Michael E. Scheurer

Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.

Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the groups consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address. Cancer 2008;113(7 suppl):1953–68.

Measuring the Prevalence of Overweight in Texas Schoolchildren

OBJECTIVES We describe results from year 1 of a surveillance system to monitor body mass index in children at the state level. METHODS A sample of 6630 children attending Texas public schools, weighted to represent 4th, 8th, and 11th grades within race/ethnic subpopulations, was assessed. Body mass index was calculated from measured height and weight; demographic information was obtained from a questionnaire. RESULTS Prevalence of overweight was 22.4%, 19.2%, and 15.5% for 4th-, 8th-, and 11th-grade students, respectively. Overweight prevalence was highest among Hispanic boys (29.5%-32.6%), fourth-grade Hispanic girls (26.7%), and fourth- and eighth-grade African American girls (30.8% and 23.1%, respectively). Eleventh-grade White/other girls had the lowest prevalence of overweight (5.5%). CONCLUSIONS These data confirm the increasing prevalence of overweight among US children, especially among Hispanic and African American students compared to White/other students and fourth-grade students relative to 8th- and 11th-grade students.

Association and Interactions between DNA Repair Gene Polymorphisms and Adult Glioma

It is generally accepted that glioma develops through accumulation of genetic alterations. We hypothesized that polymorphisms of candidate genes involved in the DNA repair pathways may contribute to susceptibility to glioma. To address this possibility, we conducted a study on 373 Caucasian glioma cases and 365 cancer-free Caucasian controls to assess associations between glioma risk and 18 functional single-nucleotide polymorphisms in DNA repair genes. We evaluated potential gene-gene and gene-environment interactions using a multianalytic strategy combining logistic regression, multifactor dimensionality reduction and classification and regression tree approaches. In the single-locus analysis, six single-nucleotide polymorphisms [ERCC1 3′ untranslated region (UTR), XRCC1 R399Q, APEX1 E148D, PARP1 A762V, MGMT F84L, and LIG1 5′UTR] showed a significant association with glioma risk. In the analysis of cumulative genetic risk of multiple single-nucleotide polymorphisms, a significant gene-dosage effect was found for increased glioma risk with increasing numbers of adverse genotypes involving the aforementioned six single-nucleotide polymorphisms (Ptrend = 0.0004). Furthermore, the multifactor dimensionality reduction and classification and regression tree analyses identified MGMT F84L as the predominant risk factor for glioma and revealed strong interactions among ionizing radiation exposure, PARP1 A762V, MGMT F84L, and APEX1 E148D. Interestingly, the risk for glioma was dramatically increased in ionizing radiation exposure individuals who had the wild-type genotypes of MGMT F84L and PARP1 A762V (adjusted odds ratios, 5.95; 95% confidence intervals, 2.21-16.65). Taken together, these results suggest that polymorphisms in DNA repair genes may act individually or together to contribute to glioma risk. (Cancer Epidemiol Biomarkers Prev 2009;18(1):204–14)

Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival

PURPOSE Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. PATIENTS AND METHODS Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; <or= 12 months) and long-term survivors (LTS; >or= 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. RESULTS We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients >or= 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). CONCLUSION Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

Reactivation of human herpesvirus-6 (HHV-6) frequently occurs following hematopoietic SCT (HSCT), and has been associated with clinical consequences in many patient populations. HHV-6 reactivation and HHV-6 encephalitis seem to occur more frequently in patients undergoing HSCT with cord blood (CB) as the stem cell source. We have conducted a systematic literature review and meta-analysis to investigate the clinical significance of this correlation. A systematic review of publications indexed in PubMed was performed for HSCT studies published over the past 10 years that fit inclusion criteria. Data on prevalences of HHV-6 reactivation and HHV-6 encephalitis post HSCT were abstracted from 19 papers. Meta-analyses were conducted to calculate combined prevalence estimates. The prevalences of HHV-6 reactivation and encephalitis were compared among CB vs non-CB HSCT. Prevalences of HHV-6 reactivation and HHV-6 encephalitis were significantly higher in patients receiving CB as the stem cell source than in patients receiving another stem cell source (72.0% vs 37.4%, P<0.0001; 8.3% vs 0.50%, P<0.0001, respectively). HHV-6 reactivation and HHV-6 encephalitis are significant complications in the post-HSCT setting, particularly in patients receiving CB as the stem cell source. Thus, patients undergoing umbilical CB transplantation should be closely monitored for HHV-6 reactivation.

