PM2.5, vegetation density, and childhood cancer: a case-control registry-based study from Texas 1995-2011.

BACKGROUND: Air pollution is positively associated with some childhood cancers while greenness is inversely associated with some adult cancers. The interplay between air pollution and greenness in childhood cancer etiology is unclear. We estimated the association between early life air pollution and greenness exposure and childhood cancer in Texas (1995-2011). METHODS: We included 6,101 cancer cases and 109,762 controls (aged 0-16 years). We linked residential birth address to census tract annual average particulate matter ≤2.5 µg/m³ (PM2.5) and Normalized Difference Vegetation Index (NDVI). We estimated odds ratios (OR) and 95% confidence intervals (95% CI) between PM2.5/NDVI interquartile range increases and cancer. We assessed statistical interaction between PM2.5 and NDVI (likelihood ratio tests). RESULTS: Increasing residential early life PM2.5 exposure was associated with all childhood cancers (OR 1.10, 95% CI: 1.06-1.15), lymphoid leukemias (OR: 1.15, 95% CI: 1.07-1.23), Hodgkin lymphomas (OR: 1.27, 95% CI: 1.02-1.58), non-Hodgkin lymphomas (OR: 1.24, 95% CI: 1.02-1.51), ependymoma (OR: 1.27, 95% CI: 1.01-1.60) and others. Increasing NDVI exposure was inversely associated with ependymoma (0-4-year-old OR: 0.75, 95% CI: 0.58-0.97) and medulloblastoma (OR: 0.75, 95% CI: 0.62-0.91), but positively associated with malignant melanoma (OR: 1.75, 95% CI: 1.23-2.47) and Langerhans cell histiocytosis (OR: 1.56, 95% CI: 1.07-2.28). There was evidence of statistical interaction between NDVI and PM2.5 (p < .04) for all cancers. DISCUSSION: Increasing early life exposure to PM2.5 increased the risk of childhood cancers. NDVI decreased risk of two cancers yet increased risk of others. These findings highlight the complexity between PM2.5 and NDVI in cancer etiology.

Racial and ethnic and socioeconomic disparities in childhood cancer incidence trends in the United States, 2000-2019.

BACKGROUND: Population-based surveillance of pediatric cancer incidence trends is critical to determine high-risk populations, drive hypothesis generation, and uncover etiologic heterogeneity. We provide a comprehensive update to the current understanding of pediatric cancer incidence trends by sex, race and ethnicity, and socioeconomic status (SES). METHODS: The Surveillance, Epidemiology, and End Results 22 data (2000-2019) was used to summarize age-adjusted incidence rates for children and adolescents aged 0-19 years at diagnosis. The annual percentage change (APC) and 95% confidence interval (CI) were estimated to evaluate incidence trends by sex, race and ethnicity, and SES overall and for cancer subtypes. Tests of statistical significance were 2-sided. RESULTS: Substantial variation was observed overall and for several histologic types in race and ethnicity- and SES-specific rates. Overall, we observed a statistically significant increase in incidence rates (APC = 0.8%, 95% CI = 0.6% to 1.1%). All race and ethnic groups saw an increase in incidence rates, with the largest occurring among non-Hispanic American Indian and Alaska Native children and adolescents (APC = 1.7%, 95% CI = 0.5% to 2.8%) and the smallest increase occurring among non-Hispanic White children and adolescents (APC = 0.7%, 95% CI = 0.5% to 1.0%). The lowest SES quintiles saw statistically significant increasing trends, while the highest quintile remained relatively stable (quintile 1 [Q1] APC = 1.6%, 95% CI = 0.6% to 2.6%; quintile 5 [Q5] APC = 0.3%, 95% CI = -0.1% to 0.7%). CONCLUSIONS: Childhood cancer incidence is increasing overall and among every race and ethnic group. Variation by race and ethnicity and SES may enable hypothesis generation on drivers of disparities observed.

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma.

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia.

Importance: Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL. Objective: To compare the prevalence of cCMV infection between ALL cases and matched controls. Design, Setting, and Participants: In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother's race and ethnicity. Data were analyzed from November to May 2022. Exposures: cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots. Main Outcomes and Measures: ALL diagnosed in children aged 0 to 14 years. Results: A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19). Conclusions and Relevance: In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Growth Hormone Deficiency in Childhood Intracranial Germ Cell Tumor Survivors.

