Pediatric Cancer Risk Research Articles

Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies.

Childhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility. We performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants. A diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient's tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes. We uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Novel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as KAT6A in gliomas, SETD5 in neuroblastoma, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer. Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk. Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.

Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children.

Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population-based registry linkage study. This study includes all live births in Texas during the years 1999-2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age. In the total birth cohort (n=6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith-Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20-71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83-5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37-39.69) and macroglossia (HR, 11.18; 95% CI, 6.35-19.70). This population-based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology.

Using existing pediatric cancer data from the Gabriella Miller Kids First Data Resource Program.

Childhood cancer and birth defects are leading causes of childhood mortality, and studies suggest that birth defects increase pediatric cancer risk. The Gabriella Miller Kids First Pediatric Research Program (Kids First) seeks to alleviate these conditions by building an expansive resource of genetic and clinical data from patients with pediatric cancer and birth defects and their families. This article describes the data and support provided by the Kids First Data Resource Center and the Kids First Data Resource Center Data Resource Portal, which enables the public to review Kids First studies and request access to individual data. The Kids First Portal contains data from more than 34 000 participants and connects with CAVATICA (Seven Bridges Genomics, Inc, now part of Velsera), a cloud-based analysis and sharing platform. Researchers have used Kids First data to investigate a variety of cancers and further funding opportunities are available. The Kids First Portal is a unique resource that unites pediatric cancer and birth defects to uncover their genetic etiology and improve patients' lives.

Genetic predisposition and evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors.

The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking. In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives. Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected. Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

Pediatric Cancer in the Northeast United States-Letter.

To the Editor,Rees and colleagues (1) examined whether the pediatric cancer rate in the Northeast region is higher than in other regions of the United States. In June 2018, the Centers for Disease Control and Prevention (CDC) released a report indicating that New Hampshire's (NH) pediatric cancer rate is the highest in the United States (2). The NH Department of Health and Human Services determined that the pediatric incidence rate of two rare cancers was significantly higher than expected in a five-town area of NH (3). Understanding whether cancer rates are significantly higher in any particular region and/or state is an important component of identifying and modifying causal risk factors.Rees and colleagues concluded that the pediatric cancer rate in the Northeast region is statistically significantly higher than in other regions. Furthermore, they conclude that the causal risk factor(s) for NH pediatric cancers are likely regional, not localized, deemphasizing environmental contributors while noting that NH and the northeast region have more United States Environmental Protection Agency National Priorities List sites per capita than other regions of the United States.While we are grateful for the attention to the alarming CDC report, we take strong issue with the conclusions drawn by the authors. The hypothesis did not test whether the NH pediatric cancer rate is different than other states within the Northeast region or whether the regional cancer rate is driven primarily by NH. The conclusions in this article are an overextension of the analysis and are a disservice to the important task of identifying and modifying localized causal risk factors for cancer prevention.A significantly elevated regional risk of pediatric cancer in the Northeast is a valuable finding and one piece of a larger puzzle of data analysis and interpretation. The high incidence rate in the Northeast and NH demands further investigation. There are many contextual effects of pediatric cancers to explore; there are also geographic community-level exposures that potentially contribute to an increased risk of cancer [e.g., perfluoroalkyl and polyfluoroalkyl substance (PFAS)-contaminated drinking water and air]. The authors have access to individual-level data which would facilitate analysis of possible community-level contextual effects contributing to elevated cancer risk. For example, we recently found an elevated risk of several types of cancer in a community with known PFAS contamination in groundwater (4).Finally, it is worth noting that the authors used a Bonferroni correction to avoid type 1 error, in which the null hypothesis is rejected for spurious associations resulting from multiple comparisons. A conservative alpha of 0.01, rather than the standard alpha of 0.05, was used to assess statistical significance. Biostatisticians debate the necessity of conservative alphas, given large adjustments to avoid a type 1 error increase the likelihood of a type 2 error, where meaningful group differences are missed. We suggest a more prudent approach rather than one that risks an unwarranted trade-off in the likelihood of type 1 and 2 errors. In fact, the CDC used a 95% confidence interval when they determined that the pediatric cancer rate in NH is the highest in the nation.A full and transparent assessment of the environmental and public health damage is an essential step in that process since most cancer diagnoses could be prevented by minimizing environmental causes (5). The field would be well served by using resources to inspect internal surveillance, policies, and regulations to prevent environmental exposure and focus attention and resources on prevention and mitigation. We sincerely hope that Rees and colleagues, and others, direct resources to identifying and modifying localized factors contributing to cancers while focusing on prevention. We owe it to NH children who experience the highest risk of pediatric cancer in the nation.See the Response, p. 150No disclosures were reported.

