BACKGROUND: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset. PROCEDURE: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. RESULTS: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. CONCLUSIONS: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero.

BACKGROUND: Infant leukaemia is likely initiated in utero.\n\nMETHODS: We examined whether analgesic use during pregnancy was associated with risk by completing telephone interviews of the mothers of 441 infant leukaemia cases and 323 frequency-matched controls, using unconditional logistic regression.\n\nRESULTS: With the exception of a reduced risk for infant acute myeloid leukaemias with non-aspirin non-steroidal anti-inflammatory drugs (NSAID) use early in pregnancy (odds ratios=0.60; confidence intervals: 0.37-0.97), no statistically significant associations were observed for aspirin, non-aspirin NSAIDs, or acetaminophen use in early pregnancy or after knowledge of pregnancy.\n\nCONCLUSION: Overall, analgesic use during pregnancy was not significantly associated with the risk of infant leukaemia.

Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

BACKGROUND: There is increasing interest in the possible association between cancer incidence and vitamin D through its role as a regulator of cell growth and differentiation. Epidemiological studies in adults and one paediatric study suggest an inverse association between sunlight exposure and cancer incidence.$\$n$\$nMETHODS: We carried out an ecological study using childhood cancer registry data and two population-level surrogates of sunlight exposure, (1) latitude of the registry city or population centroid of the registry nation and (2) annual solar radiation. All models were adjusted for nation-level socioeconomic status using socioeconomic indicators.$\$n$\$nRESULTS: Latitude and radiation were significantly associated with cancer incidence, and the direction of association was consistent between the surrogates. Findings were not consistent across tumour types.$\$n$\$nCONCLUSION: Our ecological study offers some evidence to support an association between sunlight exposure and risk of childhood cancer.

Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible.

In a case-control study of infant leukaemia, we assessed agreement between medical records and mother's self-reported pregnancy-related conditions and procedures and infant treatments. Interview and medical record data were available for 234 case and 215 control mothers. Sensitivity, specificity and predictive values for maternal report were estimated for case and control mothers separately, taking the medical record as correct. For most perinatal conditions, sensitivity and specificity were over 75%. Low sensitivity was observed for maternal protein or albumin in the urine (cases: 12% [95% exact confidence interval (CI) 8%, 18%]; controls: 11% [95% CI 7%, 17%]) and infant supplemental oxygen use (cases: 25% [95% CI 11%, 43%]; controls: 24% [95% CI 13%, 37%]). Low specificity was found for peripheral oedema (cases: 47% [95% CI 37%, 58%]; controls: 54% [95% CI 43%, 64%]). Sensitivity for maternal hypertension appeared much lower for cases (cases: 46% [95% CI 28%, 66%]; controls: 90% [95% CI 70%, 99%]; P = 0.003). We did not detect other case-control differences in recall (differentiality), even though the average time between childbirth and interview was 2.7 years for case and 3.7 years for control mothers. Many conditions exhibited notable differences between interview and records. We recommend use of multiple measurement sources to allow both cross-checking and synthesis of results into more accurate measures.

Dried blood spots (DBS) are collected uniformly from US newborns to test for metabolic and other disorders. Because evidence exists for prenatal origins of some diseases, DBS may provide unique prenatal exposure records. Some states retain residual DBS and permit their use in aetiological studies. The primary study aim was to assess the feasibility of obtaining residual DBS from state newborn screening programmes for paediatric and adolescent cancer patients nationwide with parental/subject consent/assent. Families of leukaemia and lymphoma patients aged <21 years diagnosed from 1998 to 2007 at randomly selected Children's Oncology Group institutions across the US were questioned (n = 947). Parents/guardians and patients aged a 18 years were asked to release DBS to investigators in spring 2009. DBS were then requested from states. Overall, 299 families (32%) released DBS. Consenting/assenting patients were born in 39 US states and 46 DBS were obtained from five states; 124 DBS were unobtainable because patients were born prior to dates of state retention. State policies are rapidly evolving and there is ongoing discussion regarding DBS storage and secondary research uses. Currently, population-based DBS studies can be conducted in a limited number of states; fortunately, many have large populations to provide reasonably sized paediatric subject groups. © 2011 Blackwell Publishing Ltd.

