Chromosomal translocations in childhood leukemia: natural history, mechanisms, and epidemiology.

The root causes of childhood leukemia will be discovered by understanding the mechanism of mutations in the context of the cell of origin and time in life of the child. Molecular studies using archival DNA samples and twins with concordant leukemia have demonstrated that most childhood leukemia translocation subtypes occur before to birth and occur in early progenitors. Translocation breakpoints typically harbor evidence of nonhomologous end-joining repair mechanisms, but in only a few examples are the causative mechanisms of breakage evident, such as V(D)J recombinase gene activation. Epidemiologic differences in the rates of translocations between populations may point to causal clues. Leukemia like all cancers is the product of two or more genetic and/or epigenetic events, and the natural history and mechanisms of these two events are likely independent, resulting in two or more "causes" of leukemia. Complementary mutations include point mutations, deletions, and epimutations, which have distinct associated causal mechanisms.