Parametric Models for Survival Analysis of Childhood Cancer Patients' Data

Background: The rate of childhood cancer death has dropped steadily over the past 50 years. The pediatric cancer risk has remained under investigation. Objectives: This study aims at investigating the associated factors with the survival of pediatric patients with retinoblastoma, sarcoma, brain tumor, and leukemia cancer. Methods: The cohort study of 1879 children with retinoblastoma, sarcoma, brain tumor, and leukemia aged < 1, 1 - 5, 6 - 10, 11 - 15, and > 15 years in Mahak Hospital and Rehabilitation Complex from 2007 to 2016 were enrolled in the study. Median survival time was reported for each cancer. Parametric survival models including Gompertz, Weibull, lognormal, and log‑logistic models were fitted. Then, the model with almost minimum Akaike information criterion (AIC) was chosen. The hazard ratio (HR) and the analysis were performed by R3.5.1. Results: Totally, 270 (14.37%) patients with Retinoblastoma, 667 (35.5%) with leukemia, 625 (33.26%) with a Brain tumor, and 317 (16.87%) with Sarcoma were included in this study; 815 (43.37%) patients were female. Gompertz's model was chosen to fit the data due to the minimum AIC. The associated factors with the survival of childhood cancers were as follows: age < 1 year, parental relation, loco-regional relapse and chemotherapy alone (HR: 7.63, 1.56, 4.61, 1.12) in leukemia, other nationalities, metastasis or metastasis and loco-regional relapse and chemotherapy alone (HR = 3.74, 5.75, 2.12) in retinoblastoma, loco-regional relapse and metastasis (HR = 2.40, 3.71) in brain tumor, other ages except for 5 - 10 years, parental relation, chemotherapy alone, and metastasis (HR = 33.3, 1.80, 3.57, 3.8) in sarcoma. Conclusions: Age, parental familial relationships, combination therapy, and metastasis of primary cancer were the risk factors for survival of children with 4 common cancers of leukemia, retinoblastoma, brain tumors, and sarcoma, using the Gompertz model.

Clinical and molecular features of pediatric cancer patients with Lynch syndrome.

The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at-risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis. Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD.

Abstract 3652: Maternal body mass index, diabetes, and gestational weight gain and risk for pediatric cancer in offspring: A systematic review and meta-analysis

Abstract Introduction: Pediatric cancer incidence has steadily increased concurrent with the rise in adult obesity, however, associations between maternal obesity and associated comorbidities and pediatric cancer risk remain understudied. Methods: A comprehensive and systematic literature search in PubMed and EMBASE databases from their inception to March 15th, 2021. Eligible studies reported risk estimates, sample sizes, and provided sufficient description of outcome and exposure ascertainment. Studies were excluded if not complete, published, peer-reviewed studies, or if provided incompatible exposure data. Data quality was assessed according to Newcastle-Ottawa Scale (NOS) guidelines and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects models were used to estimate pooled effects. Results: Thirty-four studies were included, covering 3,404,747 subjects and 14,706 pediatric cancer cases for pre-pregnancy BMI; 14,748,772 subjects and 44,628 pediatric cancer patients for maternal diabetes; and 2,124,647 participants and 15,915 pediatric cancer cases for gestational weight gain. Pre-pregnancy BMI was significantly associated with leukemia risk in offspring (OR per 5-unit BMI increase =1.07 [95% CI = 1.04-1.11] I2 = 0.0%). Any maternal diabetes was positively associated with acute lymphoblastic leukemia risk (OR=1.46 [95% CI = 1.28-1.67] I2 = 0.0%), even after restricting to birthweight-adjusted analyses (OR [95% CI] = 1.74 [1.29-2.34] I2 = 0.0%), and inversely associated with risk of central nervous system tumors (OR=0.73 [95% CI = 0.55-0.97] I2 = 0.0%). Pre-gestational diabetes (OR=1.57 [95% CI = 1.11-2.24] I2 = 26.8%) and gestational diabetes (OR=1.40 [95% CI = 1.12-1.75] I2 = 0.0%) were also significantly associated with acute lymphoblastic leukemia risk. No significant associations were observed for gestational weight gain and pediatric cancer risk. Conclusions: Maternal obesity and diabetes may be etiologically linked to pediatric cancer, particularly leukemia and central nervous system tumors. Our findings support appropriate weight management and glycemic control as important components of maternal care and offspring health. Further validation studies are warranted. Citation Format: Andrew R. Marley, Allison Domingues, Taumoha Ghosh, Lucie M. Turcotte, Logan G. Spector. Maternal body mass index, diabetes, and gestational weight gain and risk for pediatric cancer in offspring: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3652.

