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1.  Farm residence and lymphohematopoietic cancers in the Iowa Women’s Health Study 
Environmental research  2014;133:353-361.
Cancer incidence in male farmers has been studied extensively; however, less is known about risk among women residing on farms or in agricultural areas, who may be exposed to pesticides by their proximity to crop fields. We extended a previous follow-up of the Iowa Women’s Health Study cohort to examine farm residence and the incidence of lymphohematopoietic cancers. Further, we investigated crop acreage within 750 m of residences, which has been associated with higher herbicide levels in Iowa homes.
We analyzed data for a cohort of 37,099 Iowa women aged 55–69 years who reported their residence location (farm, rural (not a farm), town size based on population) at enrollment in 1986. We identified incident lymphohematopoietic cancers (1986–2009) by linkage with the Iowa Cancer Registry. Using a geographic information system, we geocoded addresses and calculated acreage of pasture and row crops within 750 m of homes using the 1992 National Land Cover Database. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariate analyses of cancer risk in relation to both residence location and crop acreage.
As found in an earlier analysis of residence location, risk of acute myeloid leukemia (AML) was higher among women living on farms (HR= 2.23, 95%CI: 1.25–3.99) or rural areas (but not on a farm) (HR= 1.95, 95%CI: 0.89–4.29) compared with women living in towns of > 10,000 population. We observed no association between farm or rural residence and non-Hodgkin lymphoma (NHL; overall or for major subtypes) or multiple myeloma. In analyses of crop acreage, we observed no association between pasture or row crop acreage within 750 m of homes and risk of leukemia overall or for the AML subtype. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) risk was nonsignificantly elevated among women with pasture acreage within 750 m of their home (HRs for increasing tertiles= 1.8, 1.8 and 1.5) and with row crop acreage within 750 m (HRs for increasing tertiles of acreage= 1.4, 1.5 and 1.6) compared to women with no pasture or row crop acreage, respectively.
Iowa women living on a farm or in a rural area were at increased risk of developing AML, which was not related to crop acreage near the home. Living near pasture or row crops may confer an increased risk of CLL/SLL regardless of residence location. Further investigation of specific farm-related exposures and these cancers among women living on farms and in agricultural areas is warranted.
PMCID: PMC4324553  PMID: 25038451
Farm residence; Pesticides; Iowa Women’s Health Study; GIS; Land use
2.  The Children’s Oncology Group Childhood Cancer Research Network (CCRN) 
Cancer  2014;120(19):3007-3015.
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.
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.
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.
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.
PMCID: PMC4287245  PMID: 24889136
childhood cancer; United States; clinical trials; incidence; catchment
3.  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.
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.
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.
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.
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.
PMCID: PMC4287257  PMID: 25044669
case–control study; exposure; hepatoblastoma; low birth weight; NICU
4.  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.
PMCID: PMC4045651  PMID: 24301523
Infant; leukemia; exome; MLL3
5.  Parental tobacco and alcohol use and risk of hepatoblastoma in offspring: A report from the Children’s Oncology Group 
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.
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.
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.
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.
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.
PMCID: PMC4188411  PMID: 23950215
hepatoblastoma; alcohol; smoking; childhood cancer
6.  The transcription factor Miz-1 is required for embryonic and stress-induced erythropoiesis but dispensable for adult erythropoiesis 
Myc-interacting zinc finger protein 1 (Miz-1) is a BTB/POZ domain transcription factor that regulates complex processes such as proliferation and apoptosis. Constitutively Miz-1-deficient animals arrest embryonic development at E14.5 due to severe anemia and fetal liver cells lacking Miz-1 show a high cell death rate and a significant reduction of mature Ter119+ckit- or Ter119+CD71-/low cells. Consistently, the numbers of BFU-Es and CFU-Es were severely reduced in colony forming assays. Mice with conditional Miz-1 alleles deleted around E14.5 were born at expected ratios, but had reduced numbers of erythrocytes, and showed an increase in reticulocytes and Macro-RBCs in the peripheral blood. When challenged with the hemolytic agent phenylhydrazine (PHZ), Miz-1 deficient mice responded with a severe anemia after 4 days of treatment, but showed a delay in the recovery from this anemia with regard to RBC counts, hematocrit and hemoglobin levels compared to controls. In addition, an accumulation of immature CD71+Ter119+ cells occurred in the bone marrow and spleen of mice lacking a functional Miz-1. We conclude from our studies that Miz-1 is important for erythroid differentiation and development. Moreover, Miz-1 is necessary to maintain a peripheral red blood cell homeostasis in particular in response to hemolysis after oxidative stress.