OBJECTIVE: Utilizing data from the largest study to date, we examined associations between maternal preconception/prenatal exposure to household chemicals and infant acute leukemia. METHODS: We present data from a Children's Oncology Group case-control study of 443 infants (<1 year of age) diagnosed with acute leukemia [including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)] between 1996 and 2006 and 324 population controls. Mothers recalled household chemical use 1 month before and throughout pregnancy. We used unconditional logistic regression adjusted for birth year, maternal age, and race/ethnicity to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We did not find evidence for an association between infant leukemia and eight of nine chemical categories. However, exposure to petroleum products during pregnancy was associated with AML (OR = 2.54; 95% CI:1.40-4.62) and leukemia without mixed lineage leukemia (MLL) gene rearrangements ("MLL-") (OR = 2.69; 95% CI: 1.47-4.93). No associations were observed for exposure in the month before pregnancy. CONCLUSIONS: Gestational exposure to petroleum products was associated with infant leukemia, particularly AML, and MLL- cases. Benzene is implicated as a potential carcinogen within this exposure category, but a clear biological mechanism has yet to be elucidated.

Carcinomas in children are rare and have not been well studied.

Background:Congenital anomalies have been found more often in children with cancer than in those without. Rib abnormalities (RAs) have been associated with childhood cancer; however, studies have...

Childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) is usually initiated in utero and is thought to progress to overt leukemia under the influence of delayed exposure to a common infection. Based on the hypothesis that polymorphic HLA-DP variants can restrict T-cell responses to infection, we previously compared DP supertype frequencies in BCP ALL patients with that of unrelated newborn controls. We reported that the DP2 supertype was associated with susceptibility, whereas DP1 was associated with protection. However, the association of genetic variants in children with early-onset diseases such as ALL may be a proxy for parental effects. Here we examine whether maternal DP1 and DP2 are associated with BCP ALL by fitting log-linear models in a combined series of family triads (both parents and case child) and dyads (1 parent and case child; n = 571) in comparison with similar models in non-BCP leukemia (n = 198). We report no evidence of maternal DP1 or DP2 associations with BCP ALL, but we did identify suggestive evidence of maternal undertransmission of the infrequent supertypes DP11 and DP15. Although these results require confirmation, they suggest that DP11 and DP15 may be protective or that there is transmission ratio distortion of these supertypes in BCP ALL. © 2011 American Society for Histocompatibility and Immunogenetics.

Background: Few risk factors have been established for childhood germ cell tumors (GCT). Parental infertility and infertility treatment may be associated with GCT development but these risk factors have not been fully investigated. Methods: A case-control study of childhood GCT was conducted through the Children's Oncology Group (COG). Cases, under the age of 15 years at diagnosis, were recruited through COG institutions from January 1993 to December 2002. Controls were obtained through random digit dialing. Information about infertility and infertility treatment along with demographic factors was collection through maternal interviews. Subgroups created by gender, age at diagnosis, and tumor location were examined separately. Statistical analysis was performed using multivariate logistic regression models. Results: Overall, no association between GCT and infertility or its treatment was found. In subgroup analysis, females whose mothers had two or more fetal losses were found to be at increased risk for non-gonadal tumors (Odds ratio (OR)=3.32, 95% Confidence interval (CI)=1.12-9.88). Younger maternal age was associated with a lower risk of gonadal GCT in females (OR=0.52, 95% CI=0.28-0.96). There was an increased risk of all GCT and gonadal GCT in males born to older mothers (OR=2.88, 95% CI=1.13-7.37 and OR=3.70, 95% CI=1.12-12.24). Conclusion: While no association between parental infertility or its treatment and childhood GCT was found overall, possible associations with maternal age and history of recurrent fetal loss were found in subgroups defined by gender. © 2011 Elsevier Ltd.

