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1.  Parental tobacco and alcohol use and risk of hepatoblastoma in offspring: A report from the Children’s Oncology Group 
Background
Hepatoblastoma (HB) is a rare pediatric liver tumor that has significantly increased in incidence over the last several decades. The International Agency for Cancer Research (IARC) recently classified HB as a tobacco-related cancer. Parental alcohol use has shown no association. We examined associations between parental tobacco and alcohol use around the time of pregnancy and HB in a large case-control study.
Methods
Maternal interviews were completed for 383 cases diagnosed in the U.S. during 2000–2008. Controls (n=387) were identified through U.S. birth registries and frequency-matched to cases on birth weight, birth year, and region of residence. We employed unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between parental smoking and maternal drinking and offspring HB.
Results
We found no association between HB and maternal smoking at any time (OR=1.0; 95% CI=0.7–1.4), within the year before pregnancy (OR=1.1; 95% CI=0.8–1.6), early in pregnancy (OR=1.0; 95% CI=0.7–1.6), or throughout pregnancy (OR=0.9; 95% CI=0.5–1.6). We observed marginally positive associations between HB and paternal smoking in the year before pregnancy (OR=1.4; 95% CI=1.0–2.0) and during pregnancy (OR=1.4; 95% CI=0.9–2.0). Maternal alcohol use was not associated with HB.
Conclusion
Our results do not provide evidence for an etiological relationship between maternal smoking or drinking and HB, and only weak evidence for an association for paternal smoking in the year before pregnancy.
Impact
Our study provides limited support for HB as a tobacco-related cancer; however, it remains wise to counsel prospective parents on the merits of smoking cessation.
doi:10.1158/1055-9965.EPI-13-0432
PMCID: PMC4188411  PMID: 23950215
hepatoblastoma; alcohol; smoking; childhood cancer
2.  Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group 
Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex, and age. The following atopic conditions were assessed: allergies, asthma, eczema, and hives; in addition we examined other immune-related factors: birth order, day-care attendance, and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income, and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41–0.87), hives (OR=0.61, 95% CI: 0.38–0.97), day-care attendance (OR=0.48, 95% CI: 0.32–0.71), and breastfeeding for ≥12 months (OR=0.36, 95% CI: 0.18–0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system’s role in the development of this tumor.
doi:10.1002/ijc.28363
PMCID: PMC3869863  PMID: 23824786
Allergies; atopy; epidemiology; rhabdomyosarcoma; soft tissue sarcoma
3.  The Children’s Oncology Group Childhood Cancer Research Network (CCRN) 
Cancer  2014;120(19):3007-3015.
BACKGROUND
The Childhood Cancer Research Network (CCRN) was established within the Children’s Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer.
METHODS
During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data.
RESULTS
Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age <20 years were registered in the CCRN, including 45%, 57%, 51%, 44%, and 24% of those diagnosed at birth, ages 1 to 4 years, ages 5 to 9 years, ages 10 to 14 years, and ages 15 to 19 years, respectively. Some malignancies were better represented in the CCRN (leukemia, 59%; renal tumors, 67%) than others (retinoblastoma, 34%). There was little evidence of differences by sex or race/ethnicity, although rates in nonwhites were somewhat lower than rates in whites.
CONCLUSIONS
Given the low observed-to-expected ratio, it will be important to identify challenges and barriers to registration to improve case ascertainment, especially for rarer diagnoses and older age groups; however, it is encouraging that some diagnoses in younger children are fairly representative of the population. Overall, the CCRN is providing centralized, real-time access to cases for research and could be used as a model for other national cooperative groups.
doi:10.1002/cncr.28813
PMCID: PMC4287245  PMID: 24889136
childhood cancer; United States; clinical trials; incidence; catchment
4.  Neonatal Medical Exposures and Characteristics of Low Birth Weight Hepatoblastoma Cases: A Report From the Children's Oncology Group 
Pediatric blood & cancer  2014;61(11):2018-2023.
Background
Hepatoblastoma is a malignancy of young children. Low birth weight is associated with significantly increased risk of hepatoblastoma and neonatal medical exposures are hypothesized as contributors. This study represents the largest case–control study of hepatoblastoma to date and aimed to define the role of neonatal exposures in hepatoblastoma risk among low birth weight children.
Procedure
Incident hepatoblastoma cases who were born <2,500 g (N = 60), diagnosed between 2000 and 2008, were identified through the Children's Oncology Group. Controls were recruited through state birth registries (N = 51). Neonatal medical exposures were abstracted from medical records. Subjects from the Vermont Oxford Network were used for further comparisons, as were existing reports on neonatal medical exposures.