Abstract 1998: A population-based assessment of cancer risk in children with recurrent multiple congenital anomalies

Abstract Purpose: There is emerging evidence that children with multiple congenital anomalies have a higher risk of developing cancer compared to unaffected children. However, there have been few population-based estimates of cancer risk among children with well-described patterns of recurrent multiple congenital anomalies (MCAs). VACTERL association is one such pattern that is defined by the presence of ≥3 of the following in the absence of a genetic diagnosis: vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal, and limb anomalies. VACTERL occurs in approximately 5% of children with Fanconi anemia (FA), a known cancer predisposition syndrome. In spite of this, there are no population-based estimates of cancer risk in children with VACTERL. Therefore, we investigated if VACTERL confers an elevated risk of pediatric cancer by examining a birth cohort of >7 million children from three U.S. states (Texas, North Carolina, and Oklahoma) for the period 1997-2013. Methods: Demographic and diagnostic data from birth certificates, birth defects registries, and cancer registries were linked in each state and pooled for analysis. For this analysis, children with chromosomal anomalies were excluded. We used Cox proportional hazards models to evaluate the risk of cancer before 19 years of age in three birth defect groups: (1) VACTERL; (2) ≥3 major anomalies but not VACTERL; and (3) 1 to 2 major anomalies. A hazard ratio (HR) and 95% confidence interval (CI) was calculated in each group for: (1) overall cancer risk and (2) risk of embryonal tumors (e.g., neuroblastoma, medulloblastoma, hepatoblastoma) based on reported associations between birth defects and these pediatric cancers. Results: In our cohort of 7,767,786 births, we identified: 2,090 children (0.02%) with VACTERL; 32,558 children with ≥3 non-VACTERL defects; and 201,871 children with 1 to 2 defects. Respectively, these three groups had 10, 167, and 684 cases of cancer. Compared to children without birth defects, children with VACTERL (HR=3.9, 95% CI: 2.1 - 7.2), ≥3 non-VACTERL defects (4.2, 3.6 - 4.9), and 1 to 2 defects (2.7, 2.5 - 2.9), were all more likely to develop cancer. Risk was higher for embryonal tumors among children with VACTERL (10.4, 4.7 - 23.1) than for those with ≥3 non-VACTERL defects (5.6, 4.2 - 7.4) or 1 to 2 defects (3.9, 3.4 - 4.5). Conclusion: In this population-based assessment, we demonstrated that children with VACTERL were more likely than other groups to develop cancer, particularly embryonal tumors, although the absolute cancer risk was <1%. Surprisingly, acute myeloid leukemia, a common malignancy among individuals with FA, was not diagnosed in any of the children with VACTERL, suggesting these associations are distinct from FA. These findings demonstrate that VACTERL subtypes and other recurrent MCAs may represent novel cancer predisposition syndromes. Citation Format: Alexander Renwick, Jeremy M. Schraw, Tania A. Desrosiers, Amanda E. Janitz, Michael E. Scheurer, Mark A. Canfield, Peter H. Langlois, Angela E. Scheuerle, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk in children with recurrent multiple congenital anomalies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1998.

Maternal Body Mass Index, Diabetes, and Gestational Weight Gain and Risk for Pediatric Cancer in Offspring: A Systematic Review and Meta-Analysis.

