Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom.

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear. Methods: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations. Results: Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases. Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Phenotypic and genetically predicted leucocyte telomere length and lung cancer risk in the prospective UK Biobank.

We investigated phenotypic leucocyte telomere length (LTL), genetically predicted LTL (gTL), and lung cancer risk among 371 890 participants, including 2829 incident cases, from the UK Biobank. Using multivariable Cox regression, we found dose-response relationships between longer phenotypic LTL (p-trendcontinuous=2.6×10-5), longer gTL predicted using a polygenic score with 130 genetic instruments (p-trendcontinuous=4.2×10-10), and overall lung cancer risk, particularly for adenocarcinoma. The associations were prominent among never smokers. Mendelian Randomization analyses supported causal associations between longer telomere length and lung cancer (HRper 1 SD gTL=1.87, 95% CI: 1.49 to 2.36, p=4.0×10-7), particularly adenocarcinoma (HRper 1 SD gTL=2.45, 95%CI: 1.69 to 3.57, p=6.5×10-6).

Genetic analyses identify evidence for a causal relationship between Ewing sarcoma and hernias.

Knowledge of Ewing sarcoma (EWS) risk factors is exceedingly limited; however, multiple small, independent studies have suggested a possible connection between hernia and EWS. By leveraging hernia summary statistics from the UK Biobank and a recently published genome-wide association study of EWS (733 EWS cases and 1,346 controls), we conducted a genetic investigation of the relationship of 5 hernia types (diaphragmatic, inguinal, umbilical, femoral, and ventral) and EWS. We discovered a positive causal relationship between inguinal hernia and EWS (OR 1.27, 95% confidence interval [CI] 1.01-1.59, and p = 0.041) through Mendelian randomization analysis. Further analyses suggested shared pathways through three genes: HMGA2, LOX, and FBXW7. Diaphragmatic hernia showed a stronger causal relationship with EWS among all of the hernia types (OR 2.26, 95% CI 1.30-3.95, p = 0.004), but no statistically significant local correlation pattern was observed. No evidence of a causal or genetic relationship was observed between EWS and the other three hernia types, including umbilical hernia, despite a previous report indicating an OR as high as 3.3. The finding of our genetic analysis provided additional support to the hypothesis that EWS and hernias may share a common origin.

Shared and distinct genetic etiologies for different types of clonal hematopoiesis.

Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.

Serum biomarkers are altered in UK Biobank participants with mosaic chromosomal alterations.

Age-related clonal expansion of cells harbouring mosaic chromosomal alterations (mCAs) is one manifestation of clonal haematopoiesis. Identifying factors that influence the generation and promotion of clonal expansion of mCAs are key to investigate the role of mCAs in health and disease. Herein, we report on widely measured serum biomarkers and their possible association with mCAs, which could provide new insights into molecular alterations that promote acquisition and clonal expansion. We performed a cross-sectional investigation of the association of 32 widely measured serum biomarkers with autosomal mCAs, mosaic loss of the Y chromosome, and mosaic loss of the X chromosome in 436 784 cancer-free participants from the UK Biobank. mCAs were associated with a range of commonly measured serum biomarkers such as lipid levels, circulating sex hormones, blood sugar homeostasis, inflammation and immune function, vitamins and minerals, kidney function, and liver function. Biomarker levels in participants with mCAs were estimated to differ by up to 5% relative to mCA-free participants, and individuals with higher cell fraction mCAs had greater deviation in mean biomarker values. Polygenic scores associated with sex hormone binding globulin, vitamin D, and total cholesterol were also associated with mCAs. Overall, we observed commonly used clinical serum biomarkers related to disease risk are associated with mCAs, suggesting mechanisms involved in these diseases could be related to mCA proliferation and clonal expansion.

GWAS Explorer: an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a prospective cohort study of nearly 155,000 U.S. volunteers aged 55-74 at enrollment in 1993-2001. We developed the PLCO Atlas Project, a large resource for multi-trait genome-wide association studies (GWAS), by genotyping participants with available DNA and genomic consent. Genotyping on high-density arrays and imputation was performed, and GWAS were conducted using a custom semi-automated pipeline. Association summary statistics were generated from a total of 110,562 participants of European, African and Asian ancestry. Application programming interfaces (APIs) and open-source software development kits (SKDs) enable exploring, visualizing and open data access through the PLCO Atlas GWAS Explorer website, promoting Findable, Accessible, Interoperable, and Re-usable (FAIR) principles. Currently the GWAS Explorer hosts association data for 90 traits and >78,000,000 genomic markers, focusing on cancer and cancer-related phenotypes. New traits will be posted as association data becomes available. The PLCO Atlas is a FAIR resource of high-quality genetic and phenotypic data with many potential reuse opportunities for cancer research and genetic epidemiology.