Results
Case–control comparisons were hindered by poor matching within birth weight strata. Cases were smaller and received more aggressive neonatal treatment compared to controls, and reflected high correlation levels between birth weight and treatments. Similar difficulty was encountered when comparing cases to Vermont Oxford Network subjects; cases were smaller and required more aggressive neonatal therapy. Furthermore, it appears hepatoblastoma cases were exposed to a greater number of diagnostic X-rays than in case series previously reported in the neonatal literature.
Conclusions
This study presents the largest case series of hepatoblastoma in <2,500 g birth weight infants with accompanying neonatal medical exposure data. Findings confirm that birth weight is highly correlated with exposure intensity, and neonatal exposures are themselves highly correlated, which hampers the identification of a causal exposure among hepatoblastoma cases. Experimental models or genetic susceptibility testing may be more revealing of etiology.
doi:10.1002/pbc.25128
PMCID: PMC4287257  PMID: 25044669
case–control study; exposure; hepatoblastoma; low birth weight; NICU
5.  Fetal Growth and Childhood Acute Lymphoblastic Leukemia: Findings from the Childhood Leukemia International Consortium (CLIC) 
Positive associations have been reported between measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth – weight-for-gestational-age and proportion of optimal birth weight (POBW) – were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI 0.77, 0.95) respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin like growth factors.
doi:10.1002/ijc.28314
PMCID: PMC3797193  PMID: 23754574
birth weight; fetal growth; leukemia; childhood; pooled analysis; meta-analysis
6.  Excess congenital non-synonymous variation in leukemia-associated genes in MLL− infant leukemia: A Children’s Oncology Group Report 
Leukemia  2013;28(6):1235-1241.
Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. While most cases are accompanied by MLL-rearrangements and harbor very few somatic mutations; less is known about the genetics of the cases without MLL translocations. We performed the largest exome sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared to randomly selected genes within the same patients and unaffected pediatric controls. IL AML patients had more overall variation than IL ALL patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.
doi:10.1038/leu.2013.367
PMCID: PMC4045651  PMID: 24301523
Infant; leukemia; exome; MLL3
7.  Case-parent analysis of variation in pubertal hormone genes and pediatric osteosarcoma: a Children’s Oncology Group (COG) study 
Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in genesis. Prior studies have suggested that variants in genes in the estrogen metabolism (ESTR) and insulin-like growth factor/growth hormone (IGF/GH) pathways are associated with OS. We examined 798 single nucleotide polymorphisms (SNPs) in 42 genes from these pathways in a case-parent study (229 complete triads and 56 dyads) using buccal cell samples. Relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant were estimated using log-linear models. After Bonferroni correction, 1 SNP within the ESTR pathway (rs1415270: RR = 0.50 and 8.37 for 1 and 2 vs. 0 copies, respectively; p = 0.010), and two SNPs in the IGF/GH pathway (rs1003737: RR = 0.91 and 0.0001 for 1 and 2 vs. 0 copies, respectively; p <0.0001 and rs2575352: RR = 2.62 and 0.22 for 1 and 2 vs. 0 copies; p < 0.0001) were significantly associated with OS incidence. These results confirm previous findings that variation in the estrogen metabolism and bone growth pathways influence OS risk and further support a biologically and epidemiologically plausible role in OS development.
PMCID: PMC3508538  PMID: 23205180
Osteosarcoma; case-parent study; growth and development; insulin-like growth factor pathway; estrogen metabolism pathway
8.  ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: A report from the Children’s Oncology Group 
Leukemia research  2013;37(8):936-942.
Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dosedependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios≥1.33, Ptrend≤0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction≥0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction≥0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.
doi:10.1016/j.leukres.2013.04.022
PMCID: PMC3731070  PMID: 23692655
acute lymphoblastic leukemia; children; genetic susceptibility; gene-environment interaction
9.  Long-term stability of folate in dried blood spots stored in several conditions 
The Journal of pediatrics  2013;163(2):596-597.e1.
