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.

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.

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.

Background

Few risk factors have been established for childhood germ cell tumors (GCT). Parental infertility and infertility treatment may be associated with GCT development but these risk factors have not been fully investigated.

Methods

A case-control study of childhood GCT was conducted through the Children’s Oncology Group (COG). Cases, under the age of 15 years at diagnosis, were recruited through COG institutions from January 1993 to December 2002. Controls were obtained through random digit dialing. Information about infertility and infertility treatment along with demographic factors was collection through maternal interviews. Subgroups created by gender, age at diagnosis, and tumor location were examined separately. Statistical analysis was performed using multivariate logistic regression models.

Results

Overall, no association between GCT and infertility or its treatment was found. In subgroup analysis, females whose mothers had two or more fetal losses were found to be at increased risk for non-gonadal tumors (Odds ratio (OR) = 3.32, 95% Confidence interval (CI) = 1.12–9.88). Younger maternal age was associated with a lower risk of gonadal GCT in females (OR = 0.52, 95% CI = 0.28–0.96). There was an increased risk of all GCT and gonadal GCT in males born to older mothers (OR = 2.88, 95% CI = 1.13–7.37 and OR = 3.70, 95% CI = 1.12–12.24).

Conclusion

While no association between parental infertility or its treatment and childhood GCT was found overall, possible associations with maternal age and history of recurrent fetal loss were found in subgroups defined by gender.

Background

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).

Methods

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.

Results

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).

Conclusions

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.

Impact

NSAIDs may reduce, while acetaminophen may increase, myeloid leukemia risk in women.

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.

Summary

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.

Background

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.

Methods

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).

Results

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.

Conclusions

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.

Maternal diet during pregnancy may be associated with cancer in offspring. Intake of individual foods, as well as dietary patterns, can be used when examining these relations. Here, the authors examined associations between maternal dietary intake patterns and pediatric germ cell tumors (GCTs) using principal components analysis and logistic regression. Mothers of 222 GCT cases aged less than 15 years who were diagnosed at a Children's Oncology Group institution between 1993 and 2001 and those of 336 frequency-matched controls completed a self-administered food frequency questionnaire of diet during early pregnancy. Four dietary patterns were identified: “Western,” “fruits and vegetables,” “protein,” and “healthful.” With adjustment for birth weight, parity, and vitamin use, the fruits and vegetables pattern was significantly associated with a lower odds for GCTs (odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.69, 0.99; 2 sided). Upon stratification, the fruits and vegetables pattern was significantly associated with a lower odds in males (OR = 0.66, 95% CI: 0.47, 0.92) but not females (OR = 0.91, 95% CI: 0.72, 1.14). A quantitative assessment of assumed nondifferential reporting error indicated no notable deviations from unadjusted odds ratio estimates. Results of this exploratory analysis suggest that maternal prenatal dietary patterns could be considered in future studies of GCTs in offspring.

We developed extraction and analysis protocols for element detection in neonatal blood spots (NBSs) using sector-field inductively coupled plasma-mass spectrometry (SF-ICP-MS). A 5% (v/v) nitric acid element extraction protocol was optimized and used to simultaneously measure 28 elements in NBS card filter paper and 150 NBSs. NBS element concentrations were corrected for filter paper background contributions estimated from measurements in samples obtained from either unspotted or spotted NBS cards. A lower 95% uncertainty limit (UL) that accounted for ICP-MS method, filter paper element concentration, and element recovery uncertainties was calculated by standard methods for each individual’s NBS element concentration. Filter paper median element levels were highly variable within and between lots for most elements. After accounting for measurement uncertainties, 11 elements (Ca, Cs, Cu, Fe, K, Mg, Na, P, Rb, S, Zn) had lower 95% ULs >0 ng/spot with estimated concentrations ranging from 0.05->50,000 ng/spot in ≥50% of NBS samples in both correction methods. In a NBS sample minority, Li, Cd, Cs, Cr, Ni, Mo, and Pb had estimated concentrations ≥20-fold higher than the respective median level. Taking measurement uncertainties into account, this assay could be used for semiquantitative newborn blood element measurement and for detection of individuals exposed to supraphysiologic levels of some trace elements. Adequate control of filter paper element contributions remains the primary obstacle to fully quantitative element measurement in newborn blood using NBSs.

The effect of glutathione S-transferase variants on pediatric busulfan metabolism was investigated by noncompartmental and population pharmacokinetic modeling. Twenty-nine children who underwent related or unrelated bone marrow or umbilical cord blood hematopoietic cell transplant were retrospectively studied. GSTA1, GSTP1, and GSTM1 variants were explored for their effects on busulfan exposures. Noncompartmental pharmacokinetic analyses showed that carriers of GSTA1*B had a 2.6-fold higher busulfan area under the curve and concentration at steady state compared with noncarriers (P ≤ .01). Population pharmacokinetic modeling demonstrated that carriers of GSTA1*B reduced busulfan clearance by 30%. Monte Carlo simulations were then performed to assess busulfan dosing regimens based on GSTA1 genotypes. Simulations determined that dosing based on GSTA1 genotype, weight, and age resulted in fewer children exceeding the upper therapeutic limit compared with dosing using age and weight only. Larger, prospective studies are needed to confirm these findings.

