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1.  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.
PMCID: PMC3726183  PMID: 23255344
Epidemiology; etiology; prevention
2.  Maternal pregnancy events and exposures and risk of hepatoblastoma: A Children's Oncology Group (COG) study 
Cancer epidemiology  2013;37(3):318-320.
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.
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.
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.
We found little evidence that maternal illness or most medication use during pregnancy are associated with hepatoblastoma in offspring.
PMCID: PMC3626752  PMID: 23312454
hepatoblastoma; pregnancy complications; self medication; body weight changes; case-control studies
3.  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.
PMCID: PMC3664189  PMID: 23303597
acute myeloid leukemia; children; epidemiology
4.  Reproductive, lifestyle and anthropometric risk factors for cancer in elderly women 
With an increasing elderly population, the United States will experience an increased cancer burden in the coming years. We evaluated associations between anthropometric, lifestyle and reproductive factors and risk of breast, ovarian, and colorectal cancer in a prospective study of postmenopausal women with a focus on diagnoses occurring among very elderly women (≥75 years).
For each cancer type, we estimated associations with relevant exposures in two age bands (< vs. ≥75 years of age). During 22 years of follow-up, 322 ovarian, 1,311 colon, 315 rectal, and 2,664 breast cancers occurred among 37,459 postmenopausal women (mean age at baseline 62 years, range 55–71 years).
For ovarian cancer, we identified few significant associations in either age band. Colon cancer cases had a higher body mass index and were less likely to report estrogen or aspirin use than non-cases, yet these associations were consistent in both age bands. Few risk factors were identified for rectal cancer in women ≥75 years of age. For breast cancer, notably different patterns were revealed, with alcohol consumption associated with risk in the younger group and previous hysterectomy associated with risk only in the older group.
These analyses suggest some important differences in risk factors for cancer depending on age at diagnosis.
This study suggests that etiologic differences may exist in cancers occurring in the very elderly. The ongoing demographic shift in the United States provides a strong rationale for studies evaluating cancer etiology in the elderly.
PMCID: PMC3617066  PMID: 23429062
cancer risk; elderly; ovarian; colorectal; breast
5.  Trends in Incidence and Survival of Pediatric and Adolescent Germ Cell Tumors in the United States, 1975-2006 
Cancer  2010;116(20):4882-4891.
Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors with uncertain etiology. We used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program to evaluate trends in incidence and survival of GCTs in boys and girls ≤ 19 years of age. Few studies have evaluated trends in pediatric GCTs. Results from these analyses may provide clues to the etiology of GCTs.
Frequencies, incidence rates and five-year relative survival rates stratified by sex were evaluated overall and for demographic subgroups based on age (0-9 and 10-19 years), race (white, black, and other), and ethnicity (non-Hispanic and Hispanic) as sample size permitted.
In whites, the incidence of GCTs was lower for females than males in the 10-19 year age group (RR=0.47, 95% CI 0.42—0.53) while the rates were similar in the 0-9 year age group. In contrast, incidence rates were higher in black females than in black males in both age groups (RR=2.01, 95%CI 1.08—3.84 in 0-9 year olds; RR=3.30, 95% CI 2.13—5.28 in 10-19 year olds). The incidence of ovarian GCT was significantly higher in Hispanic than non-Hispanic girls in the 10—19 year age group. Incidence rates increased during the study period in boys ages 10-19 (APC 1.2, 95% CI 0.4—2.1) and girls ages 0-9 (APC 1.9, 95% CI 0.3-2.5).
The incidence of pediatric GCTs in the United States is increasing only in certain subgroups, suggesting that the etiology is not completely overlapping in all age groups. Differences in incidence patterns by race and ethnicity merit further investigation.
PMCID: PMC3931133  PMID: 20597129
pediatric cancer; germ cell tumors; SEER; incidence
6.  Highly Reliable Procedural Teams: The Journey to Spread the Universal Protocol in Diagnostic Imaging 
The Permanente Journal  2014;18(1):33-37.
The Joint Commission’s Universal Protocol has been widely implemented in surgical settings since publication in 2003, and the elements are applied to procedures occurring in other health care arenas, in particular, diagnostic imaging. The teams underwent human factors training and then adapted key interventions used in surgical suites to their workflows. Perception of the safety climate improved 25% in interventional radiology and 4.5% in mammography. Perception of the teamwork climate decreased 5.4% in interventional radiology and 16.6% in mammography. The study reveals unexpected challenges and requires long-term effort and focus.