Approximately 10,700 children under the age of 15 years are newly diagnosed with cancer each year in the United States (American Cancer Society, 2008), including nearly 3,500 children with leukemia. Even with great advances in treatment over the last several decades, leukemia remains a major source of disease-related morbidity and mortality in children. Of the leukemias, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise the vast majority in childhood, occurring at a frequency of approximately 76% and 18%, respectively (Ries et al. 1999). Other leukemias can occur in children, but are extremely rare, including biphenotypic or mixed lineage leukemia, chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), and chronic lymphocytic leukemia (CLL). This review focuses on the epidemiology of childhood ALL and AML. Below, we provide an overview of the classification systems used, including how these entities may help define the timing of when the leukemia might have occurred. Second, international and national data with regard to incidence and survival rates, along with trends, are described. Further, risk factors associated with childhood leukemia are discussed including inherited syndromes, exposures and conditions, and genetic susceptibility as measured through single nucleotide polymorphisms (SNPs). Finally, we discuss challenges and potential future directions that may lead to more fruitful understanding of the underlying causes of childhood leukemia.

The causes of childhood cancers are largely unknown. Birth order has been used as a proxy for prenatal and postnatal exposures, such as frequency of infections and in utero hormone exposures. We investigated the association between birth order and childhood cancers in a pooled case-control dataset. The subjects were drawn from population-based registries of cancers and births in California, Minnesota, New York, Texas and Washington. We included 17,672 cases <15 years of age who were diagnosed from 1980 to 2004 and 57,966 randomly selected controls born 1970–2004, excluding children with Down syndrome. We calculated odds ratios and 95% confidence intervals using logistic regression, adjusted for sex, birth year, maternal race, maternal age, multiple birth, gestational age and birth weight. Overall, we found an inverse relationship between childhood cancer risk and birth order. For children in the fourth or higher birth order category compared to first-born children, the adjusted OR was 0.87 (95% CI: 0.81, 0.93) for all cancers combined. When we examined risks by cancer type, a decreasing risk with increasing birth order was seen in the central nervous system tumors, neuroblastoma, bilateral retinoblastoma, Wilms tumor and rhabdomyosarcoma. We observed increased risks with increasing birth order for acute myeloid leukemia but a slight decrease in risk for acute lymphoid leukemia. These risk estimates were based on a very large sample size, which allowed us to examine rare cancer types with greater statistical power than in most previous studies, however the biologic mechanisms remain to be elucidated.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5-9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (P = 0·04). MBL patients had significantly higher mean absolute lymphocyte counts (2·4 × 10(9) /l) and B-cell counts (0·53 × 10(9) /l) than those with a normal B-cell immuno-phenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.

BACKGROUND: Little has been reported on socioeconomic (SES) patterns of risk for most forms of childhood cancer. METHODS: Population-based case-control data from epidemiological studies of childhood cancer conducted in five US states were pooled and associations of maternal, paternal and household educational attainment with childhood cancers were analysed. Odds ratios (ORs) and 95% confidence intervals were estimated using logistic regression, controlling for confounders. RESULTS: Although there was no association with parental education for the majority of cancers evaluated, there was an indication of a positive association with lower education for Hodgkin's and Burkitt's lymphoma and Wilm's tumour, with the ORs ranging from 1.5 to >3.0 times that of more educated parents. A possible protective effect was seen for lower parental education and astrocytoma and hepatoblastoma, with ORs reduced by 30 to 40%. CONCLUSIONS: These study results should be viewed as exploratory because of the broad nature of the SES assessment, but they give some indication that childhood cancer studies might benefit from a more thorough assessment of SES.

