Childhood Brain Cancer Research Articles

Two faces of WNT signaling

Endogenous WNT antagonists have roles in both childhood brain cancer and melanoma in the elderly.

An epigenetic gateway to brain tumor cell identity.

Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks and disruption of chromatin structure. In this Review, we describe the convergence of genetic, metabolic and microenvironmental factors on mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state and neoplastic transformation, as well as addressing the potential to exploit these alterations as new therapeutic strategies for the treatment of brain cancer.

IMPS-13IMMUNOLOGIC PROFILING OF PEDIATRIC CNS MALIGNANCIES FOR THE RATIONAL SELECTION OF IMUNOTHERAPEUTIC TRIALS

BACKGROUND: Although clinical trials have resulted in significant improvements in childhood brain cancer treatments, further progress using strategically targeted, potentially less toxic modalities are needed. Immunotherapy is one such emerging treatment approach. The degree of tumor-infiltrating cytotoxic T-lymphocytes (CTLs) directly correlates with prognosis for several cancer types. MHC Class I is down-regulated in 40-90% of adult cancers, rendering them resistant to CTL attack, correlating with poorer prognosis. MHC I expression in medulloblastomas is associated with poor prognostic factors, a pattern opposite of most other cancer-MHC I associations described. Natural Killer (NK)-cell based therapies, dependent upon low MHC I expression, are therefore proposed as an immunotherapeutic approach to medulloblastomas. Very little literature exists classifying MHC I expression in other pediatric brain cancers, despite several ongoing trials using MHC I-dependent strategies. This lack of data raises uncertainty of which immunotherapies are optimal for these diseases. Toward this end, we classified key immunologic characteristics of pediatric brain tumors. METHODS: We interrogated pre-clinical and clinical mRNA microarray databases to identify tumor types which exhibit MHC I and the associated b-2-microglobulin molecule expression. We up-regulated MHC I expression in vitro in pediatric CNS tumor cell lines and identified intra-tumoral innate and adaptive immunologic cellular infiltrates within pediatric CNS tumor samples through immunohistochemistry. RESULTS: We found that atypical teratoid/rhabdoid tumors (AT/RT) and ependymomas exhibit decreased, whereas medulloblastomas and glioblastomas express higher MHC I mRNA levels than most other pediatric cancer types. We discovered MHC I can be up-regulated in vitro in medulloblastomas and AT/RT's, indicating a reversible epigenetic mechanism for down-regulation. There were decreased NK and regulatory T-cell, while increased CTL infiltrates in recurred versus diagnostic pediatric glioblastoma tumor samples. CONCLUSIONS: The immunologic profiling of pediatric brain cancers will guide rational selection of immune-based therapies, serving as an important biomarker for patient inclusion in immunotherapeutic trials.

Childhood brain cancer and its psychosocial impact on survivors and their parents: A qualitative thematic synthesis

PurposeThe multiple late-effects experienced by survivors of childhood brain tumors, are not only a source of great distress for survivors, but also for their parents and siblings. The aim of this review is to systematically identify and synthesize qualitative evidence on how survivors of childhood brain tumors and their parents experience life after surviving childhood brain tumors. MethodsBased on literature search in seven databases, 10 qualitative studies, published between 2004 and 2014 were included. ResultsSurviving a childhood brain tumor was experienced as paradox for survivors and their parents. While parents and survivors celebrated making it through the cancer experience, they nonetheless encountered a world with loss and new challenges. In short, the experience of survival was a bittersweet experience for survivors and their parents. Survivors and their parents experienced change that included living with uncertainty, intensification of the parenting role, a changing social world, a different way of being, and the need for additional help. ConclusionResults from this synthesis reinforce that surviving a childhood brain tumor should be viewed as a point on a continuum of living with a brain tumor. Psychosocial effects of surviving brain cancer affect the entire family unit. A need for psychosocial support is evident, although development of such supports necessitates a more full understanding of challenges face by the child affected, their parents, and siblings. The limitations noted in this synthesis reinforce that more qualitative research is needed in this subject area.

The calcium-sensing receptor and integrins modulate cerebellar granule cell precursor differentiation and migration.