Background and Aims: Intracranial germ cell tumor (iGCT) survivors have multiple risk factors for growth hormone (GH) deficiency, a commonly reported late effect in childhood cancer survivors. The objective of this study is to examine the prevalence of GH deficiency among childhood iGCT survivors. Methods: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), a case parent triad study conducted using the Children's Oncology Group registry protocols, including 216 cases with iGCTs. Data on late effects and outcomes are available for 129 iGCT cases who consented for a follow-up study including a self-administered questionnaire and medical record retrieval. GH deficiency was identified via self-report and validated through medical record review. Chi-squared and Fisher's exact tests were used to examine cases with GH deficiency predating iGCT detection. Logistic regression was used to identify predictors of GH deficiency as a late effect. Results: Of 129 iGCT cases who participated in the late effects study, 45% had GH deficiency; 18% had GH deficiency predating the iGCT and 27% developed GH deficiency within a median of 19 months after diagnosis. Younger age at diagnosis, suprasellar location, and higher radiation doses were associated with GH deficiency as a late effect. Conclusions: GH deficiency is highly prevalent as an early clinical sign for iGCT and frequently arises as an early late effect after treatment. Additional investigation is needed to address earlier detection and treatment for this highly prevalent late effect in iGCT survivors.

Parental Age and Childhood Lymphoma and Solid Tumor Risk: A Literature Review and Meta-Analysis.

BACKGROUND: Although advanced parental age has been definitively linked to pediatric acute lymphoblastic leukemia, studies of parental age and pediatric solid tumors have not reached firm conclusions. This analysis aimed to elucidate the relationship between parental age and pediatric solid tumors through meta-analysis of existing studies based in population registries. METHODS: We searched Medline (PubMed) and Embase for registry-based studies of parental age and solid tumors through March 2022. We performed random-effects meta-analysis to estimate pooled effects and 95% confidence intervals (CIs). All statistical tests were 2-sided. RESULTS: A total of 15 studies covering 10 childhood solid tumor types (30 323 cases and 3 499 934 controls) were included in this analysis. A 5-year increase in maternal age was associated with an increased risk of combined central nervous system tumors (odds ratio [OR] = 1.07, 95% CI = 1.04 to 1.10), ependymoma (OR = 1.19, 95% CI = 1.09 to 1.31), astrocytoma (OR = 1.10, 95% CI = 1.05 to 1.15), rhabdomyosarcoma (OR = 1.14, 95% CI = 1.03 to 1.25), and germ cell tumors (OR = 1.06, 95% CI = 1.00 to 1.12). A 5-year increase in paternal age was associated with an increased risk of non-Hodgkin lymphoma (OR = 1.06, 95% CI = 1.00 to 1.12). CONCLUSIONS: This meta-analysis of registry-based analyses of parental age and childhood cancer supports the association between older maternal age and certain childhood solid cancers. There is also some evidence that paternal age may be associated with certain cancers such as non-Hodgkin lymphoma. However, as maternal and paternal age are highly correlated, disentangling potential independent causal effects of either factor will require large studies with extensive data on potential confounders.

Global variation in young adult central nervous system tumor incidence by region, age, and sex from 1988 to 2012.

BACKGROUND: Central nervous system (CNS) tumors result in tremendous morbidity and mortality. Incidence of CNS tumors in young adults is less studied. It is unknown how young adult CNS tumor incidence has changed globally in recent decades. METHODS: We used Cancer Incidence in Five Continents (CI5) data (1988-2012) to estimate incidence rates (IR), average annual percent change in incidence (AAPC; 95% confidence intervals [95% CI]), and male-to-female incidence rate ratios (IRR; 95% CI) by six histologies and age at diagnosis (20-29years, 30-39years). Tumors were classified as astrocytic, medulloblastoma, ependymal, oligodendroglial, meninges, and other embryonal. Geographic regions were defined using the United Nations Statistics Division geoscheme. RESULTS: There were 78,240 CNS tumor cases included. 20-29-year-old (yo) rates were lower than 30-39 yo in most regions for astrocytic, oligodendroglial and ependymal tumors. Globally, astrocytic tumor incidence decreased (20-29 yo AAPC: - 0.70; 95% CI: - 1.32, - 0.08) while incidence increased for oligodendroglial (20-29 yo AAPC: 3.03; 95% CI: 1.57-4.51; 30-39 yo AAPC: 2.67; 95% CI: 0.79-4.58), ependymal (20-29 yo AAPC: 1.16; 95% CI: 0.31-2.03; 30-39 yo AAPC: 2.29; 95% CI: 1.14-3.46), medulloblastoma (30-39 yo AAPC: 0.6; 95% CI: 0.04-1.24) and tumors of the meninges (20-29 yo AAPC: 1.55; 95% CI: 0.04-3.07). There was a 20-40% male incidence excess in all histologies except for meninge tumors (30-39 yo IRR: 0.71; 95% CI: 0.61, 0.84). CONCLUSIONS: Incidence of oligodendroglial and ependymal tumors increased globally in 20-39 yo suggesting better diagnoses or changes in risk factors. Males had a higher incidence of CNS tumors for most tumors studied and in most regions.