We examined stability of folate in 50 subjects’ dried cord blood spots stored for 9 months at −80 °C, 4 °C, ambient and humid conditions. Mean folate declined progressively, but most subjects were +/− 3 ranks of their −80 °C position. Meaningful information about relative concentrations was retained across conditions.
doi:10.1016/j.jpeds.2013.03.043
PMCID: PMC3725212  PMID: 23623515
10.  Cotinine and trans 3'-Hydroxycotinine in Dried Blood Spots as Biomarkers of Tobacco Exposure and Nicotine Metabolism 
Tobacco use is the major preventable cause of premature death in the United States. Secondhand smoke (SHS) exposure also contributes to a number of premature deaths as well as other negative health outcomes. An accurate assessment of tobacco smoke exposure is critical to understanding these disease processes. The plasma concentration of cotinine, the primary metabolite of nicotine, is widely accepted as a quantitative measure of tobacco and SHS exposure. However, it is not always feasible to collect plasma. Dried blood spots (DBS), which are collected routinely from newborns and often from young children for lead screening, provide an alternative sampling method. We have developed a quantitative high throughput liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the analysis of cotinine in DBS. The limit of quantitation was 0.3 ng/g (~ 0.2 ng/ml plasma). Cotinine levels in DBS from 83 smokers and 99 nonsmokers exposed to SHS were determined. Plasma cotinine concentrations in these subjects ranged from <0.02 to 443 ng/ml. Cotinine was detected in DBS from 157 subjects, and the correlation between cotinine in plasma and DBS was excellent, 0.992 (p<0.001). We also determined the ratio of trans-3'-hydroxycotinine to cotinine, a measure of nicotine metabolism, in DBS from smokers. This ratio in DBS was well correlated with the ratio in plasma, 0.94 (p<0.001). In a small study we confirmed the feasibility of using extant DBS collected for lead screening to assess SHS exposure in children.
doi:10.1038/jes.2013.7
PMCID: PMC4048618  PMID: 23443235
Second hand smoke exposure; lead; smoking
11.  Children’s Oncology Group’s 2013 Blueprint for Research: Epidemiology 
Pediatric blood & cancer  2012;60(6):10.1002/pbc.24434.
Investigators worldwide have for over forty years conducted case-control studies aimed at determining the causes of childhood cancer. The central challenge to conducting such research is the rarity of childhood cancer, thus many studies aggregate cases through clinical trials organizations such as COG. Rarity also precludes the use of prospective study designs, which are less prone to recall and selection biases. Despite these challenges a substantial literature on childhood cancer etiology has emerged but few strong environmental risk factors have been identified. Genetic studies are thus now coming to the fore with some success. The ultimate aim of epidemiologic studies is to reduce the population burden of childhood cancer by suggesting preventive measures or possibly by enabling early detection.
doi:10.1002/pbc.24434
PMCID: PMC3726183  PMID: 23255344
Epidemiology; etiology; prevention
12.  Maternal pregnancy events and exposures and risk of hepatoblastoma: A Children's Oncology Group (COG) study 
Cancer epidemiology  2013;37(3):318-320.
Background
Hepatoblastoma is a rare childhood liver cancer with an obscure etiology, however it is potentially associated with selected pregnancy events and hepatoblastoma risk in offspring.
Methods
Adjusted unconditional logistic regression estimated odds ratios (OR) and corresponding 95% confidence intervals (CI) for self-reported pregnancy events and medication use in a sample of mothers of 383 childhood hepatoblastoma cases and 387 controls.
Results
Risk of hepatoblastoma was significantly associated with maternal first trimester weight gain (OR=1.02; 95% CI 1.00, 1.04 per 1 lb increase and nearly significantly with maternal multivitamin use (OR=0.73; 95% CI 0.51,1.03). Hepatoblastoma was not associated with other maternal weight changes, maternal illness or medication use during pregnancy.
Conclusion
We found little evidence that maternal illness or most medication use during pregnancy are associated with hepatoblastoma in offspring.
doi:10.1016/j.canep.2012.12.005
PMCID: PMC3626752  PMID: 23312454
hepatoblastoma; pregnancy complications; self medication; body weight changes; case-control studies
13.  The Childhood Leukemia International Consortium 
Cancer epidemiology  2013;37(3):336-347.
Background
Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions.
Objectives
The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies.
Methods
By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens.
Conclusions
CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.
doi:10.1016/j.canep.2012.12.011
PMCID: PMC3652629  PMID: 23403126
Leukemia; Children; Consortium; Epidemiology; Genetics
14.  Epidemiology of Childhood Acute Myeloid Leukemia 
Pediatric blood & cancer  2013;60(5):728-733.
Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identify several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors.
doi:10.1002/pbc.24464
PMCID: PMC3664189  PMID: 23303597
acute myeloid leukemia; children; epidemiology
15.  Cancer risk among children with very low birth weight 
Pediatrics  2009;124(1):96-104.
Objective:
Risk of hepatoblastoma is strongly increased among children with very low birth weight (VLBW: <1,500 grams). Because data on VLBW and other childhood cancers is sparse, we examined the risk of malignancy following VLBW in a large dataset.
