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.

>"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.

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.

So which combinations of mutations cause cancer then? Replace BRAF in my pseudo-equations above with "combination of mutations".

There are hundreds of thousands of mutation combinations that lead to cancer. This is why it is such a difficult problem.

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.

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.

>"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/

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?

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.

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.