BackgroundPediatric cancer incidence has steadily increased concurrent with rising adult obesity, but associations between maternal obesity and associated comorbidities and pediatric cancer risk remain understudied. We aimed to quantitatively characterize associations of pediatric cancer risk with maternal prepregnancy body mass index (BMI), gestational weight gain, and maternal diabetes.MethodsWe performed a comprehensive and systematic literature search in Ovid and EMBASE from their inception to March 15, 2021. Eligible studies reported risk estimates and sample sizes and provided sufficient description of outcome and exposure ascertainment. Random effects models were used to estimate pooled effects.ResultsThirty-four studies were included in the analysis. Prepregnancy BMI was positively associated with leukemia risk in offspring (odds ratio [OR] per 5-unit BMI increase =1.07, 95% confidence intervals [CI] = 1.04 to 1.11; I2 = 0.0%). Any maternal diabetes was positively associated with acute lymphoblastic leukemia risk (OR = 1.46, 95% CI = 1.28 to 1.67; I2 = 0.0%), even after restricting to birthweight-adjusted analyses (OR = 1.74, 95% CI = 1.29 to 2.34; I2 = 0.0%), and inversely associated with risk of central nervous system tumors (OR = 0.73, 95% CI = 0.55 to 0.97; I2 = 0.0%). Pregestational diabetes (OR = 1.57, 95% CI = 1.11 to 2.24; I2 = 26.8%) and gestational diabetes (OR = 1.40, 95% CI = 1.12 to 1.75; I2 = 0.0%) were also positively associated with acute lymphoblastic leukemia risk. No statistically significant associations were observed for gestational weight gain.ConclusionsMaternal obesity and diabetes may be etiologically linked to pediatric cancer, particularly leukemia and central nervous system tumors. Our findings support weight management and glycemic control as important components of maternal and offspring health. Further validation is warranted.

The congenital melanocytic nevus: a rare clinical image.

Congenital melanocytic nevus affects around 1% of newborns. Facial melanocytic nevus may be linked to an increased risk of pediatric cancer. Furthermore, because the lesions reveal hair and dark pigmentation, the cosmetic and emotional impacts might be substantial. A 6-year-old female was brought to the outpatient department with complaints of black discoloration of the left side of the face and excessive hair growth on a particular site. After detailed history collection and physical examination, it reveals that the black discoloration is since birth. The physician diagnosed her with congenital melanocytic nevus and hence referred them to the dermatology department for further management.

Genetic Predisposition to Solid Pediatric Cancers.

Progresses over the past years have extensively improved our capacity to use genome-scale analyses—including high-density genotyping and exome and genome sequencing—to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.

The recurrent SETBP1 c.2608G\u2009>\u2009A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate

BackgroundSchinzel-Giedion syndrome (SGS) is a multiple malformation syndrome mainly characterized by severe intellectual disability, distinctive facial features, and multiple congenital anomalies, including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as an increased pediatric cancer risk. Recently, SGS has been associated with de novo heterozygous deleterious variants in the SETBP1 gene; to date, nine different variants, clustering in exon 4 of SETBP1, have been identified in 25 patients.Case presentationIn this study, by using Whole Exome Sequencing (WES), we identified a patient with a recurrent missense mutation in SETBP1, the c.2608G > A, p.(Gly870Ser) variant, previously reported as likely pathogenic. This finding allowed us to confirm the suspected clinical diagnosis of SGS. Clinical features of patients carrying the same variant, including our patient, were evaluated by a review of medical records.ConclusionsOur study confirms SGS as a severe disorder potentially presenting at birth as a critically ill neonate and demonstrates the causal role of the c.2608G > A, p.(Gly870Ser) variant in the etiology of the syndrome. Moreover, although the cohort of SETBP1-patients reported in the literature is still small, our study reports for the first time the prevalence of the variant (about 27%, 7/26). Finally, given the heterogeneity of clinical presentations of affected patients hospitalized in Neonatal Intensive Care Units (NICU) and/or Pediatric Intensive Care Units (PICU), in agreement with emerging data from the literature, we suggest that WES should be used in the diagnosis of unexplained syndromic conditions, and even as part of a standard first-line diagnostic approach, as it would allow a better diagnosis, counseling and management of affected patients and their families.