Clonal hematopoiesis due to mosaic chromosomal alterations: Impact on disease risk and mortality.

Mosaic chromosomal alterations (mCAs) are the clonal expansion of large somatically acquired structural chromosomal changes present on the autosomes and sex chromosomes. Most studies of mCAs use existing genotype array intensity data from large populations to investigate potential risk factors and disease outcomes associated with mCAs. In this review, we perform a comprehensive examination of existing evidence for mCA disease and mortality associations and provide a framework for interpreting these associations in the context of important biases specific to mCA studies. Our goal is to motivate well-designed mCA studies to assist in unlocking the potential of mCAs to improve understanding of the effects of ageing and accelerate translational applications for improving public health.

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.

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.

Exploration of genetic ancestry and socioeconomic status in the incidence of neuroblastoma: An ecological study.

Although global differences in the incidence of neuroblastoma have been examined, the underlying mechanism has yet to be elucidated. Previous studies have suggested genetic ancestry and human development index (HDI) as contributing factors, but few studies have been conducted at the international level. Here, we aimed to examine whether the frequency of common genomic variation associated with neuroblastoma can affect its risk at the ecological level with consideration of the HDI. Minor allele frequencies (MAFs) for 22 single-nucleotide polymorphisms (SNPs) were abstracted from the Geography of Genetic Variants Browser. The number of incident neuroblastomas for each population was obtained from the Cancer Incidence in Five Continents series. Further, population pseudo-polygenic risk scores (pp-PRSs) were calculated as a sum of MAFs at the population level, each of which was weighted by effect sizes from prior studies. Negative binomial regression was used to estimate the incidence rate ratios (IRRs) and the 95% confidence intervals (CIs) to examine whether differences in MAFs across the population influence the risk of neuroblastoma, with and without adjustment for HDI and whether pp-PRSs can be a predictor of the risk of neuroblastoma. Overall, our results indicated that the neuroblastoma risk associated with variation in SNP frequency could not be differentiated from that of HDI at the ecological level. Additionally, pp-PRSs were not significantly associated with the risk of neuroblastoma (IRR: 0.99, 95% CI: 0.62-1.60). Further study using individual-level data is warranted to minimize the bias related to the use of population-level data in this study.

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.

International trends in incidence of osteosarcoma (1988-2012).

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. The etiology of OS is largely unknown but may be informed by comparisons of incidence and trends between geographic regions. Using the Cancer Incidence in Five Continents (CI5) data from 1988 to 2012, we present OS age-standardized incidence rates (ASRs; cases/million) and average annual percent change (AAPC) and 95% confidence interval (CI) by geographic region among the age groups 0-9, 10-19, 20-29, 30-59, 60-79, 0-79. Among the 10-19 age group, we also used the most recent data (2008-2012) to present the ASRs for each country. We observed little variation in OS incidence between geographic regions in 2008-2012 across all age groups. Overall, the ASR for 0-79 ranged from 2 cases per million in Southern Asia to 4.2 in Sub-Saharan Africa. A bimodal distribution in incidence was observed with peaks in the 10-19 and 60-79 age groups across all regions over time. Overall, OS incidence was relatively stable across 1988-2012 with the only statistically significant increases in the 0-79 age group observed in Eastern Asia (AAPC: 1.8; 95% CI: 0.6, 1.9) and Sub-Saharan Africa (AAPC: 3.1; 95% CI: 0.5, 5.8). The small variation in incidence between regions and the stability in incidence over time suggests that OS carcinogenesis is not influenced by environmental or time-varying exposures.

Comparative international incidence of Ewing sarcoma 1988 to 2012.