The Joint Commission’s Universal Protocol has been widely implemented in surgical settings since publication in 2003. The elements improved patient safety in operating rooms, and the same rigor is being applied to procedures occurring in other health care arenas, in particular, diagnostic imaging.
In 2011, Kaiser Permanente West Los Angeles’s Diagnostic Imaging Department desired to adapt previous work on Universal Protocol implementation to improve patient safety in interventional radiology and mammography procedures.
The teams underwent human factors training and then adapted key interventions used in surgical suites to their workflows. Time-out posters, use of whiteboards, “glitch books,” and regular audits provided structure to overcome the risks that human factors present.
Main Outcome Measures:
Staff and physician perceptions of the teamwork and safety climates in their modalities were measured using the Safety Attitudes Questionnaire at baseline and at 18 months after training. Unusual Occurrence Reports were also reviewed to identify events and near misses that could be prevented. Implementation of key process changes were identified as process measures.
Perception of the safety climate improved 25% in interventional radiology and 4.5% in mammography. Perception of the teamwork climate decreased 5.4% in interventional radiology and 16.6% in mammography. Unusual occurrences were underreported at baseline, and there is ongoing reluctance to document near misses.
This work provides important considerations of the impact of departmental cultures for the implementation of the Universal Protocol in procedural areas. It also reveals unexpected challenges, and requires long-term effort and focus.
PMCID: PMC3951028  PMID: 24626070
7.  Genetic Variants Modify Susceptibility to Leukemia in Infants: A Children’s Oncology Group Report 
Pediatric blood & cancer  2012;60(1):31-34.
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.
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.
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).
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.
PMCID: PMC3381932  PMID: 22422485
leukemia; genetic susceptibility; infants
8.  Peri-gestational Dietary Folic Acid Deficiency Protects Against Medulloblastoma Formation in a Mouse Model of Nevoid Basal Cell Carcinoma Syndrome 
Nutrition and cancer  2013;65(6):857-865.
Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the peri-gestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n=126) were randomized to one of three diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) one month prior to mating with Ptch1+/− C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio (HR)=0.47; 95% confidence interval (CI) 0.27–0.80) at one year. No significant difference in incidence was observed between the control and high FA groups. Low maternal peri-gestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes.
PMCID: PMC3771499  PMID: 23909730
9.  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.
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.
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.
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.
PMCID: PMC3751424  PMID: 23937514
DNA collection; Buccal cells; Pediatric epidemiology
10.  Medical conditions and risk of adult myeloid leukemia 
Cancer causes & control : CCC  2012;23(7):1083-1089.
Although a few previous studies have reported positive associations between adult myeloid leukemia and a history of certain medical conditions, the etiology of most cases remains largely unknown. Our purpose was to examine associations between certain medical conditions and adult myeloid leukemia.
Using logistic regression, we evaluated associations between 16 self-reported medical conditions and myeloid leukemia in a case–control study of 670 cases [including 420 acute myeloid leukemia (AML) and 186 chronic myelogenous leukemia (CML)] and 701 population-based controls.
We observed significant positive associations between AML and ulcerative colitis (odds ratio (OR) = 3.8; 95 % confidence interval (CI), 1.1–13) and between CML and peptic ulcer (OR = 2.0; 95% CI, 1.1–3.8). A personal cancer history increased both AML (OR = 2.6; 95% CI, 1.7–3.9) and CML (OR = 3.5; 95% CI, 2.0–5.8) risk even after excluding individuals who reported prior radiation and/or chemotherapy treatment.
Certain inflammatory medical conditions and a personal history of cancer, independent from therapy, are associated with an increased risk of myeloid leukemia.
PMCID: PMC3571859  PMID: 22576581
Acute myeloid leukemia; Chronic myeloid leukemia; Autoimmune disorders; Medical conditions
11.  DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors 
BMC Cancer  2013;13:313.
Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development.
We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing.
Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location.
Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.
