Leukemia is the most common childhood cancer. With the exception of Down syndrome, prenatal radiation exposure, and higher birth weight, particularly for acute lymphoid leukemia (ALL), few risk factors have been firmly established. Translocations present in neonatal blood spots and the young age peak of diagnosis suggest that early-life factors are involved in childhood leukemia etiology.

We confirmed the strong association of hepatoblastoma with very low birth weight (relative risk <1000 g vs >or=2000 g=25.6; 95% confidence interval: 7.70-85.0) and demonstrated independent associations with congenital abnormalities and maternal Asian race in a population-based Minnesota study that included 36 cases and 7788 controls.

More than 13,000 children are estimated to be newly diagnosed with cancer each year in the United States ([1][1]). Despite substantial improvements in survival over the last several decades, cancer is still the leading cause of death due to disease in children ages 1 to 14 years ([2][2]). The

Leukemia is the most common childhood cancer and a major source of morbidity and mortality. The etiology of childhood leukemia remains largely unknown. Cytogenetic abnormalities determine disease subtypes, prognosis, clinical presentation, and course and may help in discovering etiological factors. Epidemiologic investigations of leukemia are complicated by many factors, including the rarity of the disease, necessitating careful study design. Two emerging areas of interest in leukemia etiology are birth weight and diet. High birth weight has been associated with increased risk of childhood leukemia. The biological mechanism behind this association may involve insulin-like growth factor I (IGF-I), which is associated with high birth weight. IGF-I may act by increasing the absolute number of stem cells available for transformation, stimulating the growth of cells that are already transformed, or a combination of effects. Diet has been linked with leukemia. Maternal dietary DNA topoisomerase II (DNAt2) inhibitor intake is associated with infant acute myeloid leukemia (AML) with the MLL gene translocation. Increased intake of fruits and vegetables has been associated with decreased leukemia risk and, relatedly, lack of maternal folate supplementation has been associated with increased childhood leukemia risk, possibly by causing DNA hypomethylation and increased DNA strand breaks. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms modify this risk.

BACKGROUND: Children with Down syndrome (DS) have from 10 to 20 times the risk of developing acute leukemia than the general pediatric population. There is mixed evidence for associations between reproductive history or infertility and acute leukemia among children without DS. METHODS: The authors conducted a case-control study of acute leukemia among children with DS to investigate possible risk factors in this population. From 1997 to 2002, 158 children aged <20 years with DS who had a diagnosis of acute leukemia (97 children with acute lymphoblastic leukemia [ALL] and 61 children with acute myeloid leukemia [AML]) were enrolled at Children's Oncology Group (COG) institutions. Controls with DS (n = 173) were selected from the cases' primary care clinic and frequency matched to cases on age. Telephone interviews were conducted with mothers of cases and controls assessing reproductive history, infertility, and infertility treatment. RESULTS: Null results were observed overall and by subtype for reproductive factors, including previous pregnancy outcomes and contraceptive use, and for most infertility outcomes. There was an increased risk of AML among children with DS whose parents had ever tried for >/=1 year to become pregnant (odds ratio [OR], 2.22; 95% confidence interval [95% CI], 1.14-4.33). A 1-year increase in maternal age also was associated with AML (OR, 1.06; 95% CI, 1.01-1.12). CONCLUSIONS: Although the questionnaire was limited in this area, the results suggested that the risk for AML may be raised in children with DS because of infertility. In that the risk of infertility, along with having a child with DS, increase with age, these results warrant more research.

Three previous retrospective studies noted a positive association between birthmarks and childhood cancer. The objective of this study was to determine whether the incidence of cancer is increased in children with birthmarks relative to those without birthmarks using data from the Collaborative Perinatal Project cohort, a large, prospective study.

Leukemias with MLL gene rearrangements predominate in infants (<1 year of age), but not in older children, and may have a distinct etiology. High birth weight, higher birth order, and prior fetal loss have, with varying consistency, been associated with infant leukemia, but no studies have reported results with respect to MLL status. Here, we report for the first time such an analysis. During 1999 to 2003, mothers of 240 incident cases (113 MLL(+), 80 MLL(-), and 47 indeterminate) and 255 random digit dialed controls completed a telephone interview. Odds ratios and 95% confidence intervals for quartile of birth weight, birth order, gestational age, maternal age at delivery, prior fetal loss, pre-pregnancy body mass index, and weight gain during pregnancy were obtained using unconditional logistic regression; P for linear trend was obtained by modeling continuous variables. There was a borderline significant linear trend of increasing birth weight with MLL(+) (P = 0.06), but not MLL(-) (P = 0.93), infant leukemia. Increasing birth order showed a significant inverse linear trend, independent of birth weight, with MLL(+) (P = 0.01), but not MLL(-) (P = 0.18), infant leukemia. Other variables of interest were not notably associated with infant leukemia regardless of MLL status. This investigation further supports the contention that molecularly defined subtypes of infant leukemia have separate etiologies.

