The Etiology of Acute Childhood Leukemias

Acute lymphoblastic leukaemia is the most common childhood cancer, accounting for close to 25% of newly diagnosed cancers in children less than 15 years of age. Leukemia incidence rates are reasonably constant at 5 per 100.000 person-years, with 80% of the cases being ALL. A variety of hypotheses regarding the etiology and potential pathogenic mechanism of childhood ALL have been described. As with other cancers, multiple steps lead to clinically detectable leukaemia from a preleukemic precursor cell. Neonatal events can play a role in the development of childhood ALL because evidence of the leukemic event can be detected at birth in many cases. Molecular techniques using PCR have documented the presence of the same leukaemia-specific fusion-gene sequences in neonatal blood spots as are present in diagnostic samples form children with leukaemia. There is a higher concordance rate in monochorionic twins than in dichorionic twins or in siblings. Children with Down syndrome are at significantly increased risk for developing leukaemia, especially the rare subtype acute megakaryoblastic leukaemia (FAB M7). Environmental factors may also play a role. Maternal exposures to the DNA-damaging agents and radiation have been linked to the diagnosis of acute leukaemia. Infections may also be linked to childhood leukaemia. The largest epidemiologic study of childhood ALL however did not find a correlation between day care attendance or time in day care and the risk of developing ALL. Thus, different mechanisms may play a role in the etiology of acute leukaemia in a given child. Examples from the AML-BFM study for AML in Down syndrome and of the EWOG-MDS study for children with juvenile myelomonocytic leukaemia (JMML) are given in the lecture.