PMCID: PMC3701494  PMID: 23806198
Germ Cell Tumor; Teratoma; DNA Methylation; Imprinting
12.  MLL gene rearrangements in infant leukemia vary with age at diagnosis and selected demographic factors: A Children’s Oncology Group (COG) study 
Pediatric blood & cancer  2011;58(6):836-839.
Infant leukemias have a high frequency of mixed lineage leukemia (MLL) gene rearrangements.
Using data from a large etiologic study, we evaluated the distribution of selected demographic factors among 374 infant leukemia cases by leukemic subtype, MLL status and diagnosis age.
Overall, 228 cases were MLL+. Compared to white infants, black infants were significantly less likely to have MLL+ leukemia. Further, there was a statistically significantly higher age at diagnosis for infants with t(9;11) translocations compared to all other translocation partners in both acute lymphoblastic leukemia and acute myeloid leukemia cases.
These patterns may provide important etiological insight into the biology of infant leukemia.
PMCID: PMC3208122  PMID: 21800415
epidemiology; infants; leukemia; MLL
13.  Parental infertility, infertility treatment and hepatoblastoma: a report from the Children's Oncology Group 
Human Reproduction (Oxford, England)  2012;27(6):1649-1656.
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).
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.
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.
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.
PMCID: PMC3357199  PMID: 22473396
case–control studies; hepatoblastoma; infertility; selection bias
14.  Childhood Cancer Incidence Trends in Association With US Folic Acid Fortification (1986–2008) 
Pediatrics  2012;129(6):1125-1133.
Epidemiologic evidence indicates that prenatal vitamin supplementation reduces risk for some childhood cancers; however, a systematic evaluation of population-based childhood cancer incidence trends after fortification of enriched grain products with folic acid in the United States in 1996–1998 has not been previously reported. Here we describe temporal trends in childhood cancer incidence in association with US folic acid fortification.
Using Surveillance, Epidemiology, and End Results program data (1986–2008), we calculated incidence rate ratios and 95% confidence intervals to compare pre- and postfortification cancer incidence rates in children aged 0 to 4 years. Incidence trends were also evaluated by using joinpoint and loess regression models.
From 1986 through 2008, 8829 children aged 0 to 4 years were diagnosed with malignancies, including 3790 and 3299 in utero during the pre- and postfortification periods, respectively. Pre- and postfortification incidence rates were similar for all cancers combined and for most specific cancer types. Rates of Wilms tumor (WT), primitive neuroectodermal tumors (PNETs), and ependymomas were significantly lower postfortification. Joinpoint regression models detected increasing WT incidence from 1986 through 1997 followed by a sizable decline from 1997 through 2008, and increasing PNET incidence from 1986 through 1993 followed by a sharp decrease from 1993 through 2008. Loess curves indicated similar patterns.
These results provide support for a decrease in WT and possibly PNET incidence, but not other childhood cancers, after US folic acid fortification.
PMCID: PMC3362910  PMID: 22614769
child; cancer; epidemiology; folic acid; incidence; trends
15.  Feasibility of neonatal dried blood spot retrieval amid evolving state policies (2009–2010): A Children’s Oncology Group study 
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.
PMCID: PMC3664237  PMID: 21980944
biological specimen banks; child; epidemiologic methods; informed consent; neonatal screening; neoplasms
16.  Self-report versus medical record – perinatal factors in a study of infant leukaemia: a study from the Children’s Oncology Group 
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.
PMCID: PMC3614401  PMID: 21980943
medical records; maternal recall; reproducibility; misclassification; recall bias
17.  Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children’s Oncology Group 
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.
PMCID: PMC3614405  PMID: 21980945
childhood cancer; infant leukaemia; maternal smoking; maternal alcohol; illicit drug use
18.  GATA-1 Utilizes Ikaros and Polycomb Repressive Complex 2 To Suppress Hes1 and To Promote Erythropoiesis 
Molecular and Cellular Biology  2012;32(18):3624-3638.