In the developing cerebellum granule cell precursors (GCPs) proliferate in the external granule cell layer before differentiating and migrating to the inner granule cell layer. Aberrant GCP proliferation leads to medulloblastoma, the most prevalent form of childhood brain cancer. Here, we demonstrate that the calcium-sensing receptor (CaSR), a homodimeric G-protein coupled receptor, functions in conjunction with cell adhesion proteins, the integrins, to enhance GCP migration and cell homing by promoting GCP differentiation. During the second postnatal week a robust peak in CaSR expression was observed in GCPs; reciprocal immunoprecipitation experiments conducted during this period established that the CaSR and β1 integrins are present together in a macromolecular protein complex. Analysis of cell-surface proteins demonstrated that activation of the CaSR by positive allosteric modulators promoted plasma membrane expression of β1 integrins via ERK2 and AKT phosphorylation and resulted in increased GCP migration toward an extracellular matrix protein. The results of in vivo experiments whereby CaSR modulators were injected i.c.v. revealed that CaSR activation promoted radial migration of GCPs by enhancing GCP differentiation, and conversely, a CaSR inhibitor disrupted GCP differentiation and promoted GCP proliferation. Our results demonstrate that an ion-sensing G-protein coupled receptor acts to promote neuronal differentiation and homing during cerebellar maturation. These findings together with those of others also suggest that CaSR/integrin complexes act to transduce extracellular calcium signals into cellular movement, and may function in this capacity as a universal cell migration/homing complex in the developing brain.

Poverty and the risk of leukemia and cancer in the central nervous system in children: A cohort study in a high-income country.

The association between childhood cancer and socioeconomic status is inconclusive. Family income has seldom been included in large population-based studies, and the specific contributions of it remain unknown. A total of 712,674 children born between 1967 and 2009 in the Oslo region were included. Of these, 864 were diagnosed with leukemia or cancer in the central nervous system before the age of 15 years. The association between poverty and childhood leukemia or brain cancer was analyzed using logistic regression and Cox proportional hazards models. Family income was stratified according to poverty lines. Parents' educational level and several perinatal variables were also examined. Family poverty during the first 2 years of life was associated with lymphoid leukemia before the age of 15 years: odds ratio 1.72, 95% confidence interval 1.11-2.64. In the same age group we found a significant dose response, with a 21% increased risk of lymphoid leukemia with increasing poverty. The risk for intracranial and intraspinal embryonal tumors in the whole study period was lower for children in the middle family income category. For astrocytomas there was a more than 70% increased risk in the medium income category when analyzing the two first years of life. The observed increase was reduced when all years each child contributed to the study were included. The risk of cancer in the central nervous system overall was 20% higher in the medium income category compared to the high-income category. Being born into a household of low family income the first 2 years of life was found to be a risk factor for development of lymphoid leukemia. For astrocytomas we observed an increased risk among children born into the medium income category throughout the first two years of life.

Childhood cancers in families with and without Lynch syndrome

Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24%) and non-Lynch syndrome families (179/94,302; 0.19%; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95% CI 107-206) per million population per year in Lynch syndrome families and 115 (95% CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families.

Long-term psychiatric outcomes in pediatric brain tumor survivors.

The increased efficacy of cancer treatments has led to a greater survival rate of patients with pediatric brain cancers. Therefore, it is imperative to explore the long-term consequences of therapies employed to treat pediatric brain tumors. The goal of this study was to provide a review of literature regarding the downstream psychological and psychiatric consequences experienced by adult survivors of pediatric brain cancer as a result of treatment, tumor type, or tumor location. A PubMed MeSH search and additional online database searches were conducted to include pertinent studies that discussed psychological deficits in childhood brain cancer survivors. The studies included were subjected to data extraction to quantify relevant information for further analysis. A total of 17 papers with 5320 pediatric brain tumor patients were incorporated in our review. Mean age at diagnosis (8.13 ± 0.77years), mean follow-up time (9.98 ± 3.05years), and male-to-female ratios (1.08:1) were compiled from studies reporting this information. Incidences of depression (19%), anxiety (20%), suicidal ideation (10.9%), schizophrenia and its related psychoses (9.8%), and behavioral problem (28.7%) were higher among pediatric brain cancer survivors than in the normal population. Craniospinal radiotherapy and/or surgery corresponded to an increased likelihood of developing adverse deficits. Astrocytomas or other glial tumors were linked to poorer outcomes. Physicians treating pediatric brain tumor patients should be aware of the possible consequences associated with treatment. Psychiatric monitoring is warranted in survivors of pediatric brain tumors, but further investigation is needed to elucidate late outcomes regarding tumor type and location.