Assisted reproductive technology and the risk of pediatric cancer: A population based study and a systematic review and meta analysis

BackgroundThere is controversy whether exposure to assisted reproductive technology (ART) is associated with increased risk of pediatric cancer.We aimed at calculating the overall risk of pediatric cancers after ART in a large cohort of exposed women; and to conduct a systematic review and meta- analysis of cohort studies examining overall risk of pediatric cancers after ART. MethodsAll children born in Israel who were members of Maccabi Health Services (MHS) between 1999 and 2016 after ART, were linked to the Israeli Registry of Childhood Cancer (IGS) to identify those with cancer diagnosed before 16 years of age. In parallel we conducted a systematic review and meta-analysis of observational cohort studies with more than 5000 ART- exposed cases that measured pediatric cancer after ART. ResultsIn the cohort study, the risk ratio for pediatric cancer after ART in general was 0.95 (95% CI, 0.76–1.19). The RR was 1.09 (95% CI, 0.79–1.48) for IVF treatments. Meta- analysis of 13 cohort studies with a total of 750,138 women exposed to ART (with 1152 pediatric cancers) and 214,008,000 unexposed controls (with 30,458 pediatric cancers) did not reveal increased risk for pediatric cancers (RR 0.99; 95% CI, 0.85–1.15). ConclusionsBased on very large numbers, ART in general, and IVF in particular, are not associated with overall increased risk of pediatric cancer.

Assisted reproductive technology is not associated with an increased risk of pediatric cancer

Assisted reproductive technology is not associated with an increased risk of pediatric cancer

Maternal Folate Intake and Risk of Childhood Brain and Spinal Cord Tumors: A Systematic Review and Meta-Analysis

Background: Many epidemiological studies have investigated the effect of maternal diet and prenatal multivitamin supplementation on pediatric cancer risk. Childhood brain and spinal cord tumors (CBSCT) have been attributed to different possible risk factors. Methods: We conducted a systematic review and meta-analysis on maternal folate intake before and during pregnancy and the risk of CBSCT. We systematically reviewed publications obtained by searching the Insitute for Scientific Information Web of Knowledge and PubMed literature databases. We extracted the risk estimate of the highest and the lowest reported categories of intake from each study and conducted a meta-analysis using a random-effects model. Results: The results of the pooled analysis of all 10 studies, 1 cohort and 9 case-control studies, indicated that maternal folate intake was inversely associated with CBSCT risk (OR 0.77; 95% CI 0.67–0.88, p < 0.001; I² = 51.22%, p = 0.001). Separate analyses on the basis of the source of folate (folic acid supplementation, dietary folate) and in relation to the timing of exposure (before pregnancy, during pregnancy) found that folic acid supplementation was associated with an approximately 23% reduction in ­CBSCT risk (OR 0.77, 95% CI 0.66–0.90, p = 0.001; I² = 53.18%, p = 0.001) and consumption during pregnancy was associated with an approximately 20% reduction in CBSCT risk (OR 0.80, 95% CI 0.67–0.97, p = 0.020; I² = 62.48%, p < 0·001). Conclusions: Maternal consumption of folic acid is associated with a reduced risk of CBSCT. Further investigations are necessary to increase the reliability of the results and estimate the relationship between dose-response and the best outcome.

Abstract 2083: Innate immunity polymorphisms and risk of pediatric cancer

Abstract In Mexico, cancer represents the second leading cause of death in the pediatric population. The identification of susceptibility genes associated with cancer has been one of the main challenges of human genomics. Several studies have proposed that genetic variation in immune-related genes could be a determinant of susceptibility in different types of cancer. In the present study we evaluated the possible association between 10 polymorphisms in genes that participate in innate immunity and the risk of pediatric cancer. We analyzed genotyping data from 101 patients from Hospital Infantil de México “Federico Gómez” (HIM) with confirmed diagnosis of pediatric cancer. The genotypes were compared with 274 healthy adults without a medical history of pediatric cancer. For each polymorphism we calculated allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE). The association between cancer and pediatric cancer was analyzed using Pearson chi-square and odds ratio (OR); survival analyses were performed by the log rank test and Kaplan-Meier curves. Our results show that risk of pediatric cancer in our sample is significantly associated with the genetic variants IL8-251 (p= 0.04327, OR= 0.701, IC 95% = 0.496-0.990), IL6-174 (p= 0.0037, OR= 2.413, IC 95% = 1.310-4.445), and IL10-592 (p= 0.0062, OR= 0.670, IC 95% = 0.502-0.894). However, we did not find any significant association between selected polymorphisms and overall or disease-free survival. Citation Format: Gabriela E. Mercado, Gabriela A. Rosales-Bravo, David Velazquez-Fernandez, Marta Zapata-Tarres, Luis E. Juarez-Villegas. Innate immunity polymorphisms and risk of pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2083.