Since the mid-1990s, epidemiologists have anecdotally reported difficulty in recruiting controls using random digit dialing (RDD), but few empirical data have been published. From 1982 to 2003, epidemiologists from the Children's Oncology Group conducted 17 case-control studies using RDD controls. Data for calculating RDD and field response rates were available from eight and 13 of these studies, respectively. Over the period of analysis, the contact rate declined 2.5% per year (95% confidence interval (CI): -3.4, -1.6; p = 0.001), from above 90% in the 1980s to 63-69% in the most recent studies. The response rate (the product of the contact and cooperation rates) showed a decline parallel to that of the contact rate (-2.4% per year, 95% CI: -3.2, -1.6; p < 0.001), from above 80% in the 1980s to 50-67% after the mid-1990s. Field response rates appeared to have declined modestly. The overall response rate (the product of the RDD response and field response rates) paralleled that of the RDD response rate and decreased 2.4% per year (95% CI: -2.7, -2.0; p < 0.001). The current low response rates for RDD indicate a substantial potential for selection bias and a need to seek alternative sources of controls.

Maternal smoking while pregnant is a plausible risk factor for childhood cancers because many seem to initiate in utero and tobacco-specific carcinogens cross the placenta. Social desirability bias may affect maternal report of smoking in case-control studies and could explain inconsistently observed associations with offspring cancer. Detection of tobacco smoke biomarkers in dried blood spots (DBS), which are increasingly stored by newborn screening programs, may improve retrospective assessment of fetal tobacco exposure. As proof-of-principle, we examined cotinine in DBS of 20 infants enrolled in a pilot study of pregnancy among low-income women. We recruited 107 pregnant women (<30 weeks of gestation) from six Women, Infants, and Children clinics in Minneapolis and St. Paul in 1999. Blood samples obtained at enrollment were tested for total cotinine using gas chromatography/mass spectrometry. Women were then interviewed at 7 months of gestation to determine current smoking habits. DBS were obtained from the Minnesota Department of Health. We tested DBS from 10 infants whose mothers had detectable serum cotinine at baseline and 10 control infants whose mothers had none. One quarter of each DBS was assayed for cotinine using gas chromatography/mass spectrometry; levels were estimated assuming 50 μL blood per sample. Mean cotinine was 29 ng/mL (SD, 7.5), 45 ng/mL (SD, 9.7), and 9 ng/mL (SD, 7.4), respectively, among infants of all smokers, infants of four women who acknowledged smoking at 7 months of gestation, and infants of nonsmokers. These results suggest that DBS analysis may identify infants of women who smoke throughout pregnancy. Copyright © 2007 American Association for Cancer Research.

As random digit dialing becomes increasingly unfeasible for many types of studies, alternative methods for control selection are needed, especially for studies of childhood cancer. US birth registries are an appealing source of young control children because they are population based, provide demographic and pregnancy data for comparison of participants with the study base, and maintain data that enable matching on birth characteristics. Here the authors describe the ability of US birth registries to release information sufficient to locate potential control subjects for two ongoing case-control studies of hepatoblastoma and infant leukemia. The birth registries of 32 states, in which 75.8% of US children 0-5 years of age resided in 2004, agreed to participate in control selection. Data sufficient to track participants and to characterize nonrespondents were available from a majority of registries. These results suggest that birth registries may be used to select controls for studies of rare childhood diseases on a national scale.

Historically, the study of rare malignancies, including retinoblastoma, angiosarcoma, and vaginal clear cell carcinoma, has led to major findings in our understanding of cancer etiology. Leukemias that occur in children less than 1 year of age likely represent another rare group that could potentially lead to further understanding of carcinogenesis.The vast majority of infants present with a genetic abnormality in their leukemia cells that affects the MLL gene on chromosome band 11q23, and a substantial body of evidence supports the contention that these MLL abnormalities (mostly rearrangements) occur in utero (1).Thus, the window of exposure is very brief.We and others have shown that specific environmental exposures (2, 3) and genotypes (4-7) may be unique to these MLL abnormalities in infant leukemias.Here, Pombo-de-Oliveira et al.(8) demonstrate an association between infant leukemia and maternal hormone use before and during pregnancy, which appeared to vary by timing of exposure and MLL status. The authors further show an association of MLL-positive infant leukemia with quinolones, which, although imprecise, is interesting given these drugs that interact with DNA topoisomerase II (9).These results support differing etiologies for molecularly defined subtypes of infant leukemia.Rarity is the major obstacle to elucidating translocation-specific risk factors but may be overcome by cooperative group participation (10) and international collaboration.Epidemiologic investigations may also be informed by mechanistic studies, which have sought to correlate prenatal exposures with the frequency of MLL transcripts or chromosome breakage at the 11q23 locus in cord blood (11, 12).Thus, we expect big developments from this small cancer.