Background

Leukemia in infants is rare and has not been well-studied apart from leukemia in older children. Differences in survival and the molecular characteristics of leukemia in infants vs. older children suggest a distinct etiology, likely involving prenatal factors.

Procedure

We examined the association between eight categories of maternally-reported congenital abnormalities (CAs) (cleft lip or palate, spina bifida or other spinal defect, large or multiple birthmarks, other chromosomal abnormalities, small head or microcephaly, rib abnormalities, urogenital abnormalities, and other) and infant leukemia in a case-control study. The study included 443 cases diagnosed at <1 year of age at a Children’s Oncology Group institution in the United States or Canada from 1996-2006 and 324 controls. Controls were recruited from the cases’ geographic area either by random digit dialing (1999-2002) or through birth certificates (2003-2008) and were frequency-matched to cases on birth year. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjustment for birth year and a measure of follow-up time to account for differences in the CA observation period.

Results

No statistically significant associations were observed between infant leukemia and any CA (OR=1.2; 95% CI 0.8-1.9), birthmarks (OR=1.4, 95% CI 0.7-2.5), urogenital abnormalities (OR=0.7; 95% CI 0.2-2.0), or other CA (OR=1.4; 95% CI 0.7-2.8). Results were similar for acute lymphoblastic and myeloid leukemia cases. Fewer than five subjects were in the remaining CA categories precluding analysis.

Conclusions

Overall, we did not find evidence to support an association between CAs and infant leukemia.

BACKGROUND

Little is known about the potential risk factors for infant leukemia. With its very young age at diagnosis, exposures occurring in the perinatal period are suspected. Parental infertility and infertility treatment have been studied with regard to childhood cancer in general, but rarely in individual cancer subtypes.

METHODS

A case–control study of infant leukemia was conducted through the Children's Oncology Group, including cases diagnosed from January 1996 to December 2006 and controls selected through random digit dialing and birth certificate tracing. Maternal phone interviews were conducted to obtain information about infertility, infertility treatment and demographic factors. All cases as well as subgroups defined by mixed lineage leukemia (MLL) translocation status and leukemia subtype were examined. Statistical analysis was performed using multivariate logistic regression models.

RESULTS

No significant associations between infertility or its treatment and combined infant leukemia were found. In subgroup analyses, there was a significant increase in the risk of MLL− leukemia for children born to women not trying to conceive compared with those trying for <1 year for all types combined [odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.01–2.59] and for acute lymphoblastic leukemia (OR = 2.50, 95% CI = 1.36–4.61).

CONCLUSIONS

There were no positive associations between parental infertility or infertility treatment and infant leukemia. While this is the largest study to date, both selection and recall bias may have impacted the results. However, for infant leukemia, we can potentially rule out large increases in risk associated with parental infertility or its treatment.

The candidate tumor suppressor BAP1 is a deubiquitinating enzyme (DUB) involved in the regulation of cell proliferation, although the molecular mechanisms governing its function remain poorly defined. BAP1 was recently shown to interact with and deubiquitinate the transcriptional regulator host cell factor 1 (HCF-1). Here we show that BAP1 assembles multiprotein complexes containing numerous transcription factors and cofactors, including HCF-1 and the transcription factor Yin Yang 1 (YY1). Through its coiled-coil motif, BAP1 directly interacts with the zinc fingers of YY1. Moreover, HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes. We further show that BAP1 and HCF-1 are recruited by YY1 to the promoter of the cox7c gene, which encodes a mitochondrial protein used here as a model of BAP1-activated gene expression. Our findings (i) establish a direct link between BAP1 and the transcriptional control of genes regulating cell growth and proliferation and (ii) shed light on a novel mechanism of transcription regulation involving ubiquitin signaling.

Cytosine arabinoside (ara-C) is irreversibly deaminated by cytidine deaminase (CDD) to a nontoxic metabolite. A common polymorphism, A79C, in CDD changes a lysine residue to glutamine resulting in decreased enzyme activity. We determined CDD A79C genotypes for 457 children with AML treated on CCG 2941 and 2961 and analyzed the impact of CDD genotype on therapy outcomes. Post-Induction treatment related mortality (TRM) was significantly elevated in children with the CC genotype (5 year TRM 17 ± 13% CC vs 7 ± 4% AA, 5 ± 4% AC, p= 0.05). This was more notable in children who received IDA-FLAG (ara-C= 7590 mg/m2) (5 year TRM 24 ± 21% CC vs 6 ± 6% AA, 6 ± 7% AC, p=0.07) as consolidation therapy compared to IDA-DCTER (ara-C= 800 mg/m2) (5 year TRM 15 ± 20% CC vs 8 ± 6% AA, 4 ± 6% AC; p=0.29). Relapse-free survival was non-significantly increased in children with the CC genotype treated with IDA-FLAG (76 ± 20% CC vs 59 ± 12% AA and 55 ± 14% AC; p= 0.40). These data indicate that children with a low activity CDD genotype are at increased risk of treatment-related mortality with Ara-C based therapy for AML.