The transcription factor Hairy Enhancer of Split 1 (HES1), a downstream effector of the Notch signaling pathway, is an important regulator of hematopoiesis. Here, we demonstrate that in primary erythroid cells, Hes1 gene expression is transiently repressed around proerythroblast stage of differentiation. Using mouse erythroleukemia cells, we found that the RNA interference (RNAi)-mediated depletion of HES1 enhances erythroid cell differentiation, suggesting that this protein opposes terminal erythroid differentiation. This is also supported by the decreased primary erythroid cell differentiation upon HES1 upregulation in Ikaros-deficient mice. A comprehensive analysis led us to determine that Ikaros favors Hes1 repression in erythroid cells by facilitating recruitment of the master regulator of erythropoiesis GATA-1 alongside FOG-1, which mediates Hes1 repression. GATA-1 is then necessary for the chromatin binding of the NuRD remodeling complex ATPase MI-2, the transcription factor GFI1B, and the histone H3K27 methyltransferase EZH2 along with Polycomb repressive complex 2. We show that EZH2 is required for the transient repression of Hes1 in erythroid cells. In aggregate, our results describe a mechanism whereby GATA-1 utilizes Ikaros and Polycomb repressive complex 2 to promote Hes1 repression as an important step in erythroid cell differentiation.
PMCID: PMC3430200  PMID: 22778136
19.  Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study 
The enzymes folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH) are essential for determining intracellular folate availability for one-carbon metabolism (OCM) pathways. FPGS adds glutamyl groups to the folate molecule, thereby converting folate into the preferred substrate for several enzymes in OCM pathways. GGH removes glutamyl groups, allowing folate metabolites to leave the cell. The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) in the FPGS and GGH genes influence measured plasma homocysteine levels. Study participants were a sub-cohort (n = 482) from the Singapore Chinese Health Study. SNPs were selected using HapMap tagSNPs and SNPs previously reported in the scientific literature. Multiple linear regression was used to evaluate the association between individual SNPs and plasma homocysteine levels. Two FPGS (rs10106, rs1098774) and 9 GGH (rs719235, rs1031552, rs1800909, rs3758149, rs3780126, rs3824333, rs4617146, rs11545076, rs11545078) SNPs were included in the final analysis. Neither of the FPGS SNPs, but three GGH SNPs were associated with plasma homocysteine levels: rs11545076 (p=0.001), rs1800909 (p=0.02), and rs3758149 (p = 0.006). Only one (rs11545076) remained statistically significant after adjusting for multiple comparisons. This study suggests that GGH SNPs, rs11545076, rs1800909, and rs3758149, may have functional relevance and result in alterations in plasma homocysteine levels. Since this is one of the first studies to assess FPGS and GGH genetic variants in relation to plasma homocysteine, further research is needed to confirm these findings and characterize the functional effects of these variants.
PMCID: PMC3253895  PMID: 22018726
FPGS; GGH; Folate; Homocysteine; SNP
20.  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
21.  Pediatric germ cell tumors and parental infertility and infertility treatment: a Children’s Oncology Group Report 
Cancer epidemiology  2011;35(5):e25-e31.
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.
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.
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).
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.
PMCID: PMC3142313  PMID: 21474408
Germ cell tumor; infertility; pediatrics; epidemiology
22.  Non-steroidal anti-inflammatory drug (NSAID) and acetaminophen use and risk of adult myeloid leukemia 
Little is known about the causes of adult leukemia. A few small studies have reported a reduced risk associated with regular use of non-steroidal anti-inflammatory drugs (NSAIDs).
In a population-based case-control study, we evaluated analgesic use among 670 newly diagnosed myeloid leukemia cases [including 420 acute myeloid leukemias (AML) and 186 chronic myeloid leukemias (CML)] and 701 controls aged 20–79 years. Prior use of aspirin, ibuprofen, acetaminophen, other NSAIDs, and cyclooxygenase-2 (COX-2) inhibitors was assessed and included frequency, duration, and quantity. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression adjusting for potential confounders.
Regular/extra strength aspirin use was inversely associated with myeloid leukemia in women (OR=0.59, 95%CI=0.37–0.93) but not men (OR=0.85, 95%CI=0.58–1.24). In contrast, acetaminophen use was associated with an increased risk of myeloid leukemia in women only (OR=1.60, 95%CI=1.04–2.47). These relationships were stronger with increasing dose and duration. When stratified by leukemia type, aspirin use was inversely associated with AML and CML in women. No significant overall associations were found with ibuprofen or COX-2 inhibitors for either sex; however, a decreased risk was observed with other anti-inflammatory analgesic use for women with AML or CML (OR=0.47, 95%CI=0.22–0.99; OR=0.31, 95%CI=0.10–0.92, respectively).