Racial/ethnic and sex differences in young adult malignant brain tumor incidence by histologic type.

BACKGROUND: Brain tumors are among the top four cancers in young adults. We assessed important windows of tumor development and examined the interplay of race/ethnicity, age, and sex in young adult brain tumor incidence. METHODS: Using SEER 18 data (2000-2017), incidence rates were estimated by Poisson regression in individuals aged 20-39 years at diagnosis. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated by race/ethnicity, sex and age for 12 malignant histologies. RESULTS: White incidence for all histologies was higher (White vs. Black IRR: 2.09, 95% CI: 1.94, 2.24; White vs Asian Pacific Islander IRR: 1.88, 95% CI: 1.75, 2.03; White vs Hispanic IRR: 1.70, 95% CI: 1.62, 1.78; White vs American Indian IRR: 1.40, 95% CI: 1.14, 1.73). Minority groups had higher lymphoma incidence (White vs Black IRR: 0.32, 95% CI: 0.25, 0.40, White vs Hispanic HR: 0.55, 95% CI: 0.44, 0.68). Males had higher incidence than females for all histologies (IRR: 1.36, 95% CI: 1.31, 1.41). Male rates were highest for lymphoma (male-to-female [MF] IRR: 2.00, 95% CI: 1.65, 2.42) and glioblastoma (MF IRR: 1.61, 95% CI: 1.48, 1.75). The male excess in incidence was similar by race/ethnicity and increased with age (20-24-year-old IRR: 1.18, 95% CI: 1.07, 1.29; 35-39-year-old IRR: 1.44, 95% CI: 1.35, 1.54). CONCLUSIONS: A White race and male incidence excess was observed among brain tumors. IMPACT: The male excess was similar by race/ethnicity and increased with age suggesting male sex may be an intrinsic risk factor for brain tumor development.

Sex differences in associations between birth characteristics and childhood cancers: a five-state registry-linkage study.

BACKGROUND: There is a well-recognized male excess in childhood cancer incidence; however, it is unclear whether there is etiologic heterogeneity by sex when defined by epidemiologic risk factors. METHODS: Using a 5-state registry-linkage study (cases n = 16,411; controls n = 69,816), we estimated sex-stratified odds ratios (OR) and 95% confidence intervals (95% CI) between birth and demographic characteristics for 16 pediatric cancers. Evidence of statistical interaction (p-interaction < 0.01) by sex was evaluated for each characteristic in each cancer. RESULTS: Males comprised > 50% of cases for all cancers, except Wilms tumor (49.6%). Sex interacted with a number of risk factors (all p-interaction < 0.01) including gestational age for ALL (female, 40 vs. 37-39 weeks OR: 0.84, 95% CI 0.73-0.97) and ependymoma (female, 40 vs. 37-39 OR: 1.78, 95% CI 1.14-2.79; female, ≥ 41 OR: 2.01. 95% CI 1.29-3.14), birth order for AML (female, ≥ 3rd vs. 1st OR: 1.39, 95% CI 1.01-1.92), maternal education for Hodgkin lymphoma (male, any college vs. < high school[HS] OR: 1.47, 95% CI 1.03-2.09) and Wilms tumor (female, any college vs. HS OR: 0.74, 95% CI 0.59-0.93), maternal race/ethnicity for neuroblastoma (male, black vs. white OR: 2.21, 95% CI 1.21-4.03; male, Hispanic vs. white OR: 1.86, 95% CI 1.26-2.75; female, Asian/Pacific Islander vs. white OR: 0.28, 95% CI 0.12-0.69), and paternal age (years) for hepatoblastoma in males (< 24 vs. 25-29 OR: 2.17, 95% CI 1.13-4.19; ≥ 35 vs. 25-29 OR: 2.44, 95% CI 1.28-4.64). CONCLUSIONS: These findings suggest etiologic heterogeneity by sex for childhood cancers for gestational age, maternal education, and race/ethnicity and paternal age.