Childhood Brain Cancer in Florida: A Bayesian Clustering Approach

In this article, we focus on geocoded data for pediatric brain cancer in Florida. Specifically, we examine zip code level pediatric brain cancer counts from the Florida Association of Pediatric Tumor Programs (FAPTP) childhood cancer registry from 2000–2010 and assess the degree of spatial clustering in these data. We assume Bayesian models for relative risk and examine a variety of posterior measures that indicate excess risk (exceedence probability of relative risk or positive residual). We assume a standard Poisson convolution model and examine a zero-inflated (ZI) model with a factored intercept. We conclude that there is evidence of excess risk in a number of relatively dispersed zip codes across the state but there appears to be some concentration of high excess risk in Polk, Lake, and Sumter counties (west of Orlando and north east of Tampa). These excesses are confirmed across the models.

GE-21 * DRASTIC GENOMIC DIVERGENCE OF RECURRENT MEDULLOBLASTOMA INVALIDATES TARGETED THERAPIES DISCOVERED AT DIAGNOSIS

Recurrence of the childhood brain cancer medulloblastoma is almost universally fatal. The current strategy for clinical trials is to test novel therapies at the time of recurrence, using targets discovered at diagnosis. To define the relationship between naive and post-treatment medulloblastoma, we developed a functional genomic transposon-driven mouse-model. Deep sequencing of the commonly inserted genes in diagnostic and recurrent tumors revealed dramatic divergence post-therapy, with recurrences demonstrating a convergence on the TP53 pathway. Loss of function insertions in Tp53 are clonal in the recurrence, result in loss of expression of the Tp53 target gene P21, and arise through selection of minor subclones present before therapy. The majority of insertions identified at diagnosis are no longer present at recurrence, and therefore represent futile targets for therapy. To validate these findings, we studied 36 pairs of human primary/recurrent tumors by whole genome sequencing. When comparing SNVs, indels or structural aberrations, we found minimal genetic overlap between the dominant clones at diagnosis versus recurrence. Recurrent tumors have more genomic aberrations than their paired diagnostic sample, and commonly display alterations in the TP53 (SHH), or the TP53 and TGF-β pathways (Group 3/4 tumors). Clonal dynamics between primary and recurrent tumors was measured using ultra-deep sequencing (1,500X). Overall, recurrent tumors share little genetic identity with their diagnostic tumor, arise through clonal selection, target specific signaling pathways to avoid cell death, and assume clinical dominance after therapy. Our findings undermine the key assumption that diagnostic medulloblastoma samples provide rational targets for therapy in recurrent disease, and provide a simple reason for the failure of prior trials of targeted therapy. Repeated genetic convergence on specific signaling pathways at the time of recurrence suggests that it may be possible to develop ‘anticipatory therapy’ delivered up front to prevent the later emergence of minor resistant clones driving recurrence.

Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors.

Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p=0.001). ALT was highly enriched in primitive neuroectodermal tumors (12%), choroid plexus carcinomas (23%) and high-grade gliomas (22%). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p=1.01×10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p=0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63±12 and 23±10% for ALT positive and negative tumors, respectively (p=0.03), while for children with TP53 mutant choroid plexus carcinomas, 5years overall survival was 67±19 and 27±13% for ALT positive and negative tumors, respectively (p=0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.

Bayesian Joinpoint Regression Model for Childhood Brain Cancer Mortality

The Bayesian approach of joinpoint regression is widely used to analyze trends in cancer mortality, incidence and survival data. The Bayesian joinpoint regression model was used to study the childhood brain cancer mortality rate and its average percentage change (APC) per year. Annual observed mortality counts of children ages 0-19 from 1969-2009 obtained from Surveillance Epidemiology and End Results (SEER) database of National Cancer Institute (NCI) were analyzed. It was assumed that death counts are probabilistically characterized by the Poisson distribution and they were modeled using log link function. Results were compared with the mortality trend obtained using joinpoint software of NCI.

