IntroductionThe acute leukemias of childhood are a heterogeneous group of diseases. In this review of the descriptive and analytic epidemiology of these malignancies, specific subgroups are emphasized, as defined by morphology, cytogenetic features, or molecular markers. There is evidence that specific leukemic subgroups may have distinct etiologies, and that molecular abnormalities associated with particular subgroups may be linked with specific causal mechanisms. Moreover, the mutations produced at the successive stages of leukemogenesis, from initiation through induction to promotion, may all involve separate etiologic processes.It is also important to note that changes over time in diagnostic practice and precision may account in part for some reported epidemiologic trends. Moreover, changes in terminology and classification schemes for leukemia make it difficult to make direct comparisons between studies, particularly if risk factors differ for different subgroups. However, in assessing risk factors, studies of the childhood leukemias present several methodologic advantages. The interval between exposure to putative risk factors and onset of leukemia may be shorter, recall of exposures is likely to be better, and intervening factors may be fewer than those associated with adult leukemias. These characteristics of childhood leukemia may facilitate identification of the most likely risk factors for the various leukemic subgroups. Furthermore, they lend themselves to an approach that includes both population studies and molecular epidemiologic techniques, permitting the design of research to assess genetic–environmental causal interactions. As studies of potential environmental causes of childhood leukemia have now accumulated to a degree that allows data synthesis, and in order to succinctly summarize the literature, recent meta-analyses rather than individual studies are cited preferentially below.

BACKGROUND: A recent study suggested a markedly increased risk of hepatoblastoma (HB) among children conceived with treatment for infertility. However, it is not clear whether this finding is confounded by the association between HB and low birthweight (LBW).\n\nMETHODS: Associations between parental infertility and its treatment and HB were examined using data from a case-control study conducted through the Children's Oncology Group (COG). Telephone interviews were completed for 383 mothers of cases diagnosed with HB at US COG institutions between January 2000 and December 2008 and for 387 mothers of controls recruited through state birth registries. Logistic regression was used to examine possible associations.\n\nRESULTS: After adjusting for birthweight and other potential confounders, no significant association was found for any of the measures of parental infertility or its treatment. In HB cases conceived through assisted reproductive technology (ART), 4 of 16 also had Beckwith-Wiedemann syndrome (BWS) compared with 9 of 365 in HB cases without ART.\n\nCONCLUSIONS: Little evidence of an association between parental infertility or its treatment and HB was found. The relationship found in a previous study could be due to LBW and BWS which are risk factors for HB and also associated with parental infertility and its treatment.

Background: Studies of family history of cancer and non-malignant diseases in childhood acute lymphoblastic leukemia (ALL) show inconsistent findings. Most studies show no increased risk with family history of cancer. Non-malignant diseases such as allergic diseases, autoimmune diseases, birth defects and thyroid diseases have been reported to be associated with ALL. Methods: We conducted a case-control study of family history of cancer and selected non-malignant conditions (allergic diseases, autoimmune diseases, birth defects, and thyroid diseases). ALL cases were obtained from Children's Cancer Group institutions from January 1989 to June 1993. Controls were recruited via random digit dialing. Family history for first degree relatives and grandparents of ALL cases and controls was collected by structured telephone questionnaires. Conditional logistical regression was used to calculate odds ratios adjusting for potential confounders. Results: We found a borderline association of ALL and having a family member with a history of cancer in cases (n= 1842) compared to controls (n= 1986) (OR = 0.98, 95%CI = 0.93, 1.00) and an inverse association for esophageal cancer based on small numbers. Family history of food and drug allergies demonstrated a modestly reduced risk (OR = 0.83, 95%CI = 0.73, 0.95) as did family history of rheumatoid arthritis (OR = 0.79, 95%CI = 0.65, 0.96). There were no associations with family history of any autoimmune diseases, immunodeficiencies, birth defects, thyroid diseases and risk of childhood ALL. Conclusions: These results show no association of overall family history of cancer with childhood ALL, while providing additional evidence for an inverse association with family history of allergic disease. Two potentially new associations of ALL with family history of esophageal cancer and rheumatoid arthritis require confirmation in other studies and validation with medical records. © 2011.

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.

Family history of testicular cancer is an established risk factor for adult testicular germ cell tumors (GCT). We evaluated the association between family history of cancer and pediatric GCT in a Children's Oncology Group case-control study that included 274 GCT cases (195 female and 79 male) diagnosed < age 15 years and 418 controls frequency matched to cases on sex and age. Family history data were collected through telephone interviews with biological mothers and fathers and unconditional logistic regression was used to evaluate associations with GCT adjusting for potential confounders. A family history of cancer with onset < age 40 years was associated with a reduced risk of GCT among female cases (Odds Ratio (OR) = 0.50, 95% Confidence Interval (CI) 0.28-0.89) and an increased risk among male cases (OR = 2.56, 95% CI 1.02-6.44). Male cases were more likely to report family history of melanoma compared with male controls (OR = 4.65, 95% CI 1.40-15.4). There was an inverse association between family history of ovarian or uterine cancers and GCT in girls (OR = 0.46, 95% CI 0.22-0.96). These sex and cancer site specific associations should be confirmed in additional studies as they may provide clues to the etiology of pediatric GCT.

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.