Racial and ethnic disparities in pediatric cancer incidence among children and young adults in the United States by single year of age.

BACKGROUND: Incidence rates of pediatric cancers in the United States are typically reported in 5-year age groups, obscuring variation by single year of age. Additionally, racial and ethnic variation in incidence is typically presented in broad categories rather than by narrow age ranges. METHODS: The Surveillance, Epidemiology, and End Results (SEER) 18 data (2000-2017) were examined to calculate frequencies and age-adjusted incidence rates among individuals aged birth to 39 years. Incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) were estimated as the measure of association for rate comparisons by race and Hispanic origin overall and by single year of age. RESULTS: Several histologic types showed substantial variation in race/ethnicity-specific and overall rates by single year of age. Overall, Black children and young adults experienced substantially decreased incidence of acute lymphoid leukemia (IRR, 0.52; 95% CI, 0.49-0.55) compared to Whites, and this decreased incidence was strongest at ages 1 through 7 years and 16 through 20 years. Hispanic individuals experienced decreased overall incidence of Hodgkin lymphoma (IRR, 0.50; 95% CI, 0.48-0.52) and astrocytoma (IRR, 0.54; 95% CI, 0.52-0.56) and increased risk of acute lymphoblastic leukemia (IRR, 1.46; 95% CI, 1.42-1.51) compared to non-Hispanic Whites, and the increased risk was strongest at ages 10 through 23 years. Substantial decreased risk across many tumor types was also observed for Asian/Pacific Islanders and American Indian/Alaska Natives. CONCLUSIONS: Examination of incidence rates for pediatric cancers by narrow age groups may provide insights regarding etiological differences in subgroups. Additionally, variation in age-specific incidence rates by race and ethnicity may enable hypothesis generation on drivers of disparities observed.

Trends in pediatric lymphoma incidence by global region, age and sex from 1988-2012.

BACKGROUND: Global variation in lymphoma incidence by type and age at diagnosis, region, sex, and Human Development Index (HDI) categories has not been reported, may shed light on potential biologic mechanisms and identify areas for targeted interventions. METHODS: Using the Cancer Incidence in Five Continents data from 1988 to 2012, we identified Hodgkin (HL), non-Hodgkin (NHL), and Burkitt lymphoma (BL) diagnosed in children aged 0-19 years. We estimated incidence rates (IRs; cases/million) and average annual percent change in incidence (AAPC; 95 % CI) by geographic region, sex, and HDI for each age group (0-9years and 10-19 years). RESULTS: There were 42,440 NHL, 38,683 H L, and 7703 included. Southern European (SE) 10-19-year-olds (yo) had the highest IR of NHL (19.6 cases/million) in 2008-2012. HL IRs for 0-9yo were <6 cases/million and >25 cases/million for 10-19yo in European regions and Oceania (OC). BL IRs were generally <5cases/million. Northern Europe (NE), SE, and OC 10-19yo had significantly increased APPCs in incidence for all lymphomas with the largest increases in BL (NE AAPC: 7.69 %; 95 % CI: 5.27, 10.16; SE AAPC: 5.21 %; 95 % CI: 3.26, 7.19; OC AAPC: 3.97 %; 95 % CI: 3.26, 4.70). BL incidence increased among males of all ages by approximately 2 %. NHL and BL incidence increased significantly among 10-19yo in very high HDI countries by approximately 3 %. CONCLUSIONS: Southern and Northern Europe and Oceania displayed increased incidence of all lymphomas studied from 1988 to 2012. BL incidence significantly increased in 8 of 15 global regions, males, and higher HDI countries over the study period. Mechanisms underlying these increases remain to be elucidated.