Background

Congenital cytomegalovirus (CMV) infection was recently identified as a risk factor for childhood acute lymphocytic leukemia by detecting the presence of CMV sequences in neonatal blood spots. In this study, we asked whether clinically apparent CMV infection could be identified prior to hematologic malignancy, using high-quality Swedish population-based registries.

Methods

CMV infection was identified with appropriate ICD-9 or ICD-10 codes in the Patient and Medical Birth Registries, and childhood malignancies below the age of 15 years were identified in the Cancer Registry, among 2,782,507 children born in Sweden 1987 to 2014.

Results

Observing all CMV infections registered earlier than 6 months prior to malignancy diagnosis, an increased HR of CMV-related infections, adjusting for congenital malformations, deformations, and chromosome abnormalities, was detected for hematologic malignancies [HR, 11.2; 95% confidence interval (CI), 5.8-21.5], but not for central nervous system tumors.

Conclusions

Higher CMV incidence was detected for children ostensibly exposed through maternal CMV infection during pregnancy with the index child.

Impact

The data are compatible with a congenital infection of CMV leading to increased risk of childhood hematologic malignancies, but not tumors of the central nervous system, although a cautious interpretation is warranted because of the small numbers.

Object

The 2-fold higher incidence of meningioma in women compared with men has long suggested a role for hormonally mediated risk factors, but specific mechanisms remain elusive.

Methods

The study included data obtained in 1127 women 29-79 years of age with intracranial meningioma diagnosed among residents of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area, and 8 Texas counties between May 1, 2006, and October 6, 2011, and data obtained in 1092 control individuals who were frequency matched for age group and geography with meningioma patients.

Results

No association was observed for age at menarche, age at menopause, or parity and meningioma risk. Women who reported breastfeeding for at least 6 months were at reduced risk of meningioma (OR 0.78, 95% CI 0.63-0.96). A significant positive association existed between meningioma risk and increased body mass index (p < 0.01) while a significant negative association existed between meningioma risk and current smoking (p < 0.01). Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67). There was no association between use of fertility medications and meningioma risk.

Conclusions

The authors' study confirms associations for body mass index, breastfeeding, and cigarette smoking but provides little evidence for associations of reproductive and menstrual factors with meningioma risk. The relationship between current use of exogenous hormones and meningioma remains unclear, limited by the small numbers of patients currently on oral hormone medications and a lack of hormone receptor data for meningioma tumors.

Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0-14 years during 1988-2011 and 122 controls matched on sex, age, and race/ethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, race/ethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryo's DNA methylation programming.

Not available.

Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.

Background

A number of studies have reported on the association between smoking and meningioma risk, with inconsistent findings. We examined the effect of gender on the association between cigarette smoking and risk of intracranial meningioma in a large population-based, case-control study.

Methods

The data include 1,433 intracranial meningioma cases aged 29 to 79 years diagnosed among residents of the states of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area and eight Texas counties between May 1, 2006 and April 28, 2011 as well as 1,349 controls that were frequency matched on age, sex, and geography. The data are analyzed separately and in a meta-analysis with six previously reported studies.

Results

Female cases who reported having ever smoked were at significantly decreased risk of intracranial meningioma (OR, 0.8; 95% CI, 0.7-0.9) in contrast to male cases who were at increased risk (OR, 1.3; 95% CI, 1.0-1.7). Similar findings were noted for current and past smokers. Smoking-induced risk for females did not vary by menopausal status. For males, increased duration of use (P = 0.04) as well as increasing number of pack-years (P = 0.02) was associated with elevated risk. A meta-analysis including 2,614 cases and 1,179,686 controls resulted in an OR for ever smoking of 0.82 (95% CI, 0.68-0.98) for women and 1.39 (95% CI, 1.08-1.79) for men.

Conclusion

The association of cigarette smoking and meningioma case status varies significantly by gender with women at reduced risk and men at greater risk.

Impact

Whether the observed differences are associated with a hormonal etiology will require additional investigation.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years); however, the etiology remains incompletely understood. Several environmental exposures have been linked to risk of childhood ALL, including air pollution. Closely related to air pollution and human development is artificial light at night (ALAN), which is believed to disrupt circadian rhythm and impact health. We sought to evaluate outdoor ALAN and air pollution on risk of childhood ALL. The California Linkage Study of Early-Onset Cancers is a large population-based case-control in California that identifies and links cancer diagnoses from the California Cancer Registry to birth records. For each case, 50 controls with the same year of birth were obtained from birth records. A total of 2,782 ALL cases and 139,100 controls were identified during 2000-2015. ALAN was assessed with the New World Atlas of Artificial Night Sky Brightness and air pollution with an ensemble-based air pollution model of particulate matter smaller than 2.5 microns (PM_2.5). After adjusting for known and suspected risk factors, the highest tertile of ALAN was associated with an increased risk of ALL in Hispanic children (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.01-1.32). There also appeared to be a borderline association between PM_2.5 level and risk of ALL among non-Hispanic White children (OR per 10 µg/m³ = 1.24, 95% CI 0.98-1.56). We observed elevated risk of ALL in Hispanic children residing in areas of greater ALAN. Further work is needed to understand the role of ALAN and air pollution in the etiology of childhood ALL in different racial/ethnic groups.

Background: Incidence rates of thyroid cancer in children and young adults (age 0-19 years) have nearly doubled over a recent 15-year period in the United States. Children with thyroid cancer may require long-term therapy and surveillance and are at greater risk for second primary malignancies. High-dose exposure to ionizing radiation is the only known nongenetic risk factor; the vast majority of cases have an unknown etiology. Methods: We conducted a population-based nested case-control study to evaluate the relationship between a range of birth characteristics and the risk of pediatric thyroid cancer. Using linked birth records and cancer registry data from California, we included 1012 cases who were diagnosed with first primary thyroid cancer at the age of 0-19 years from 1988 to 2015 and 50,600 birth-year matched controls (1:50 case to control ratio). We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) by using multivariable logistic regression models applied to the full population and stratified by thyroid cancer subtypes (papillary and follicular), race/ethnicity (white and Hispanic), and age at diagnosis (0-14 and 15-19 years). Results: Hispanic ethnicity (OR: 1.20 [CI 1.01-1.42]), higher birth weight (OR: 1.11 [CI 1.04-1.18] per 500g), and higher maternal education (13-15 years OR: 1.35 [CI 1.09-1.68], 16+ years OR: 1.35 [CI 1.07-1.71]) were associated with an increased risk of pediatric thyroid cancer, while male sex (OR: 0.21 [CI 0.18-0.25]) and higher birth order (third or higher OR: 0.81 [CI 0.68-0.98]) were associated with a decreased risk. Some heterogeneity was observed across subtype, most notably an elevated OR with higher birth order for follicular thyroid cancer, in contrast to the reduced risk for this category among papillary thyroid cancer cases (p-value for interaction = 0.01). Hispanic ethnicity was a risk factor for papillary, but not follicular thyroid cancer (p-value for interaction = 0.07). Conclusions: In this population-based study of birth characteristics and pediatric thyroid cancer, we identified several important risk factors for pediatric thyroid cancer, including female sex, Hispanic ethnicity, higher birth weight, higher maternal educational attainment, and lower birth order. Our data provide new areas for replication and investigation of biological mechanisms for this poorly understood malignancy.

Background

Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known.

Objectives

We evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study.

Methods

Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared with periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term.

Results

Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22(dual specificity phosphatase 22) demonstrated DNA hypermethylation in ALL cases but not in controls in response to total and food folate intake. We further identified 8 interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and educational level.

Conclusions

We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.