Atopic disease is hypothesized to be protective against several malignancies, including childhood/adolescent leukemia. To summarize the available epidemiologic evidence, the authors performed a meta-analysis of associations between atopy/allergies, asthma, eczema, hay fever, and hives and childhood/adolescent leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). They searched MEDLINE literature (1952–March 2009) and queried international experts to identify eligible studies. Ten case-control studies were included. Summary odds ratios and 95% confidence intervals were computed via random-effects models. Odds ratios for atopy/allergies were 1.42 (95% confidence interval (CI): 0.60, 3.35) for 3 studies of leukemia overall, 0.69 (95% CI: 0.54, 0.89) for 6 studies of ALL, and 0.87 (95% CI: 0.62, 1.22) for 2 studies of AML, with high levels of heterogeneity detected for leukemia overall and ALL. Inverse associations were observed for ALL and asthma (odds ratio (OR) = 0.79, 95% CI: 0.61, 1.02), eczema (OR = 0.74, 95% CI: 0.58, 0.96), and hay fever (OR = 0.55, 95% CI: 0.46, 0.66) examined separately. Odds ratios for ALL differed by study design, exposure data source, and latency period, indicating that these factors affect study results. These results should be interpreted cautiously given the modest number of studies, substantial heterogeneity, and potential exposure misclassification but are useful in designing future research.

During 2007, large outbreaks of equine influenza (EI) caused by Florida sublineage Clade 1 viruses affected horse populations in Japan and Australia. The likely protection that would be provided by two modern vaccines commercially available in the European Union (an ISCOM-based and a canarypox-based vaccine) at the time of the outbreaks was determined. Vaccinated ponies were challenged with a representative outbreak isolate (A/eq/Sydney/2888-8/07) and levels of protection were compared. A group of ponies infected 18 months previously with a phylogenetically-related isolate from 2003 (A/eq/South Africa/4/03) was also challenged with the 2007 outbreak virus. After experimental infection with A/eq/Sydney/2888-8/07, unvaccinated control ponies all showed clinical signs of infection together with virus shedding. Protection achieved by both vaccination or long-term immunity induced by previous exposure to equine influenza virus (EIV) was characterised by minor signs of disease and reduced virus shedding when compared with unvaccinated control ponies. The three different methods of virus titration in embryonated hens’ eggs, EIV NP-ELISA and quantitative RT-PCR were used to monitor EIV shedding and results were compared. Though the majority of previously infected ponies had low antibody levels at the time of challenge, they demonstrated good clinical protection and limited virus shedding. In summary, we demonstrate that vaccination with current EIV vaccines would partially protect against infection with A/eq/Sydney/2888-8/07-like strains and would help to limit the spread of disease in our vaccinated horse population.

Antioxidant nutrients found in fruits, vegetables, and other foods are thought to inhibit carcinogenesis and to influence immune status. We evaluated the association of these factors with risk of NHL overall and for diffuse large B-cell (DLBCL) and follicular lymphoma specifically in a prospective cohort of 35,159 Iowa women aged 55–69 years when enrolled at baseline in 1986. Diet was ascertained using a validated semi-quantitative food frequency questionnaire. Through 2005, 415 cases of NHL (including 184 DLBCL and 90 follicular) were identified. Relative risks (RRs) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for age and total energy. The strongest associations of antioxidants with risk of NHL (RR for highest versus lowest quartile; p for trend) were observed for dietary vitamin C (RR=0.78; p=0.044), α-carotene (RR=0.71; p=0.015), proanthocyanidins (RR=0.70; p=0.0024), and dietary manganese (RR=0.62; p=0.010). There were no associations with multivitamin use or supplemental intake of vitamins C, E, selenium, zinc, copper or manganese. From a food perspective, greater intake of total fruits and vegetables (RR=0.69; p=0.011), yellow/orange (RR=0.72; p=0.015) and cruciferous (RR=0.82; p=0.017) vegetables, broccoli (RR=0.72; p=0.018), and apple juice/cider (RR=0.65; p=0.026) were associated with lower NHL risk; there were no strong associations for other antioxidant-rich foods, including whole grains, chocolate, tea or nuts. Overall, these associations were mainly observed for follicular lymphoma, and were weaker or not apparent for DLBCL. In conclusion, these results support a role for vegetables and perhaps fruits, and associated antioxidants from food sources, as protective factors against the development of NHL and follicular lymphoma in particular.

Family history of testicular cancer is an established risk factor for adult testicular germ cell tumors (GCT). We evaluated the association between family history of cancer and pediatric GCT in a Children's Oncology Group case–control study that included 274 GCT cases (195 female and 79 male) diagnosed