Ewing sarcoma (ES) is the second most common primary bone tumor in children and adolescents. There are few known epidemiological or genetic risk factors for ES. Numerous reports describe incidence rates and trends within the United States, but international comparisons are sparse. We used the Cancer Incidence in Five Continents (CI5) data to estimate age standardized incidence rates (ASRs; cases per million) and 95% confidence intervals (95% CIs), male-to-female incidence rate ratios (IRRs; 95% CI), and the average annual percent change in incidence (AAPC; 95% CI) for ES by geographic region for children and adults aged 0 to 49 years. We also estimated the ASR for each country or country subpopulation among the 10- to 19-year-old age range; capturing the peak incidence of ES. In total, 15 874 ES cases ages 0 to 49 were reported in the CI5 series between 1988 and 2012. AAPC estimates varied by age group and geographic region. Most of the statistically significant AAPCs showed an increased incidence over time; the only statistically significant decreases in incidence were observed among 20- to 29-year-olds and 30- to 39-year-olds in Southern Asia at -1.93% and -1.67%. When categorized by predominant ancestry, we observed countries and subpopulations with predominately African, East Asian, and Southeast Asian ancestry had the lowest incidence rates, whereas Pacific Islanders and populations with predominantly European and North African/Middle Eastern ancestry had the highest. An excess incidence in males was observed in most regions. Our results highlight substantial variation in ES incidence across geographic populations, reflecting potential ancestral influence on disease risk.

The association between non-steroidal anti-inflammatory drugs (NSAIDs) and myelodysplastic syndromes in the Adults in Minnesota with Myelodysplastic Syndromes (AIMMS) Study.

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders. Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a chemopreventive effect in some cancers. We evaluated associations between NSAID use and MDS in a population-based case-control study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Secondary analyses stratified by sex and MDS subtype were also conducted.The analysis included 399 MDS cases and 698 controls. No significant associations between MDS and use of aspirin (OR = 0.87, 95% CI 0.67-1.14), ibuprofen (OR = 0.91, 95% CI 0.64-1.30), acetaminophen (OR = 1.29, 95% CI 0.90-1.84) or NSAIDs overall (OR = 0.92, 95% CI 0.68-1.23) were observed. No significant associations were observed in models stratified by sex or MDS subtype; however, the direction of the effect between NSAID use and MDS varied by MDS subtype. Our results do not support an association between NSAID use and MDS overall.

Trends in paediatric central nervous system tumour incidence by global region from 1988 to 2012.

BACKGROUND: Central nervous system (CNS) tumours comprise 20% of childhood cancers worldwide. Whether childhood CNS tumour incidence has increased over time across geographic regions remains to be explored. METHODS: We identified CNS cancers in the Cancer in Five Continents (CI5) data and estimated age standardized incidence rates (ASRs; cases/million children) and 95% confidence intervals (95% CI), male-to-female incidence rate ratios (IRR; 95% CI) and average annual percent change in incidence (AAPC; 95% CI) by geographic region for children aged 0-19 years where data were available using Poisson regression and generalized estimating equations (GEE). Cancers included: astrocytic tumours, medulloblastoma, ependymal, oligodendroglial and mixed glioma, glioma of uncertain origin, and other embryonal tumours. Geographic regions were defined using the United Nations geoscheme. RESULTS: There were 56 468 CNS cancers included in the study. ASRs were highest for astrocytic tumours globally in 2012 (ASR: 5.83; 95% CI: 5.68-5.99). Globally, all cancers exhibited a male excess in incidence. Regionally, only medulloblastoma had a consistently elevated male-to-female IRR at 1.4-2.2. Globally, incidence decreased for astrocytic tumours in GEE models (AAPC: -1.66; 95% CI: -3.04 to -0.26) and increased for medulloblastoma (AAPC 0.66; 95% CI: 0.19-1.14), ependymal tumours (AAPC: 1.49; 95% CI: 1.49; 95%: 0.69-2.30), glioma of uncertain origin (AAPC: 4.76; 95% CI: 1.17-1.14) and other embryonal tumours (AAPC: 3.58; 95% CI: 2.03-5.15). Regional variation in incidence trends was observed. Countries moving from lower to higher Human Development Index (HDI) over time did not appear to drive observed incidence trends. CONCLUSIONS: Epidemiologic and molecular studies on underlying mechanisms for changes in the global incidence of CNS tumours are necessary.

Childhood cancer incidence among specific Asian and Pacific Islander populations in the United States.