Long-term Anti-inflammatory and Antihistamine Medication Use and Adult Glioma Risk

A personal history of asthma or allergy has been associated with a reduced risk for adult malignant gliomas. Recent reports on the use of nonsteroidal anti-inflammatory drugs (NSAID) and the presence of risk alleles in asthma susceptibility genes showed similar inverse associations. To further explore the relationship between immune mediators and gliomas, we examined the use of NSAID and antihistamines, history of asthma or allergy, and infection in 325 glioma cases and 600 frequency-matched controls from the metropolitan area of Houston, TX (2001-2006). The regular use of NSAID was associated with a 33% reduction in the risk for glioma, suggestive of possible antitumor activity. Surprisingly, regular long-term antihistamine use among those reporting a history of asthma or allergies was significantly associated with a 3.5-fold increase in the risk for glioma. Similar to previous reports, cases in our study were less likely to have reported asthma, allergy, or a history of a number of viral infections (chickenpox or shingles, oral herpes, and mononucleosis) than controls. We therefore speculate that the observed positive association with antihistamine use may reflect an alteration of protective immune factors in susceptible individuals. Our results lend additional support for an important but unknown link between malignant brain tumors and immune mediators. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1277–81)

Childhood Brain Tumor Epidemiology: A Brain Tumor Epidemiology Consortium Review

Childhood brain tumors are the most common pediatric solid tumor and include several histologic subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors. Cancer Epidemiol Biomarkers Prev; 23(12); 2716–36. ©2014 AACR.

The Childhood Leukemia International Consortium

BACKGROUND Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case-control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene-environment interactions. OBJECTIVES The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene-environment interactions and subtype-specific associations through the pooling of data from independent studies. METHODS By September 2012, CLIC included 22 studies (recruitment period: 1962-present) from 12 countries, totaling approximately 31000 cases and 50000 controls. Of these, 19 case-control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child-parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. CONCLUSIONS CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene-environment interactions and associations among specific leukemia subtypes in different ethnic groups.

A meta‐analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have been implicated in childhood acute lymphoblastic leukemia (ALL) risk, but previously published studies were inconsistent and recent meta‐analyses were not adequate.

Role of Type 1 IFNs in Antiglioma Immunosurveillance—Using Mouse Studies to Guide Examination of Novel Prognostic Markers in Humans

Purpose: We hypothesized that the type 1 IFNs would play a pivotal role in antiglioma immunosurveillance through promotion of type 1 adaptive immunity and suppression of immunoregulatory cells. Experimental Design: We induced de novo gliomas in Ifnar1−/− (deficient for type 1 IFN receptors) or wild-type mice by intracerebroventricuar transfection of NRas and a short hairpin RNA against P53 using the Sleeping Beauty transposon system. We analyzed the survival of 587 glioma patients for single nucleotide polymorphisms (SNP) in type 1 IFN–related genes. Results: Ifnar1−/− mice exhibited accelerated tumor growth and death. Analyses of brain tumor–infiltrating lymphocytes in Ifnar1−/− mice revealed an increase of cells positive for CD11b+Ly6G+ and CD4+FoxP3+, which represent myeloid-derived suppressor cells and regulatory T cells, respectively, but a decrease of CD8+ cytotoxic T lymphocytes (CTLs) compared with wild-type mice. Ifnar1−/− mouse–derived glioma tissues exhibited a decrease in mRNA for the CTL-attracting chemokine Cxcl10, but an increase of Ccl2 and Ccl22, both of which are known to attract immunoregulatory cell populations. Dendritic cells generated from the bone marrow of Ifnar1−/− mice failed to function as effective antigen-presenting cells. Moreover, depletion of Ly6G+ cells prolonged the survival of mice with developing gliomas. Human epidemiologic studies revealed that SNPs in IFNAR1 and IFNA8 are associated with significantly altered overall survival of patients with WHO grade 2 to 3 gliomas. Conclusions: The novel Sleeping Beauty–induced murine glioma model led us to discover a pivotal role for the type 1 IFN pathway in antiglioma immunosurveillance and relevant human SNPs that may represent novel prognostic markers. Clin Cancer Res; 16(13); 3409–19. ©2010 AACR.