PMCID: PMC4165114  PMID: 25232500
BTB/POZ domain; transcription factor; Miz-1; erythropoiesis; Epo; STAT5
7.  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.
PMCID: PMC3731070  PMID: 23692655
acute lymphoblastic leukemia; children; genetic susceptibility; gene-environment interaction
8.  Risk of adult acute and chronic myeloid leukemia with cigarette smoking and cessation 
Cancer epidemiology  2013;37(4):10.1016/j.canep.2013.03.012.
Cigarette smoking is an established risk factor for adult myeloid leukemia, particularly acute myeloid leukemia (AML), but less is known about the nature of this association and effects of smoking cessation on risk.
In a large population-based case-control study of myeloid leukemia that included 414 AML and 185 chronic myeloid leukemia (CML) cases and 692 controls ages 20–79 years, we evaluated risk associated with cigarette smoking and smoking cessation using unconditional logistic regression methods and cubic spline modeling.
AML and CML risk increased with increasing cigarette smoking intensity in men and women. A monotonic decrease in AML risk was observed with increasing time since quitting, whereas for CML, the risk reduction was more gradual. For both AML and CML, among long-term quitters (≥30 years), risk was comparable to non-smokers.
Our study confirms the increased risk of myeloid leukemia with cigarette smoking and provides encouraging evidence of risk attenuation following cessation.
PMCID: PMC3819424  PMID: 23643192
Leukemia; Acute myeloid leukemia; Chronic myeloid leukemia; Cigarette smoking; Smoking cessation
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.
PMCID: PMC3725212  PMID: 23623515
10.  Targeting Natural Killer cells to Acute Myeloid Leukemia in vitro with a CD16x33 bispecific killer cell engager (BiKE) and ADAM17 inhibition 
The graft versus leukemia (GVL) effect by Natural Killer (NK) cells prevents relapse following hematopoietic stem cell transplantation. We determined whether a novel bi-specific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against AML targets.
Experimental Design
We investigated the ability of our fully humanized CD16x33 BiKE to trigger in vitro NK cell activation against HL60 (CD33+), RAJI (CD33−), and primary AML targets (de novo, refractory and post transplant) to determine whether treatment with CD16x33 BiKE in combination with an ADAM17 inhibitor could prevent CD16 shedding (a novel inhibitory mechanism induced by NK cell activation) and overcome inhibition of class I MHC recognizing inhibitory receptors.
NK cell cytotoxicity and cytokine release were specifically triggered by the CD16x33 BiKE when cells were cultured with HL60 targets, CD33+ de novo and refractory AML targets. Combination treatment with CD16x33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation. Treatment of NK cells from double umbilical cord blood transplant (UCBT) recipients with the CD16x33 BiKE resulted in activation, especially in those recipients with CMV reactivation.
CD16x33 BiKE can overcome self inhibitory signals and effectively elicit NK cell effector activity against AML. These in vitro studies highlight the potential of CD16x33 BiKE ± ADAM17 inhibition to enhance NK cell activation and specificity against CD33+ AML, which optimally could be applied in patients with relapsed AML or for adjuvant anti-leukemic therapy post-transplantation.
PMCID: PMC3715574  PMID: 23690482
NK cells; AML; CD16; BiKE; ADAM17
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.
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.
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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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