Methods:
We combined case-control datasets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which comprised 17,672 children diagnosed with cancer at 0-14 years of age and 57,966 randomly selected controls. Unconditional logistic regression was used to examine the association of cancer with VLBW and moderately low birth weights (1,500-1,999g and 2,000-2,499g) compared to moderate/high birth weight (≥2,500) adjusting for sex, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth.
Results:
Most childhood cancers were not associated with low birth weights. However, retinoblastoma and gliomas other than astrocytomas and ependymomas were possibly associated with VLBW, with respective odds ratios (OR) of 2.43 (95% Confidence Interval (CI): 1.00-5.89) and 2.13 (95% CI: 0.71-6.39). Risk of other gliomas was also increased among children weighing 1,500-1,999g at birth (OR = 3.58; 95% CI: 1.98-6.47). For hepatoblastoma the ORs associated with birth weights of 2,000-2,499g, 1,500-1999g, and 350-1,499g were 1.56 (95% CI: 0.81-2.98), 3.37 (95% CI: 1.44-7.88), and 17.18 (95% CI: 7.46-39.54), respectively
Conclusions:
These data suggest no association between most cancers and VLBW with the exception of the known association with hepatoblastoma and possible moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.
doi:10.1542/peds.2008-3069
PMCID: PMC2704984  PMID: 19564288
Infant; very low birth weight; cancer; case-control studies; registries
16.  Parental age and risk of childhood cancer: A pooled analysis 
Epidemiology (Cambridge, Mass.)  2009;20(4):475-483.
Background
Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk.
Methods
We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0–14 years during 1980–2004 and 57,966 controls born during 1970–2004. Persons with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state.
Results
Positive linear trends per 5-year maternal age increase were –observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06–1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05–1.11]), lymphoma (1.06 [1.01–1.12]), central nervous system tumors (1.07 [1.03–1.10]), neuroblastoma (1.09 [1.04–1.15]), Wilms’ tumor (1.16 [1.09–1.22]), bone tumors (1.10 [ 1.00–1.20]), and soft tissue sarcomas (1.10 [1.04–1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age.
Conclusions
Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.
doi:10.1097/EDE.0b013e3181a5a332
PMCID: PMC2738598  PMID: 19373093
17.  Childhood cancer among twins and higher order multiples 
Although several studies have found no change or a decreased risk of childhood cancer in twins, few have controlled for potential confounders such as birth weight. We examined the association of birth plurality and childhood cancer in pooled data from five U.S. states (California, Minnesota, New York, Texas, and Washington) using linked birth-cancer registry data. The data, excluding children with Down syndrome or who died before 28 days of life, included 17,672 cases diagnosed 1980–2004 at ages 28 days-14 years and 57,966 controls with all cases and controls born 1970–2004. Analyses were restricted to children weighing ≤ 4,000g at birth. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression adjusting for sex, gestational age, birth weight, birth order, maternal age, maternal race, state of birth, and birth year. Children who were multiples had no difference in risk of cancer overall (OR= 0.93, 95% CI = 0.82–1.07), but a borderline reduced risk of Wilms tumor (OR= 0.65, 95% CI = 0.39–1.09). For children diagnosed under the age of two there was a reduced risk of Wilms tumor (OR= 0.27, 95% CI = 0.09–0.86) and neuroblastoma (OR= 0.46, 95% CI = 0.25–0.84) and an increased risk of fibrosarcoma (OR= 5.81, 95% CI = 1.53–22.11). Higher order multiple birth (triplets or higher) was not associated with childhood cancer. Our analysis suggests that mechanisms other than birth weight and gestational age may influence the lower risk of Wilms tumor and neuroblastoma in multiple births.
doi:10.1158/1055-9965.EPI-08-0660
PMCID: PMC2705199  PMID: 19124494
childhood cancer; twins; multiple birth; case-control; pooled data
18.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
19.  Genetic Variants Modify Susceptibility to Leukemia in Infants: A Children’s Oncology Group Report 
Pediatric blood & cancer  2012;60(1):31-34.
Background
The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE.
Procedure
We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype (ALL, acute myeloid leukemia (AML)), and by presence (+) or absence (−) of MLL rearrangements.
Results
Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML (Odds Ratio (OR)=3.9, 95% Confidence Interval (CI)=1.8–8.4); the increased risk was similar for AML/MLL+ and MLL− cases. In contrast, risk of ALL/MLL− was increased in infants homozygous for the IKZF1 variant (OR=5.1, 95%CI=1.8–14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL− subgroup only (OR=7.2, 95%CI=2.5–20.6). There was little evidence of an association with the CEBP variant (rs2239633).
