Locations of radiation-produced DNA double strand breaks along chromosomes: a stochastic cluster process formalism.
Ionizing radiation produces DNA double strand breaks (DSBs) in chromosomes. For densely ionizing radiation, the DSBs are not spaced randomly along a chromosome: recent data for size distributions of DNA fragments indicate break clustering on kbp-Mbp scales. Different DSB clusters on a chromosome are typically made by different, statistically independent, stochastically structured radiation tracks, and the average number of tracks involved can be small. We therefore model DSB positions along a chromosome as a stationary Poisson cluster process, i.e. a stochastic process consisting of secondary point processes whose locations are determined by a primary point process that is Poisson. Each secondary process represents a break cluster, typically consisting of 1-10 DSBs in a comparatively localized stochastic pattern determined by chromatin geometry and radiation track structure. Using this Poisson cluster process model, which we call the randomly located clusters (RLC) formalism, theorems are derived for how the DNA fragment-size distribution depends on radiation dose. The RLC dose-response relations become non-linear when the dose becomes so high that DSB clusters from different tracks overlap or adjoin closely. The RLC formalism generalizes previous models, fits current data adequately and facilitates mechanistically based extrapolations from high-dose experiments to the much lower doses of interest for most applications.
Sachs
R K
RK
Department of Mathematics, University of California, Berkeley 94720, USA. sachs@math.berkeley.edu
Ponomarev
A L
AL
Hahnfeldt
P
P
Hlatky
L R
LR
D002869:Chromosome Aberrations; D002875:Chromosomes / Q000528:radiation effects*; D016000:Cluster Analysis; D004249:DNA Damage; D053938:DNA Fragmentation / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D018499:Linear Energy Transfer / Q000528:radiation effects; D008954:Models, Biological; D009716:Numerical Analysis, Computer-Assisted; D016012:Poisson Distribution; D011336:Probability; D011839:Radiation, Ionizing; D013269:Stochastic Processes