4 ms·

>"I have looked through the literature in great detail and I can’t find a single recent paper where anyone has even tried curing mice of cancer." It's interest

by nonbel 11y ago

>"I have looked through the literature in great detail and I can’t find a single recent paper where anyone has even tried curing mice of cancer." It's interesting how your perspective will change after reading the literature. It is the same thing with the various mutations claimed to cause cancer. For example, in this thread someone claims mutations to BRAF cause cancer. I am nearly certain that inspecting the literature will not result in any studies where that gene in a normal cell was mutated, and then it took on the properties of a cancer cell. Maybe we will see some data on many cell generations later and in conjunction with various other treatments, but not the direct experiment of "non-cancer cell + BRAF mutation = cancer cell" while "non-cancer ell + control treatment = non-cancer cell".

danieltillett 11y ago
Cancer in humans is never driven by one mutation - if it were there is no way we could reach adulthood. Cancer is the slow process of accumulating mutations in cell lineages - the time between the first mutation in say BRAF and a metastatic cancer is 20 to 40 years. Lots of other mutations have to happen before you get clinical cancer.
- nonbel 11y ago
  So which combinations of mutations cause cancer then? Replace BRAF in my pseudo-equations above with "combination of mutations".
  - danieltillett 11y ago
    There are hundreds of thousands of mutation combinations that lead to cancer. This is why it is such a difficult problem.
    - nonbel 11y ago
      Has anyone done a proof of principle though. You only need to test one of the combinations. I don't think anyone has been able to do this.
      - danieltillett 11y ago
        This is a good question for which I don’t have the answer. We know from epidemiological research that you need at least 5 independent mutations to get to metastatic cancer. With the new CRISPR technology it should now be possible to make cells containing just 5 mutations which should then be able to be studied. The bigger problem is these 5 mutations can be drawn from hundreds of possible genes so the combinations are almost endless.
        nonbel 11y ago
        >"We know from epidemiological research that you need at least 5 independent mutations to get to metastatic cancer." This is all based on the Armitage and Doll 1954 theory, they write: "This result will be valid for large values of t (of the order of a human lifetime) provided that p_l x t, P_2 x t, ..., p_r x t are all sufficiently small (as could be assumed in an application of this theory to human cancer)" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007940/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007940/ Here, the "the probability of occurrence of the r-th change, in that line of descent, is p, per unit time [t]". So obviously if p or t is large enough, the probability of dying from cancer goes above 1, which is non-physical. There is a simplification being made here that was reasonable in the pre-computer age. What happens if you implement the same theory without that simplification?
- nonbel 11y ago
  >"the time between the first mutation in say BRAF and a metastatic cancer is 20 to 40 years" Actually do you have a ref for this? I can't easily think of how they would date the mutation.
  - danieltillett 11y ago
    I haven’t got one off the top of my head, but it is pretty well known. An really good example was the atomic bombs in Japan. They tracked all the survivors and when they got cancer and the delay was in decades.
chrisamiller 11y ago
You're right, of course. BRAF mutations alone don't cause cancer. They're caused by the accumulation of key mutations coupled with clonal expansion. I oversimplified a bit while making a point about basket trials.
- nonbel 11y ago
  That's not what I meant. I said "and in conjunction with various other treatments", which was perhaps poor wording since by treatment I meant causing other mutations/etc. To my knowledge, no one has ever been able to take a normal cell, do X to it (where X is usually some combination of mutations), and see it becomes a cancer cell.

by nonbel 11y ago

danieltillett 11y ago

Cancer in humans is never driven by one mutation - if it were there is no way we could reach adulthood. Cancer is the slow process of accumulating mutations in cell lineages - the time between the first mutation in say BRAF and a metastatic cancer is 20 to 40 years. Lots of other mutations have to happen before you get clinical cancer.

nonbel 11y ago
So which combinations of mutations cause cancer then? Replace BRAF in my pseudo-equations above with "combination of mutations".
- danieltillett 11y ago
  There are hundreds of thousands of mutation combinations that lead to cancer. This is why it is such a difficult problem.
  - nonbel 11y ago
    Has anyone done a proof of principle though. You only need to test one of the combinations. I don't think anyone has been able to do this.
    - danieltillett 11y ago
      This is a good question for which I don’t have the answer. We know from epidemiological research that you need at least 5 independent mutations to get to metastatic cancer. With the new CRISPR technology it should now be possible to make cells containing just 5 mutations which should then be able to be studied. The bigger problem is these 5 mutations can be drawn from hundreds of possible genes so the combinations are almost endless.
      - nonbel 11y ago
        >"We know from epidemiological research that you need at least 5 independent mutations to get to metastatic cancer." This is all based on the Armitage and Doll 1954 theory, they write: "This result will be valid for large values of t (of the order of a human lifetime) provided that p_l x t, P_2 x t, ..., p_r x t are all sufficiently small (as could be assumed in an application of this theory to human cancer)" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007940/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007940/ Here, the "the probability of occurrence of the r-th change, in that line of descent, is p, per unit time [t]". So obviously if p or t is large enough, the probability of dying from cancer goes above 1, which is non-physical. There is a simplification being made here that was reasonable in the pre-computer age. What happens if you implement the same theory without that simplification?
nonbel 11y ago
>"the time between the first mutation in say BRAF and a metastatic cancer is 20 to 40 years" Actually do you have a ref for this? I can't easily think of how they would date the mutation.
- danieltillett 11y ago
  I haven’t got one off the top of my head, but it is pretty well known. An really good example was the atomic bombs in Japan. They tracked all the survivors and when they got cancer and the delay was in decades.

chrisamiller 11y ago

You're right, of course. BRAF mutations alone don't cause cancer. They're caused by the accumulation of key mutations coupled with clonal expansion. I oversimplified a bit while making a point about basket trials.

nonbel 11y ago
That's not what I meant. I said "and in conjunction with various other treatments", which was perhaps poor wording since by treatment I meant causing other mutations/etc. To my knowledge, no one has ever been able to take a normal cell, do X to it (where X is usually some combination of mutations), and see it becomes a cancer cell.