Pediatric cancer risk in association with birth defects: A systematic review.

BackgroundMany epidemiological studies have examined associations between birth defects (BDs) and pediatric malignancy over the past several decades. Our objective was to conduct a systematic literature review of studies reporting on this association.MethodsWe used librarian-designed searches of the PubMed Medline and Embase databases to identify primary research articles on pediatric neoplasms and BDs. English language articles from PubMed and Embase up to 10/12/2015, and in PubMed up to 5/12/2017 following an updated search, were eligible for inclusion if they reported primary epidemiological research results on associations between BDs and pediatric malignancies. Two reviewers coded each article based on the title and abstract to identify eligible articles that were abstracted using a structured form. Additional articles were identified through reference lists and other sources. Results were synthesized for pediatric cancers overall and for nine major pediatric cancer subtypes.ResultsA total of 14,778 article citations were identified, of which 80 met inclusion criteria. Pediatric cancer risk was increased in most studies in association with BDs overall with some notable specific findings, including increased risks for CNS tumors in association with CNS abnormalities and positive associations between rib anomalies and several pediatric cancer types.ConclusionsSome children born with BDs may be at increased risk for specific pediatric malignancy types. This work provides a foundation for future investigations that are needed to clarify specific BD types predisposing toward malignancy and possible underlying causes of both BDs and malignancy.

Parental Age and Risk of Pediatric Cancer in the Offspring: A Population-Based Record-Linkage Study in California.

Linking birth records and cancer registry data from California, we conducted a population-based study with 23,419 cases and 87,593 matched controls born during 1978-2009 to investigate the relationship of parental age to risk of pediatric cancer. Compared with children born to mothers aged 20-24 years, those born to mothers in older age groups had a 13%-36% higher risk of pediatric cancer; the odds ratio for each 5-year increase in maternal age was 1.06 (95% confidence interval (CI): 1.04, 1.09). For cancer diagnosed in children in age groups 0-14 years and 15-19 years, the odds ratios for each 5-year increase in maternal age were 1.05 (95% CI: 1.02, 1.07) and 1.14 (95% CI: 1.09, 1.19), respectively. Having an older father also conferred an increased risk, with an odds ratio for each 5-year increase of 1.03 (95% CI: 1.02, 1.05) for cancer diagnosed at ages 0-19 years and 1.03 (95% CI: 1.02, 1.05) for cancer diagnosed at ages 0-14 years. While advancing maternal age increased risk of leukemia and central nervous system tumors, older paternal age was not associated with risk of either type. Both maternal and paternal older ages were associated with risk of lymphoma. In this large, population-based record-linkage study, advancing parental age, especially advancing maternal age, was associated with higher pediatric cancer risk, with variations across types of cancer.

Childhood cancer in small geographical areas and proximity to air-polluting industries

AimPediatric cancer has been associated with exposure to certain environmental carcinogens. The purpose of this work is to analyse the relationship between environmental pollution and pediatric cancer risk. MethodWe analysed all incidences of pediatric cancer (<15) diagnosed in a Spanish region during the period 1998–2015. The place of residence of each patient and the exact geographical coordinates of main industrial facilities was codified in order to analyse the spatial distribution of cases of cancer in relation to industrial areas. Focal tests and focused Scan methodology were used for the identification of high-incidence-rate spatial clusters around the main industrial pollution foci. ResultsThe crude rate for the period was 148.0 cases per 1,000,0000 children. The incidence of pediatric cancer increased significantly along the period of study. With respect to spatial distribution, results showed significant high incidence around some industrial pollution foci group and the Scan methodology identify spatial clustering. We observe a global major incidence of non Hodgkin lymphomas (NHL) considering all foci, and high incidence of Sympathetic Nervous System Tumour (SNST) around Energy and Electric and organic and inorganic chemical industries foci group. In the analysis foci to foci, the focused Scan test identifies several significant spatial clusters. Particularly, three significant clusters were identified: the first of SNST was around energy-generating chemical industries (2 cases versus the expected 0.26), another of NHL was around residue-valorisation plants (5 cases versus the expected 0.91) and finally one cluster of Hodgkin lymphoma around building materials (3 cases versus the expected 2.2) ConclusionResults suggest a possible association between proximity to certain industries and pediatric cancer risk. More evidences are necessary before establishing the relationship between industrial pollution and pediatric cancer incidence.