Perspectives on the causes of childhood leukemia

Acute leukaemia is the most common cancer in children but the causes of the disease in the majority of cases are not known. About 80% are precursor-B cell in origin (CD19+, CD10+), and this immunophenotype has increased in incidence over the past several decades in the Western world. Part of this increase may be due to the introduction of new chemical exposures into the child's environment including parental smoking, pesticides, traffic fumes, paint and household chemicals. However, much of the increase in leukaemia rates is likely linked to altered patterns of infection during early childhood development, mirroring causal pathways responsible for a similarly increased incidence of other childhood-diagnosed, immune-related illnesses including allergy, asthma, and type 1 diabetes. Factors linked to childhood leukaemia that are likely surrogates for immune stimulation include exposure to childcare settings, parity status and birth order, vaccination history, and population mixing. In case-control studies, acute lymphoblastic leukaemia (ALL) is consistently inversely associated with greater exposure to infections, via day care and later birth order. New evidence suggests also that children who contract leukaemia may harbour a congenital defect in immune responder status, as indicated by lower levels of the immunosuppressive cytokine IL-10 at birth in children who grow up to contract leukaemia, as well as higher need for clinical care for infections within the first year of life despite having lower levels of exposure to infections. One manifestation of this phenomenon may be leukaemia clusters, which tend to appear as a leukaemia "outbreak" among populations with low herd immunity to a new infection. Critical answers to the aetiology of childhood leukaemia will require incorporating new tools into traditional epidemiologic approaches − including the classification of leukaemia at a molecular scale, better exposure assessments at all points in a child's life, a comprehensive understanding of genetic risk factors, and an appraisal of the interplay between infectious exposures and the status of immune response in individuals.