Armitage-Doll was a nice advance over previous models, but it's also incomplete (and probably flat wrong in some cases, although working on pediatric malignancies has convinced me that a second cooperating event usually is mandatory).
In normal stem cells, it appears that attrition and immune clearance gets rid of damaged cells when they cycle and senescent cells all the time (subject to some variation, not entirely age related, at least in our volunteers). We may expect higher rates in filter organs, but liver cancer isn't too common, and the paper I referenced earlier shows that this can't be just an issue of fewer divisions (I despise the oversimplified Tomasetti & Vogelstein paper because the facts simply don't support it). Colorectal is probably more common because the crypts are "facing out" ala melanocytes, thus prone to accumulating lots of environmental damage.
Anyways, the latter of your possibilities (proliferative mutants divide faster and error more often than normal counterparts) makes the most sense -- the eventual "winner" in a tumor is the cell that produces the most progeny and resists apoptosis due to stress the best. It's probably not a coincidence that these are traits which adapt a mutated cell to survive chemotherapy as well. However, spawning nonself mutations willy-nilly is a great way to attract immune attention -- particularly if you haven't blown the immune system away by nuking it with chemotherapy. :-/
maybe, or you can use the full Armitage and Doll model I described above and replace t with something like a discrete exponential decay where N(t) = number of divisions since zygote as a function of time. Ie
N(t) = N0(1 - k)^t + 1
where
N0 = N_birth - N_adult
That is, take the difference between division rate at birth and division rate as adult and fit a constant k between zero and one. It is just a first approximation at best because data on division rate by age in various tissues doesn't seem available...
The majority of pediatric malignancies are either germline related, in utero (de novo mutation/SV, potentially caused or facilitated by maternal environmental exposures), or a reverse lottery winner. There simply isn't enough time for somatic mutation to cause the sort of devastating fallout that you see in DIPG or infant leukemias. (Furthermore, even the point mutations seen in pediatric cases are characteristic and rare or absent in adults; some structural variants are also observed in adults, but they are much rarer and accompanied by fewer cooperating events)
>"There simply isn't enough time for somatic mutation to cause the sort of devastating fallout that you see in DIPG or infant leukemias."
This depends on the error + division rates (along with number of cells) in that tissue at that age though. From my research there not really such data available on any of those terms. Also, the errors need not be somatic mutation. For example, chromosomal missegregation may be much more common and potent since it can mess up the expression of many genes at once:
I'm just saying there are a number of other assumptions being made here, and if we get rid of the standard ones the Armitage-Doll model is capable of fitting the data surprisingly well.
In normal stem cells, it appears that attrition and immune clearance gets rid of damaged cells when they cycle and senescent cells all the time (subject to some variation, not entirely age related, at least in our volunteers). We may expect higher rates in filter organs, but liver cancer isn't too common, and the paper I referenced earlier shows that this can't be just an issue of fewer divisions (I despise the oversimplified Tomasetti & Vogelstein paper because the facts simply don't support it). Colorectal is probably more common because the crypts are "facing out" ala melanocytes, thus prone to accumulating lots of environmental damage.
Anyways, the latter of your possibilities (proliferative mutants divide faster and error more often than normal counterparts) makes the most sense -- the eventual "winner" in a tumor is the cell that produces the most progeny and resists apoptosis due to stress the best. It's probably not a coincidence that these are traits which adapt a mutated cell to survive chemotherapy as well. However, spawning nonself mutations willy-nilly is a great way to attract immune attention -- particularly if you haven't blown the immune system away by nuking it with chemotherapy. :-/