Gene–Environment Interaction and Susceptibility to Pediatric Brain Tumors

Kunkle, Brian W.; Sandberg, David I.; Prasanna, J. Sai; Felty, Quentin; Roy, Deodutta

doi:10.1007/978-1-4419-6752-7_9

Cited by 3 publications

(2 citation statements)

References 127 publications

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“…The five-year survival rate of medulloblastoma is low (60%) [2], and therapy is associated with sequelae in neurocognition and physical deficits. There are few established risk factors for medulloblastoma, and its etiology is not well understood [3, 4]. The incidence of childhood medulloblastoma is bimodal with peaks at the ages of 3 to 4 years and 8 to 10 years [5], suggesting the importance of early life exposures, especially those that occur in utero [6].…”

Section: Introductionmentioning

confidence: 99%

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Maternal Variation inEPHX1, a Xenobiotic Metabolism Gene, Is Associated with Childhood Medulloblastoma: An Exploratory Case-Parent Triad Study

Lupo¹,

Nousome²,

Okcu³

et al. 2012

Pediatric Hematology and Oncology

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Common epidemiologic study designs used for evaluating germline genetic determinants of childhood medulloblastoma are often subject to population stratification bias and do not account for maternal genetic effects, a proxy for the intrauterine environment, which may be important in determining etiologic factors for this outcome. The case-parent triad design overcomes these limitations. Therefore, we conducted an exploratory study among 27 childhood medulloblastoma case-parent triads recruited from the Childhood Cancer Epidemiology and Prevention Center at Texas Children’s Hospital (Houston, TX) between 2003 and 2010. We assessed 13 single nucleotide polymorphisms (SNPs) in nine xenobiotic detoxification genes, as deficiencies in this pathway may induce brain tumorigenesis. Log-linear modeling was used to assess the association between medulloblastoma and both the offspring (i.e., case) and maternal genotypes of each SNP. In our population, there were no offspring genotypes that were significantly associated with disease risk. However, the maternal EPHX1 rs1051740 genotype (RR=3.26, P=0.01) was associated with medulloblastoma risk. This exploratory study highlights the utility of the case-parent triad design, but these results should be interpreted cautiously due to the limited sample size.

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Section: Introductionmentioning

confidence: 99%

“…If these compounds are “bioactivated” rather than eliminated, they may form DNA adducts, which can be carcinogenic. Because of the high rates of cell differentiation and proliferation during development, deficiencies in this pathway may induce brain tumorigenesis [3]. …”

Section: Introductionmentioning

confidence: 99%

Maternal Variation inEPHX1, a Xenobiotic Metabolism Gene, Is Associated with Childhood Medulloblastoma: An Exploratory Case-Parent Triad Study

Lupo¹,

Nousome²,

Okcu³

et al. 2012

Pediatric Hematology and Oncology

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Proteomic and Mitochondrial Genomic Analyses of Pediatric Brain Tumors

et al. 2014

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The molecular mechanism unraveling why a particular type of pediatric brain tumor (pBT) behaves so differently from child to child or genetic/epigenetic changes in the mitochondrial genome vary from tumor to tumor is not clearly understood. Despite the identification of mitochondrial DNA (mtDNA) mutations in different types of pBT, the contribution of mitochondrial dysfunction-related genes or proteins that are selectively up- or down-regulated in pBT of different types has not been comprehensively examined. In the present study, we combined a 2D DIGE approach with protein identification using MALDI-TOF MS and LC-MS/MS, coupled with mtDNA genomics to screen brain samples for discovering changes in protein expression, and mtDNA sequence variation and mtDNA copy number in the disease states. Two-dimensional gel electrophoresis-based differential proteomic analysis of the brain tumors showed that 116 proteins were found to be up- or down-regulated in brain tumors. Some of the proteins up-regulated in tumors compared to controls were dihydropyrimidinase-like 2; glial fibrillary acidic protein isoform 2; phosphoserine aminotransferase isoform 1; Sirt2 histone deacetylase; and C10orf2 protein, mitochondrial DNA helicase. Proteins down-regulated in brain tumors compared to controls were heat shock protein 90 kDa beta, BiP; guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1, isoform CRA_d; histone H2B.1; neurofilament, light polypeptide 68 kDa; Annexin I; and RAN. These differentially expressed proteins may provide useful information for developing molecular markers of diagnostic or prognostic value. To investigate further the role of mitochondrial dysfunction, we examined the effects of mtDNA copy number, oxidative damage, and mtDNA variants as independent or combined risk factors for the development of pBTs. Bayesian network and mechanistic hierarchical structure Markov Chain Monte Carlo (MCMC) modeling were used to analyze the relationship between these variables. The combined effects of G3196, 9952A, 10006G, 100398G, oxidative mtDNA damages, and mtDNA copy number increased the probability of developing brain tumors in female children by 51 times more when compared to normal incidence of pediatric brain tumors. Comparison of mechanistic structure models also supported the finding that female children who have the wild type allele G3196, variant allele 9952A, variant allele 10006G, variant allele10398A, and high mtDNA copy number had increased probability of developing pediatric brain tumors. Estimation of nuclear genes controlling mitochondrial biogenesis and development of brain, cortical dysplasia, and the effect of the environment using MCMC method showed that these latent variables had a very significant contribution in the development of pediatric brain tumors. Together, these results suggest that mitochondrial genome and tumor proteome are important contributors to brain tumor risk in children, and findings from this study may guide the prospects for targeting mitochondria for therapeutic ...

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The potential effect of gender in CYP1A1 and GSTM1 genotype-specific associations with pediatric brain tumor

et al. 2013

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Brain tumors are the common site for solid tumors in childhood. Very few studies have investigated genes with low penetrance in relation to pediatric brain tumor (pBT) development. Brain tumors do occur more frequently in males compared to females regardless of age, tumor histology, or region of the world. Taken into account these facts, we have designed a study aimed to analyse the contribution of some genetic factors to pBP in males and females. Patients with glial and embryonic brain tumors (160 males, 124 females) and healthy controls (277 males, 187 females) were included in the study. All subjects were genotyped for eight polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), repair ERCC2 (rs1799793, rs13181), and folate pathway MTHFR (rs1801133). Genotype-specific risks of pBT were sex-dependent. GSTM1 deletion and dual deletions in GSTM1-GSTT1 loci were associated with brain tumor in males (P = 1.2 × 10(-5); odds ratio (OR) = 2.56; 95 % confidence interval (CI), 1.45-3.85 and P = 4.9 × 10(-4); OR = 3.09; 95 % CI, 1.63-5.89, relatively). The increased risk of brain tumors was evident for CYP1A1 rs2606345 (P = 0.0028; OR = 2.06; 95 % CI, 1.27-3.34) and minor haplotypes rs2606345-rs1048943-rs4646903 in females (global haplotype association P value, 0.0011). This study provides first evidence for the different pronounced pBT associations in males and females. This phenomenon possibly reflects the sexual dimorphism as an important determinant of brain tumor biology.

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Gene–Environment Interaction and Susceptibility to Pediatric Brain Tumors

Cited by 3 publications

References 127 publications

Maternal Variation inEPHX1, a Xenobiotic Metabolism Gene, Is Associated with Childhood Medulloblastoma: An Exploratory Case-Parent Triad Study

Maternal Variation inEPHX1, a Xenobiotic Metabolism Gene, Is Associated with Childhood Medulloblastoma: An Exploratory Case-Parent Triad Study

Proteomic and Mitochondrial Genomic Analyses of Pediatric Brain Tumors

The potential effect of gender in CYP1A1 and GSTM1 genotype-specific associations with pediatric brain tumor

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