2 ms·

>"pediatric malignancies" maybe, or you can use the full Armitage and Doll model I described above and replace t with something like a discrete exponential dec

by nonbel 10y ago

>"pediatric malignancies" 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... https://s18.postimg.org/9cn5vi8t5/div_Rate.jpg https://s18.postimg.org/9cn5vi8t5/div_Rate.jpg

apathy 10y ago
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)
- nonbel 10y ago
  >"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: "Nevertheless, the rate of chromosome missegregation in untreated RPE-1 and HCT116 cells is 0.025% per chromosome" https://www.ncbi.nlm.nih.gov/pubmed/18283116 https://www.ncbi.nlm.nih.gov/pubmed/18283116 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.

by nonbel 10y ago

apathy 10y ago

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)

nonbel 10y ago
>"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: "Nevertheless, the rate of chromosome missegregation in untreated RPE-1 and HCT116 cells is 0.025% per chromosome" https://www.ncbi.nlm.nih.gov/pubmed/18283116 https://www.ncbi.nlm.nih.gov/pubmed/18283116 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.