Cigarette smoke has been linked to adult myeloid leukemia; however, the association between parental smoking and childhood leukemia remains unclear. Parental smoking and the risk of childhood leukemia were examined in the Northern California Childhood Leukemia Study, a case-control study, between 1995 and 2002. The present analysis included 327 acute childhood leukemia cases (281 acute lymphoblastic leukemia (ALL) and 46 acute myeloid leukemia (AML)) and 416 controls matched on age, sex, maternal race, and Hispanic ethnicity. Maternal smoking was not associated with an increased risk of either ALL or AML. Paternal preconception smoking was significantly associated with an increased risk of AML (odds ratio = 3.84, 95% confidence interval: 1.04, 14.17); an increased risk for ALL was suggestive for paternal preconception smoking (odds ratio = 1.32, 95% confidence interval: 0.86, 2.04). Greater risks of ALL were observed compared with the risk associated with paternal preconception smoking alone, when paternal preconception smoking was combined with maternal postnatal smoking (p(interaction) = 0.004) or postnatal passive smoking exposure (p(interaction) = 0.004). These results strongly suggest that exposure to paternal preconception smoking alone or in combination with postnatal passive smoking may be important in the risk of childhood leukemia.

The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal translocations and Ig heavy chain (IGH)͞T cell antigen receptor (TCR) rearrangements to develop an understanding of the etiology and natural history of this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at the time of birth. Two patients were determined to be weakly positive for the fusion at the time of birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH͞TCR rearrangements provided additional evidence for a postnatal, preB cell origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly clustered proximal to exon 2. In sum, the translocation breakpoints displayed evidence of unique temporal, ontological, and mechanistic formation than the previously analyzed pediatric leukemia translocation breakpoints and emphasize the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality. P ediatric leukemias are a group of diverse diseases at the chromosome level, with various subtypes recognizable by recurrent translocations and aneuploidies. Although these genetic abnormalities help to categorize leukemias for treatment strategy and prognosis, they also may delineate specific causal pathways to malignancy. The consideration of individual molecular subtypes is providing clarity to epidemiological and biological studies. The best characterized example of this approach is the infant leukemias with MLL translocations (MLL ϩ ), for which epidemiologic associations and molecular analysis of breakpoints point to an in utero origin of the translocations, with reactive metabolites of genotoxic chemicals playing a potential key role (1-5). The MLL ϩ leukemias, along with the hyperdiploid subtype (leukemia clones with Ͼ50 chromosomes), also display significant associations with variants in genes encoding functional metabolic enzymes, thus implying a risk of leukemia imparted by the enzymes' substrates or products (6-8). Childhood leukemias with TEL-AML1 translocations, representing Ϸ25% of common acute lymphoblastic leukemia (cALL), share the in utero timing of translocation formation with MLL ϩ leukemias (9); however, there is currently no etiological mechanism for the formation of this translocation, apart from the nonhomologous end-joining processes that rejoin br...