fault) that they have cancer?

      Delete
    2. Cancer is the result of mutations. I can't understand how anybody could possibly entertain the idea that they built phenomenal molecular machines and complex biological systems.

      Delete
    3. Yes, it's impossible for any reasonable person to believe that different mutations might have different effects.

      Delete
    4. Yes, it's impossible for any reasonable person to believe that different mutations might have different effects.

      This thread has really helped to clarify the problems some of our familiar ID/creationist folks have with the whole concept of critical scientific thinking.

      Delete
    5. Larry
      "Ed Yong is an excellent science writer. I don't know why he is so opposed to the idea that many cancers are just due to bad luck. Why does that idea upset so many people?"

      The data supports more than luck is usually involved.

      " Other studies have shown similar reductions in risk for individual cancers, Dr Garland noted.
      In one hospital-based case–control study, women with serum concentrations above 60 ng/mL had an 83% reduction in breast cancer risk, compared with women with concentrations below 20 ng/mL (P < .001) (Eur J Cancer. 2005;41:1164-1169)."

      We have a choice what our blood levels are. By measuring blood levels and monitoring sun exposure and/or taking supplements as needed to support healthy blood levels.

      Delete
    6. Larry wrote:

      "Do they want to drop into their local children's hospital and tell all the cancer patients that they could have avoided having cancer if they had been more careful? It's their fault (or their parents fault) that they have cancer?"

      Although this isn't particular to childhood cancer, some parents are rethinking having children if one of the parents carries the BRCA2 allele associated with higher breast cancer. Genetic screening for known oncogene alleles could fall under the banner of "you could have prevented your child from having cancer".

      This also brings into question the morality of genetic screening of embryos created through in vitro fertilization, or even editing known oncogenes using CRSPR/Cas9 technology.

      Delete
    7. Larry
      "Ed Yong is an excellent science writer. I don't know why he is so opposed to the idea that many cancers are just due to bad luck. Why does that idea upset so many people?"

      The data supports more than luck is usually involved.


      And. yet again, Bill demonstrates that he doesn't understand words. Here, the words giving him trouble include "many", "data" and "usually". A dictionary might help, except those also tend be filled with words.

      In one hospital-based case–control study, women with serum concentrations above 60 ng/mL had an 83% reduction in breast cancer risk, compared with women with concentrations below 20 ng/mL (P < .001)

      Still doesn't support your claim, though, does it? Why should people with normal Vit D levels expose themselves to sunlight in attempt to reduce their risk of cancer?

      Delete
    8. Here, the words giving him trouble include "many", "data" and "usually".

      There is also "inconclusive," though to be fair it is four syllables.

      Delete
    9. LS


      What do you think are normal levels? If you have 60ng/ml in your blood you are fine for not but what is the measurement in the dead on winter? I simply suggest you monitor your level and supplement or increase sun exposure when needed. You are somewhat vulnerable because you live so far north of the equator.

      "Still doesn't support your claim, though, does it? Why should people with normal Vit D levels expose themselves to sunlight in attempt to reduce their risk of cancer?"

      Delete
    10. OTOH, as a male, I don't have a particularly high risk of breast cancer, do I?

      Delete
    11. I do have a male friend who had it and fortunately survived, though that was not a certainty during the course of the disease.

      All hail the designer who gave men nipples in which to get cancer!

      Delete
    12. Yes, in the rare instance when men do develop breast ca, the prognosis is usually not very good. I'm glad your friend did well!

      Delete
    13. LS
      "OTOH, as a male, I don't have a particularly high risk of breast cancer, do I?"

      Maintaining 60 ng/ml will help prevent most cancers. The mechanism is the same in most cell types. Vitamin d down regulates cell division and also down regulates blood vessel construction in the cell (metastasis). If you have certain mutations in genes like braca and p53 you are more vulnerable because the repair and cell death functions that prevent un wanted cell division are impaired. If you have mutations in genes like APC (part of the beta catenin destruction mechanism) then you are vulnerable because they may impair the destruction of beta catenin and vitamin d can no longer down regulate cell division. If you look at the 2016 paper I cited you will see that it covers many cancer types.

      Delete
    14. Maintaining 60 ng/ml will help prevent most cancers.

      Your idiocy is your affair. I hope not too many family members will be dragged into it.

      Delete
    15. JM
      "Your idiocy is your affair. I hope not too many family members will be dragged into it."

      So you are claiming this papers claims are false?

      Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study
      Sharon L. McDonnell , Carole Baggerly, Christine B. French, Leo L. Baggerly, Cedric F. Garland, Edward D. Gorham, Joan M. Lappe, Robert P. Heaney
      Published: April 6, 2016http://dx.doi.org/10.1371/journal.pone.0152441


      Delete
    16. This article explains why that one study has not led all doctors to scream from the highest mountaintops that everyone should take Vitamin D supplements:

      http://www.medscape.com/viewarticle/861810#vp_1

      Isn't it funny how a couple articles is all it takes to convince Bill of something he already wants to believe, but you could show him a thousand articles supporting evolution and he'll still deny it.

      Delete
    17. "..but you could show him a thousand articles supporting evolution and he'll still deny it."

      Well, I don't know how Bill would respond to that, but the problem for me is that you can't produce any articles or papers, or offer any empirical evidence to support the notion that accidents ever produced a gene, or ribosome, or replication enzymes. All you have is unwarranted faith and a house of religious cards.

      Delete
    18. Tx, we'll take that as a "Ditto." :-)

      Delete
    19. Isn't it funny how a couple articles is all it takes to convince Bill of something he already wants to believe, but you could show him a thousand articles supporting evolution and he'll still deny it.

      In fact I think it is an example of precisely the same thing as the vitamin D business. Bill's got something he wants to believe (ID or vitamin D prevents most cancers), and no amount of actual scientific evidence will shake his faith. At least the ID folks aren't getting money out of him like the vitamin folks and doctors recommending it are - right Bill, the Disco Institute hasn't got you sending money to them?

      Delete
    20. This article explains why that one study has not led all doctors to scream from the highest mountaintops that everyone should take Vitamin D supplements....

      Whatcha wanna bet if Bill quotes from that article, which part of the article it comes from? :-)

      Delete
  12. If cancer is just due to bad luck, then you can't control your own fate, and all of that going to the gym and eating "correctly" has been in vain.

    ReplyDelete
    Replies
    1. all of that going to the gym and eating "correctly" has been in vain

      Well, perhaps not quite all of it. :-) There's likely a cardiovascular benefit, and there are all sorts of potential back and knee ailments that I'm guessing might be minimized by not carrying around that spare tire (which, of course, I am trying to lose). :-)

      Delete
  13. I just noticed this article and thought that some of you might be interested in reading it:

    http://www.bbc.com/earth/story/20160601-is-cancer-inevitable?ocid=fbert

    ReplyDelete