Despite the vast genetic and environmental diversity in Asia, individuals of Asian and Pacific Islander (API) descent are often combined into a single group for epidemiologic analyses within the U.S. We used the Surveillance, Epidemiology and End Results (SEER) Detailed Asian/Pacific Islander Database to calculate incidence rates for discrete groups among children aged 0 to 19 years. Due to sample size constraints we pooled incidence among regional groups based on countries of origin: East Asians (Chinese, Japanese, Korean), Southeast (SE) Asians (Vietnamese, Laotian, Cambodian), Asian Indian/Pakistani, Oceanians (Guamanian, Samoan, Tongan) and Filipinos. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated comparing each API regional group to Non-Hispanic Whites (NHW) and East Asians. Finally, we calculated the correlation between incidence of cancer in specific API ethnicities in SEER and in originating countries in the Cancer Incidence in Five Continents. Incidence rates among API regional groups varied. Acute lymphoblastic leukemia (ALL) was lower in children of SE Asian descent (IRR 0.65, 95% CI 0.44, 0.96) compared to NHW. Acute myeloid leukemia (AML) was more common among children from Oceania compared to NHW (IRR 3.88, 95% CI 1.83, 8.22). East Asians had higher incidence rates than SE Asians but lower rates compared to children from Oceania. Correlation of some incidence rates between US-based API ethnicities and originating countries were similar. The variation observed in childhood cancer incidence patterns among API groups may indicate differences in underlying genetics and/or patterns of exposure.

Global incidence comparisons and trends in ovarian germ cell tumors by geographic region in girls, adolescents and young women: 1988-2012.

OBJECTIVE: Ovarian germ cell tumors (OGCT) are the primary ovarian malignancy affecting girls and young women. Globally, incidence rates and trends for OGCTs have not been compared in the literature and their etiology is not well described. Comparisons of incidence globally could inform etiologic hypotheses. The aim of this analysis was to evaluate geographic variation in OGCT incidence and to identify trends in incidence rates. METHODS: Data were extracted from Cancer Incidence in 5 Continents (CI5) from 1988 to 2012. Rates of OGCT in women and girls were calculated for ages 0-9, 10-19, and 20-39 years and standardized to the 2000-2025 average world population. Data were aggregated within subregions corresponding to the United Nations Statistics Division (UNSD) geoscheme. Incidence rates were compared in subregions and average annual percent change (AAPC) was estimated using Poisson regression. RESULTS: Overall, the highest incidence rates were observed in 10-19-year-olds. Incidence was generally the highest in Eastern Asia, Central America and North America. While incidence was variable by geographic region, less variation was observed in 0-9-year-olds as compared to adolescents and young adults. Significant increases in incidence were seen in some regions (Eastern Asia, Oceania, Western Europe, Southern Europe, and North America) and in countries with a high or very high human development index for one or more age groups. CONCLUSIONS: Evaluating 25 years of OGCT incidence data, the highest incidence rates and largest increases in incidence were seen in Eastern Asia. Future studies should focus on etiologic features that may account for geographic variation and increases in incidence of OGCT.

Trends in International Incidence of Pediatric Cancers in Children Under 5 Years of Age: 1988-2012.

BACKGROUND: Pediatric cancer incidence has been steadily increasing over the last several decades with the largest increases reported in infants. Few evaluations have looked at international pediatric cancer incidence trends in the youngest children. The aim of this analysis was to evaluate trends in cancer incidence in children under 5 years of age, overall and by type, using data from Cancer Incidence in 5 Continents (CI5) from 1988 to 2012 (CI5 volumes VII-XI). METHODS: Rates of cancers in children ages 0-4 years were extracted from registries available in CI5 from 1988 to 2012. To overcome small numbers in individual registries, numerators and denominators were aggregated within regions corresponding to the United Nations' geoscheme. Average annual percent change (AAPC) was estimated using Poisson regression.  Robust standard errors were used in all models to correct for overdispersion in some regions, and 95% Wald confidence intervals and P values were reported. The top five cancers by increasing AAPC were ranked within each region. RESULTS: Overall, in children under 5 years, increasing incidence was seen in multiple regions for acute lymphoblastic leukemia, acute myeloid leukemia, ependymal tumors, neuroblastoma, and hepatoblastoma. Hepatoblastoma had the largest AAPC in 11 out of 15 regions and showed an increase in all regions except southern Asia. Astrocytic tumors were the only cancer that decreased over the time period. CONCLUSIONS: We evaluated 25 years of cancer incidence in children ages 0-4 years and observed increases in incidence for hepatoblastoma, leukemia, neuroblastoma, and ependymal tumors. Further etiologic evaluation will be required to explain these increases in incidence.