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Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations., (© 2023 UICC.)

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention., (© 2022 UICC.)

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., (© 2021 UICC.)

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., (© 2021 UICC.)

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., (© 2020 UICC.)

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41-2.18, p = 4.84 × 10 -7 ). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5-2.4; p = 1.3 × 10 -8 ), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus., (© 2017 UICC.)

Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood., (© 2015 UICC.)

Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0-14 years at Children's Oncology Group institutions in 1989-2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein-Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case-control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06-1.36), particularly early-onset cancers (HR = 1.30, 95% CI: 1.06-1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16-1.65), with a suggested association for LN in first-degree relatives (HR = 3.61, 95% CI: 0.87-15.01). There were no discernable patterns for EBV+ versus EBV- HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family-based studies to garner information about genetic susceptibility to HL., (© 2015 UICC.)

Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 [95% confidence interval (CI) 0.78, 1.30] and for paternal exposure around conception 1.20 (95% 1.06, 1.38). For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 (CI 1.19, 3.18) and for paternal exposure around conception 0.91 (CI 0.66, 1.24.) based on data from 1,329 case and 12,141 control mothers, and 1,231 case and 11,383 control fathers. Our finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. We also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms., (© 2014 UICC.)

An infectious origin for pediatric Hodgkin lymphoma (HL) has long been suspected and Epstein-Barr virus (EBV) has been implicated in a subset of cases. Increased HL incidence in children with congenital and acquired immunodeficiencies, consistent associations between autoimmune diseases and adult HL and genome-wide association and other genetic studies together suggest immune dysregulation is involved in lymphomagenesis. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL diagnosed in 1989-2003 at 0-14 years at Children's Oncology Group institutions. Parents of 517 cases and 784 controls completed telephone interviews, including items regarding medical histories. Tumor EBV status was determined for 355 cases. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HL. Cases were more likely to have had an infection>1 year prior to HL diagnosis (OR=1.69, 95% CI: 0.98-2.91); case siblings were also more likely to have had a prior infection (OR=2.04, 95% CI: 1.01-4.14). Parental history of autoimmunity associated with increased EBV+ HL risk (OR=2.97, 95% CI: 1.34-6.58), while having a parent (OR=1.47, 95% CI: 1.01-2.14) or sibling (OR=1.62, 95% CI: 1.11-2.36) with an allergy was associated with EBV - HL. These results may indicate true increased risk for infections and increased risk with family history of autoimmune and allergic conditions that varies by tumor EBV status, or they may be attributable to inaccurate recall. In addition to employing biomarkers to confirm the role of immune-modulating conditions in pediatric HL, future studies should focus on family based designs., (© 2014 UICC.)

Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex and age. The following atopic conditions were assessed: allergies, asthma, eczema and hives; in addition, we examined other immune-related factors: birth order, day-care attendance and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41-0.87), hives (OR = 0.61, 95% CI: 0.38-0.97), day-care attendance (OR=0.48, 95% CI: 0.32-0.71) and breastfeeding for ≥ 12 months (OR=0.36, 95% CI: 0.18-0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system's role in the development of this tumor., (© 2013 UICC.)

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC., (Copyright © 2013 UICC.)

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 <15 years of age who were diagnosed from 1980 to 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 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., (Copyright © 2010 UICC.)

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common infant malignancy. The etiology of NB is largely unknown. We explored the association between birth record variables and subsequent NB development in a population-based case-cohort study in Minnesota by linking the birth and cancer registries. NB cases included 155 children born during 1976-2004 who were diagnosed from 28 days through 14 years of age. The comparison group included 8,752 individuals randomly sampled from the birth cohort of cases. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Controlling for birth year and sex, maternal history of one fetal loss (HR = 1.7, 95% CI 1.2-2.5), maternal prenatal drug-use (recorded starting in 1992) (HR = 5.7, 95% CI 2.3-14) and child's small size for gestational age (HR = 2.1, 95% CI 1.1-4.0) were significantly associated with NB. Age group specific analyses indicated that maternal hypertension (HR = 3.0, 95% CI 1.3-7.2) and maternal age <20 years (HR = 2.6, 95% CI 1.1-6.1) increased risks for infant NB only. Our study provides evidence that a few perinatal exposures as recorded in birth records may play a role in NB etiology.

Wilms tumor (WT) is a childhood kidney cancer with the highest rate of occurrence before the age of 2. Since it is rare, previous research has been limited and few risk factors have been established. We used a case-cohort design to examine the influence of birth characteristics on occurrence of WT in Minnesota. A total of 2,188 cases of cancer diagnosed in children aged 28 days to 14 years from 1988 to 2004 were identified using the Minnesota Cancer Surveillance System (MCSS). For each case, 4 children were randomly selected from Minnesota birth records during 1976-2004, frequency matched on birth year. Thus, a total of 8,752 children comprised the subcohort for the study, who in this analysis, served as comparison to the 138 cases of WT. Study variables included parental demographics, maternal pregnancy history and conditions and health and conditions of the child at birth. Associations with WT were assessed using hazard ratios (HR) and 95% confidence intervals (CI) calculated from stratified Cox regression models. We found an increased risk of WT for children who were large for gestational age compared to those average for gestational age and for children with congenital abnormalities. There was also an increased risk for children with a birth weight > 4,000 g compared to those with a birth weight between 2,500 and 4,000 g. All other factors examined showed no association with WT. This study contributes to the mounting evidence that children with large size at birth have an increased risk of WT., ((c) 2007 Wiley-Liss, Inc.)