Conclusion
IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy.
doi:10.1002/pbc.24131
PMCID: PMC3381932  PMID: 22422485
leukemia; genetic susceptibility; infants
20.  Invited Commentary: Childhood Acute Lymphoblastic Leukemia and Allergies: Biology or Bias? 
American Journal of Epidemiology  2012;176(11):979-983.
Previous epidemiologic studies have shown an inverse association between a personal history of atopy/allergies, both overall and among asthma, eczema, and hay fever investigated separately, and childhood acute lymphoblastic leukemia (ALL) with some consistency; however, in most of these studies, exposure data were collected by maternal interview. Now, in a population-based and records-based study in this issue of the Journal (Am J Epidemiol. 2012;176(11):970–978), Chang et al. report an increased risk for allergic conditions across different etiologic time periods, calling the former paradigm into doubt. A review of the basic biology literature shows that proposed mechanisms support either a positive or an inverse association. In light of this ambiguity, it is epidemiology's turn to determine the direction of association.
doi:10.1093/aje/kws265
PMCID: PMC3571240  PMID: 23171875
child; hypersensitivity; leukemia
21.  Predictors of mother and child DNA yields in buccal cell samples collected in pediatric cancer epidemiologic studies: a report from the Children’s Oncology group 
BMC Genetics  2013;14:69.
Background
Collection of high-quality DNA is essential for molecular epidemiology studies. Methods have been evaluated for optimal DNA collection in studies of adults; however, DNA collection in young children poses additional challenges. Here, we have evaluated predictors of DNA quantity in buccal cells collected for population-based studies of infant leukemia (N = 489 mothers and 392 children) and hepatoblastoma (HB; N = 446 mothers and 412 children) conducted through the Children’s Oncology Group. DNA samples were collected by mail using mouthwash (for mothers and some children) and buccal brush (for children) collection kits and quantified using quantitative real-time PCR. Multivariable linear regression models were used to identify predictors of DNA yield.
Results
Median DNA yield was higher for mothers in both studies compared with their children (14 μg vs. <1 μg). Significant predictors of DNA yield in children included case–control status (β = −0.69, 50% reduction, P = 0.01 for case vs. control children), brush collection type, and season of sample collection. Demographic factors were not strong predictors of DNA yield in mothers or children in this analysis.
Conclusions
The association with seasonality suggests that conditions during transport may influence DNA yield. The low yields observed in most children in these studies highlight the importance of developing alternative methods for DNA collection in younger age groups.
doi:10.1186/1471-2156-14-69
PMCID: PMC3751424  PMID: 23937514
DNA collection; Buccal cells; Pediatric epidemiology
22.  Parental infertility, infertility treatment and hepatoblastoma: a report from the Children's Oncology Group 
Human Reproduction (Oxford, England)  2012;27(6):1649-1656.
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).
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1093/humrep/des109
PMCID: PMC3357199  PMID: 22473396
case–control studies; hepatoblastoma; infertility; selection bias
23.  Feasibility of neonatal dried blood spot retrieval amid evolving state policies (2009–2010): A Children’s Oncology Group study 
SUMMARY
Dried blood spots (DBS) are collected uniformly from U.S. 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 etiologic studies. The primary study aim was to assess the feasibility of obtaining residual DBS from state newborn screening programs for pediatric and adolescent cancer patients nationwide with parental/subject consent/assent. Families of leukemia and lymphoma patients aged ≤21 years diagnosed from 1998–2007 at randomly selected Children’s Oncology Group institutions across the U.S. were queried (n=947). Parents/guardians and patients aged ≥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 U.S. states and 46 DBS were obtained from 5 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 pediatric subject groups.
doi:10.1111/j.1365-3016.2011.01228.x
PMCID: PMC3664237  PMID: 21980944
biological specimen banks; child; epidemiologic methods; informed consent; neonatal screening; neoplasms
24.  Self-report versus medical record – perinatal factors in a study of infant leukaemia: a study from the Children’s Oncology Group 
Summary
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.
doi:10.1111/j.1365-3016.2011.01226.x
PMCID: PMC3614401  PMID: 21980943
medical records; maternal recall; reproducibility; misclassification; recall bias
25.  Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children’s Oncology Group 
Summary
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.
doi:10.1111/j.1365-3016.2011.01229.x
PMCID: PMC3614405  PMID: 21980945
childhood cancer; infant leukaemia; maternal smoking; maternal alcohol; illicit drug use

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