Abstract 812: Maternal folic acid supplementation and risk of medulloblastoma in offspring

Abstract Background: Epidemiological studies can give important insights into factors that modulate disease risk. However, the inherent limitations of observational studies make causal relationships difficult to infer. For example, several case-control studies have indicated that prenatal vitamins may protect against childhood brain tumors, including medulloblastoma, and folic acid (FA) is speculated to be the modulating factor. Using a murine model, we are testing whether low maternal dietary FA during the peri-gestational period increases medulloblastoma risk in offspring. We are using a well-defined transgenic mouse model of Gorlin syndrome, which is characterized by an autosomal dominant mutation in the PTCH1 gene. Heterozygous C57BL/6 strain Ptc1+/− mice have a medulloblastoma incidence of ∼40% at one year, making this transgenic model highly suitable for childhood brain cancer etiologic studies. Methods. A total of 126 female wild-type C57BL/6 mice were randomized to one of three amino acid defined FA diets: 1) 0.3 mg/kg (low), 2) 2.0 mg/kg (control), and 3) 8.0 mg/kg (high), one month prior to mating with Ptc1+/− C57BL/6 males and maintained on their respective diets until weaning of their pups. Red blood cell (RBC) folate measurements were obtained from the dams at weaning and their association with the assigned dietary FA dose was determined using one-way ANOVA. The offspring have been genotyped and weaned heterozygotes are being followed for tumor development for one year. Interim hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards regression to examine the association between the assigned maternal dietary FA dose and offspring tumor incidence. Results. In a total of 381 offspring, the overall Ptc1+/− genotype frequency is similar to previous reports with no significant differences between dietary groups (low: 40%, control: 40%, high: 42%). RBC folate concentrations in the dams at weaning increased significantly with increasing FA dose (p<0.0001). Ptc1+/− offspring from each of the dietary groups have been followed for a mean of ∼6 months. To date, 25%, 35%, and 37% of Ptc1+/− offspring have developed tumors in the low, control, and high FA groups, respectively.Compared to the control group, the hazard for tumor development was non-significantly decreased in offspring in the low FA group (HR=0.7; 95% CI 0.3-1.4) and similar in the high FA group (HR=1.0; 95% CI 0.5-1.8). Conclusions. In contrast to our hypothesis, these preliminary results indicate that higher doses of maternal dietary FA may increase offspring brain tumor incidence. We speculate that higher dietary FA levels during the peri-gestational period may influence brain tumor progression in mice predisposed to tumor development. The implications of these findings with respect to human populations will be discussed. Supported by R03CA141440, T32CA099936, and the Children's Cancer Research Fund, Minneapolis, MN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2011-812

Effects of Daidzein and Vincristine on Medulloblastoma Cell Proliferation

Medulloblastoma – the most common type of childhood brain cancer – is a malignant tumor of the cerebellum that can spread throughout the central nervous system. Currently, the primary treatment for MB patients is chemotherapy, but its use is limited due to its negative side effects, which include cognitive and neurological dysfunctions, growth impairment of the brain, and immune system compromise. Previous studies with the isoflavone genistein determined that a diet high in soy could potentially reduce the amount of chemotherapy drugs necessary to treat MB, which would consequently reduce the risk of harmful side effects while maintaining or improving disease control. Unlike genistein, daidzein – another key soy isoflavone with high bioavailability – has not been studied. Therefore, we sought to detail the effects of vincristine coupled with daidzein on MB cell lines. For this, HTB‐186 cells were treated with daidzein and varied concentrations of vincristine. Cells in all treatment groups were incubated for 1 week. After the study period, the viable cells in each group were enumerated via a dye exclusion assay.Grant Funding Source: Saluki Scholars Research Opportunity