Our results provide additional support for the chemopreventive benefits of NSAIDs, at least in women. Since leukemia ranks fifth in person years of life lost due to malignancy, further investigation is warranted.
NSAIDs may reduce, while acetaminophen may increase, myeloid leukemia risk in women.
PMCID: PMC3153558  PMID: 21715605
aspirin; leukemia; NSAIDs; acetaminophen; prevention
23.  Birth order and Risk of Childhood Cancer: A Pooled Analysis from Five U.S. States 
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 less than 15 years of age who were diagnosed from1980-2004 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 (CNS) 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.
PMCID: PMC3008504  PMID: 20715170
birth order; case-control studies; child; epidemiology; neoplasms
24.  Vitamin supplement use among children with Down syndrome and risk of leukemia: A Children’s Oncology Group (COG) Study 
Vitamin supplements have been proposed for children with Down syndrome (DS) with claims of improving cognitive abilities, or immune or thyroid function. Several studies have shown decreased levels of zinc in this population. Because children with DS have a 50-fold increased risk of developing acute leukemia during the first 5 years of life, we explored the relation between child vitamin and herbal supplement use and the risk for leukemia in a case-control study. During the period 1997–2002, we enrolled 158 children with DS aged 0–18 years that were diagnosed with acute lymphoblastic leukemia (ALL) (n=97) or acute myeloid leukemia (AML) (n=61) at participating COG institutions. We enrolled 173 DS children without leukemia (controls), selected from the cases’ primary care clinic and frequency matched on age. Data were collected via telephone interviews with mothers of the index child regarding use of multivitamins, zinc, vitamin C, iron, and herbal supplements, including age at first use, frequency and duration. Among controls, 57% reported regular multivitamin use (≥ 3 times/week for ≥ 3 months) compared with 48% of ALL cases and 61% of AML cases. We found no evidence of an association between child’s regular multivitamin use and ALL or AML (adjusted odds ratios (ORs)=0.94 [95% confidence interval 0.52, 1.70] and 1.90 [0.73, 4.91], respectively. There was a suggestion of an increased risk for AML associated with regular multivitamin use during the first year of life or for an extended duration (ORs = 2.38 [0.94, 5.76] and 2.59 [1.02, 6.59], respectively). Despite being the largest study of DS-leukemia, our sample size was small, resulting in imprecise effect estimates. Future research should include larger sample sizes as well as a full assessment of diet including vitamin supplementation to adequately examine the relation between nutritional status and childhood leukemia.
PMCID: PMC3365502  PMID: 18426524
25.  Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study 
BMC Pediatrics  2012;12:33.
While a possible link between assisted reproductive technology (ART) and rare imprinting disorders has been found, it is not clear if this is indicative of subtler disruptions of epigenetic mechanisms. Results from previous studies have been mixed, but some methylation differences have been observed.
Children conceived through ART and children conceived spontaneously were recruited for this cross-sectional study. Information about reproductive history, demographic factors, birth characteristics, and infertility treatment was obtained from maternal interview and medical records. Peripheral blood lymphocytes and buccal cell samples were collected from participating children. Methylation analysis was performed on five loci using pyrosequencing. Statistical analysis of methylation differences was performed using linear regression with generalized estimating equations. Results are reported as differences with 95% confidence intervals (CI).
A total of 67 ART children and 31 spontaneously conceived (SC) children participated. No significant difference in methylation in lymphocyte samples was observed between groups for any loci. Possible differences were found in buccal cell samples for IGF2 DMR0 (Difference: 2.07; 95% confidence interval (CI): -0.28, 4.42; p = 0.08) and IGF2R (Difference: -2.79; 95% CI: -5.74, 0.16; p = 0.06). Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility.
Observed differences in methylation between the ART and SC groups were small for all loci in the two sample types examined and no statistical differences were observed. It is still unclear whether or not small differences observed in several studies represent a real difference between groups and if this difference is biologically meaningful. Larger studies with long term follow-up are needed to fully answer these questions.
PMCID: PMC3323893  PMID: 22433799
Assisted reproductive technology; Epigenetics; Imprinting

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