BACKGROUND: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study of CLL identified seven genetic variants that increased the risk of CLL within a European population. METHODS: We evaluated the association of these variants, or variants in linkage disequilibrium with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls. RESULTS: Of these seven single nucleotide polymorphisms (SNP), six had P trend < 0.05 and had estimated odds ratios (OR) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 [OR, 1.47; 95% confidence intervals (CI), 1.19-1.80; P trend = 0.0003] near IRF4 and rs735665 near GRAMD1B (OR, 1.47; 95% CI, 1.14-1.89; P trend = 0.003). However, no associations (P > 0.05) were found for rs11083846, nor were any found for any SNP in linkage disequilibrium with rs11083846. CONCLUSIONS: Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.

BACKGROUND: Children of different racial/ethnic backgrounds have varying risks of cancer. However, to the authors' knowledge, few studies to date have examined cancer occurrence in children of mixed ancestry.\n\nMETHODS: This population-based case-control study examined cancer among children aged <15 years using linked cancer and birth registry data from 5 US states from 1978 through 2004. Data were available for 13,249 cancer cases and 36,996 controls selected from birth records. Parental race/ethnicity was determined from birth records. Logistic regression analysis was used to examine the association of cancer with different racial/ethnic groups.\n\nRESULTS: Compared with whites, blacks had a 28% decreased risk of cancer (odds ratio [OR], 0.72; 95% confidence interval [95% CI], 0.65-0.80), whereas both Asians and Hispanics had an approximate 15% decrease. Children of mixed white/black ancestry also were found to be at decreased risk (OR, 0.71; 95% CI, 0.56-0.90), but estimates for mixed white/Asian and white/Hispanic children did not differ from those of whites. Compared with whites: 1) black and mixed white/black children had decreased ORs for acute lymphoblastic leukemia (OR, 0.39 [95% CI, 0.31-0.49] and OR, 0.58 [95% CI, 0.37-0.91], respectively); 2) Asian and mixed white/Asian children had decreased ORs for brain tumors (OR, 0.51 [95% CI, 0.39-0.68] and OR, 0.79 [95% CI, 0.54-1.16], respectively); and 3) Hispanic and mixed white/Hispanic children had decreased ORs for neuroblastoma (OR, 0.51 [95% CI, 0.42-0.61] and OR, 0.67 [95% CI, 0.50-0.90], respectively).\n\nCONCLUSIONS: Children of mixed ancestry tend to have disease risks that are more similar to those of racial/ethnic minority children than the white majority group. This tendency may help formulate etiologic studies designed to study possible genetic and environmental differences more directly.

BACKGROUND: Little is known about the potential risk factors for infant leukemia. With its very young age at diagnosis, exposures occurring in the perinatal period are suspected. Parental infertility and infertility treatment have been studied with regard to childhood cancer in general, but rarely in individual cancer subtypes.\n\nMETHODS: A case-control study of infant leukemia was conducted through the Children's Oncology Group, including cases diagnosed from January 1996 to December 2006 and controls selected through random digit dialing and birth certificate tracing. Maternal phone interviews were conducted to obtain information about infertility, infertility treatment and demographic factors. All cases as well as subgroups defined by mixed lineage leukemia (MLL) translocation status and leukemia subtype were examined. Statistical analysis was performed using multivariate logistic regression models.\n\nRESULTS: No significant associations between infertility or its treatment and combined infant leukemia were found. In subgroup analyses, there was a significant increase in the risk of MLL--leukemia for children born to women not trying to conceive compared with those trying for <1 year for all types combined [odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.01-2.59] and for acute lymphoblastic leukemia (OR = 2.50, 95% CI = 1.36-4.61).\n\nCONCLUSIONS: There were no positive associations between parental infertility or infertility treatment and infant leukemia. While this is the largest study to date, both selection and recall bias may have impacted the results. However, for infant leukemia, we can potentially rule out large increases in risk associated with parental infertility or its treatment.