Pretreatment neuropsychological deficits in children with brain tumors

Treatment of childhood brain cancer has been associated with long-term cognitive morbidity in children. In the present study, the cognitive status of children with brain tumors was examined prior to any treatment to single out the role of tumor and tumor-related factors in cognitive deficits. Eighty-three children with newly diagnosed brain tumors (mean age, 8.6 years; range, 7 months to 16.6 years; median, 9.4 years) completed an extensive battery of age-related tests to assess cognitive function before any therapeutic intervention. Magnetic resonance imaging (MRI) was used to determine tumor site and volume and tumor-related factors. Performance under test was compared with symptom duration, neurological status, epilepsy, and MRI. Cognitive difficulties are detected at diagnosis in as many as 50% of patients for some cognitive domains; 6% of patients present with true-diagnosed mental retardation. The location of the tumor is the principal determinant of cognitive deficits, with major impairment in children with cortical tumors. Symptom duration and the presence of epilepsy are significantly associated with neuropsychological disabilities, while neuroradiological tumor-related variables do not correlate clearly with neurocognitive performance. The knowledge of the pre-existing cognitive deficits is critical to evaluate the results of treatment, providing a baseline for assessing the true impact of therapy in determining cognitive decline. In addition, the study suggests that some clinical variables require careful monitoring, because they could be specifically implicated in the neuropsychological outcome; the efforts to reduce the impact of these factors could ameliorate long-term prognosis.

Divide and Conquer Strategy for Childhood Brain Cancer

Divide and Conquer Strategy for Childhood Brain Cancer

The Development of Cell Line Models of Childhood Brain Tumours

Childhood brain cancers have a significant impact on society. Currently, it is possible to make sophisticated diagnoses, but the treatments do not reflect patient differences and are out-dated. In order to develop better therapies and improve the outcome, we must first understand the underlying biology of brain cancer and how cells influence the disease process. For that purpose, several lines of brain cancer stem cells have been isolated, which have retained the characteristics of their original tissues. These in vitro human cell models are a much-needed addition to research on childhood brain cancers.

Disablingc-Mycin Childhood Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor Cells by the Potent G-Quadruplex Interactive Agent S2T1-6OTD

We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex-forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC(50), 0.25-0.39 micromol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc-dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors.

Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study

BackgroundThe etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use.ObjectivesWe aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children.MethodsWe included 526 one-to-one–matched case–control pairs. Brain cancer cases were diagnosed at < 10 years of age, and were identified from statewide cancer registries of four U.S. Atlantic Coast states. We selected controls by random digit dialing. We conducted computer-assisted telephone interviews with mothers. Using information on residential pesticide use and jobs held by fathers during the 2-year period before the child’s birth, we assessed potential exposure to insecticides, herbicides, and fungicides. For each job, two raters independently classified the probability and intensity of exposure; 421 pairs were available for final analysis. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, after adjustment for maternal education.ResultsA significant risk of astrocytoma was associated with exposures to herbicides from residential use (OR = 1.9; 95% CI, 1.2–3.0). Combining parental exposures to herbicides from both residential and occupational sources, the elevated risk remained significant (OR = 1.8; 95% CI, 1.1–3.1). We observed little association with primitive neuroectodermal tumors (PNET) for any of the pesticide classes or exposure sources considered.ConclusionsOur observation is consistent with a previous literature reporting suggestive associations between parental exposure to pesticides and risk of astrocytoma in offspring but not PNET. However, these findings should be viewed in light of limitations in exposure assessment and effective sample size.

Increased Childhood Liver Cancer Mortality and Arsenic in Drinking Water in Northern Chile

Arsenic in drinking water is an established cause of lung, bladder, and skin cancers in adults and may also cause adult kidney and liver cancers. Some evidence for these effects originated from region II of Chile, which had a period of elevated arsenic levels in drinking water, in particular from 1958 to 1970. This unique exposure scenario provides a rare opportunity to investigate the effects of early-life arsenic exposure on childhood mortality; to our knowledge, this is the first study of childhood cancer mortality and high concentrations of arsenic in drinking water. In this article, we compare cancer mortality rates under the age of 20 in region II during 1950 to 2000 with those of unexposed region V, dividing subjects into those born before, during, or after the peak exposure period. Mortality from the most common childhood cancers, leukemia and brain cancer, was not increased in the exposed population. However, we found that childhood liver cancer mortality occurred at higher rates than expected. For those exposed as young children, liver cancer mortality between ages 0 and 19 was especially high: the relative risk (RR) for males born during this period was 8.9 [95% confidence interval (95% CI), 1.7-45.8; P = 0.009]; for females, the corresponding RR was 14.1 (95% CI, 1.6-126; P = 0.018); and for males and females pooled, the RR was 10.6 (95% CI, 2.9-39.2; P < 0.001). These findings suggest that exposure to arsenic in drinking water during early childhood may result in an increase in childhood liver cancer mortality.