Compared with the general pediatric population, children with Down's syndrome have a much higher risk of acute leukemia. This case-control study was designed to explore potential risk factors for acute lymphoblastic leukemia and acute myeloid leukemia in children with Down's syndrome living in the United States or Canada. Mothers of 158 children with Down's syndrome and acute leukemia (97 acute lymphoblastic leukemia, 61 acute myeloid leukemia) diagnosed between January 1997 and October 2002 and mothers of 173 children with Down's syndrome but without leukemia were interviewed by telephone. Positive associations were found between acute lymphoblastic leukemia and maternal exposure to professional pest exterminations (odds ratio = 2.25, 95% confidence interval: 1.13, 4.49), to any pesticide (odds ratio = 2.18, 95% confidence interval: 1.08, 4.39), and to any chemical (odds ratio = 2.72, 95% confidence interval: 1.17, 6.35). Most of the associations with acute myeloid leukemia were nonsignificant, and odds ratios were generally near or below 1.0. This exploratory study suggests that household chemical exposure may play a role in the development of acute lymphoblastic leukemia in children with Down's syndrome.

In contrast to the positive association found in three studies between maternal anaemia during pregnancy and childhood leukaemia, no such association was found in infant leukaemia (odds ratio 0.85, 95% confidence interval 0.53-1.37).

Studies suggest nearly a 20-fold increased risk of leukemia in individuals with Down syndrome. Most of this increased risk appears in the first few decades of life, with the highest incidence in children less than 5 years of age. It is unknown why children with Down syndrome are at such an increased risk of leukemia. With respect to environmental exposures, it will be important to investigate risk factors associated with childhood leukemia in general (including diagnostic x-rays, pesticides, and other occupational exposures) as well as experiences common to children with Down syndrome (including routine medical screening tests, increased susceptibility to infections, and increased vitamin deficiencies).

Objective: To evaluate the relationship between neonatal oxygen supplementation (O2) and childhood cancer in the Collaborative Perinatal Project (CPP). Study design: The CPP consisted of 54,795 children born between 1959 and 1966 and followed to age 8 years. We used Cox proportional hazards modeling to examine the association between history of neonatal O2and cancer (n = 48). Results: The hazard ratio (HR) for any O2was 1.77 (95% confidence interval [CI] = 0.94 to 3.35). The HR for continuous duration of O2was near 1 and not significant. However, the HRs were 0.69 (95% CI = 0.17 to 2.88) and 2.87 (95% CI = 1.46 to 5.66) when comparing 0 to 2 and 3 or more minutes of O2, respectively, to no O2. The latter association was weaker (HR = 2.00; 95% CI = 0.88 to 4.54) and not significant (P = .10) when analysis was restricted to cancers diagnosed after age 1 year (n = 41). Conclusions: These findings are consistent with an association between O2for 3 minutes or longer and cancer in childhood, and should serve as a basis for further study. Copyright © 2005 Elsevier Inc. All rights reserved.

BACKGROUND: The MLL 11q23 translocation arises in utero and is present in 75% of infant leukemias. That MLL+ acute myeloid leukemia (AML) can arise following chemotherapy with DNA topoisomerase II (DNAt2) inhibitors suggests that these substances, which also occur naturally in foods, may contribute toward infant leukemia. We hypothesized that maternal consumption of dietary DNAt2 inhibitors during pregnancy would increase the risk of infant leukemia, particularly AML(MLL+). METHODS: This Children's Oncology Group case-control study consisted of 240 incident cases of infant acute leukemia AML and acute lymphoblastic leukemia (ALL) diagnosed during 1996 to 2002 and 255 random digit dialed controls. Maternal diet during pregnancy was determined through a food frequency questionnaire. An index of specific foods identified a priori to contain DNAt2 inhibitors as well as vegetables and fruits were created and analyzed using unconditional logistic regression. RESULTS: There was little evidence of an association between the specific DNAt2 index and leukemia overall and by subtype. An exception was AML(MLL+); odds ratios (95% confidence intervals) comparing the second to fourth quartiles to the first were 1.9 (0.5-7.0), 2.1 (0.6-7.7), and 3.2 (0.9-11.9), respectively (P for trend = 0.10). For the vegetable and fruit index, there were significant or near-significant inverse linear trends for all leukemias combined, ALL(MLL+), and AML(MLL-). CONCLUSION: Overall, maternal consumption of fresh vegetables and fruits during pregnancy was associated with a decreased risk of infant leukemia, particularly MLL+. However, for AML(MLL+) cases, maternal consumption of specific DNAt2 inhibitors seemed to increase risk. Although based on small numbers, these data provide some support for distinct etiologic pathways in infant leukemia.