Gene–Environment Interaction and Susceptibility to Pediatric Brain Tumors

  • Brian Kunkle
  • David Sandberg
  • Prasanna Jayakar
  • Quentin Felty
  • Deodutta RoyEmail author


Many pediatric brain tumors (pBTs) may result from the interplay of environmental factors with biological mechanisms at critical developmental periods in a child’s life. While several genetic disorders have been linked to development of pBTs, many pBTs may result from low-penetrant gene alterations in common pathways. Importantly, alterations and pathways that may be important to etiology in certain tumor types may not play a role in other pBT types. It is probable that heterogeneity in alterations, and possibly even pathways, exists within tumor groups as well. Identification of which pathways are most significant in the etiology of each pBT type will be critical in developing therapies for these tumors. While therapies for single gene mutations have been successful in the past for certain cancers, it is possible that therapies based on pathway inhibition will prove to be more successful in the treatment of tumors that have several mutations throughout a pathway such as pBTs. This chapter describes the current state of the research on environmental, genetic, and epigenetic factors possibly involved in the development of pBTs. It covers epidemiological research on environmental factors that have been investigated in relation to pBTs, the involvement of neural stem cells, progenitor cells, and developmental pathways in the etiology of pBTs, the genetic and epigenetic alterations that have been identified in common pBTs, and how these factors may interact with mitochondrial-nuclear signaling to increase individual susceptibility to pBTs.


Pediatric brain tumors (pBTs) Gene–environment interactions Mitochondrial-nuclear signaling Environment Individual susceptibility 


  1. Adinolfi M. 1985. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 27: 532–537.PubMedCrossRefGoogle Scholar
  2. Aleardi AM, Benard G, Augereau O, Malgat M, Talbot JC, Mazat JP, et al. 2005. Gradual alteration of mitochondrial structure and function by beta-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J Bioenerg Biomembr 37: 207–225.PubMedCrossRefGoogle Scholar
  3. Anderson LM, Diwan BA, Fear NT, Roman E. 2000. Critical windows of exposure for children’s health: cancer in human epidemiological studies and neoplasms in experimental animal models. Environ Health Perspect 108(Suppl 3): 573–594.PubMedCrossRefGoogle Scholar
  4. Autrup H. 1993. Transplacental transfer of genotoxins and transplacental carcinogenesis. Environ Health Perspect 101(Suppl 2): 33–38.PubMedCrossRefGoogle Scholar
  5. Bailey P, Cushing H. 1925. Medulloblastoma cerebelli: a common type of midcerebellar glioma of childhood. Arch Neurol Psychiatry 14: 192–223.CrossRefGoogle Scholar
  6. Baldwin RT, Preston-Martin S. 2004. Epidemiology of brain tumors in childhood–a review. Toxicol Appl Pharmacol 199: 118–131.PubMedCrossRefGoogle Scholar
  7. Bar EE, Chaudhry A, Farah MH, Eberhart CG. 2007. Hedgehog signaling promotes medulloblastoma survival via Bc/II. Am J Pathol 170: 347–355.PubMedCrossRefGoogle Scholar
  8. Barnette P, Scholl R, Blandford M, Ballard L, Tsodikov A, Magee J, et al. 2004. High-throughput detection of glutathione s-transferase polymorphic alleles in a pediatric cancer population. Cancer Epidemiol Biomarkers Prev 13: 304–313.PubMedCrossRefGoogle Scholar
  9. Birch JM, Alston RD, Kelsey AM, Quinn MJ, Babb P, McNally RJ. 2002. Classification and incidence of cancers in adolescents and young adults in England 1979–1997. Br J Cancer 87: 1267–1274.PubMedCrossRefGoogle Scholar
  10. Branstetter DG, Stoner GD, Schut HA, Senitzer D, Conran PB, Goldblatt PJ. 1987. Ethylnitrosourea-induced transplacental carcinogenesis in the mouse: tumor response, DNA binding, and adduct formation. Cancer Res 47: 348–352.PubMedGoogle Scholar
  11. Brodeur GM, Castleberry RP. 1997. Neuroblastoma. In: Principles and practice of pediatric oncology (Pizzo PA, Poplack DG, eds.). Philadelphia, PA: Lippincott, 761–797.Google Scholar
  12. Bruggeman SW, Hulsman D, Tanger E, Buckle T, Blom M, Zevenhoven J, et al. 2007. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12: 328–341.PubMedCrossRefGoogle Scholar
  13. Bunin GR. 2004. Nongenetic causes of childhood cancers: evidence from international variation, time trends, and risk factor studies. Toxicol Appl Pharmacol 199: 91–103.PubMedCrossRefGoogle Scholar
  14. Buonocore G, Perrone S, Bracci R. 2001. Free radicals and brain damage in the newborn. Biol Neonate 79: 180–186.PubMedCrossRefGoogle Scholar
  15. Cadieux B, Ching TT, VandenBerg SR, Costello JF. 2006. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 66: 8469–8476.PubMedCrossRefGoogle Scholar
  16. Calabrese V, Copani A, Testa D, Ravagna A, Spadaro F, Tendi E, et al. 2000. Nitric oxide synthase induction in astroglial cell cultures: effect on heat shock protein 70 synthesis and oxidant/antioxidant balance. J Neurosci Res 60: 613–622.PubMedCrossRefGoogle Scholar
  17. Carew JS, Huang P. 2002. Mitochondrial defects in cancer. Mol Cancer 1: 9.PubMedCrossRefGoogle Scholar
  18. Copeland WC, Wachsman JT, Johnson FM, Penta JS. 2002. Mitochondrial DNA alterations in cancer. Cancer Invest 20: 557–569.PubMedCrossRefGoogle Scholar
  19. Cottrell DA, Ince PG, Blakely EL, Johnson MA, Chinnery PF, Hanna M, et al. 2000. Neuropathological and histochemical changes in a multiple mitochondrial DNA deletion disorder. J Neuropathol Exp Neurol 59: 621–627.PubMedGoogle Scholar
  20. Delsite RL, Rasmussen LJ, Rasmussen AK, Kalen A, Goswami PC, Singh KK. 2003. Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus. Mutagenesis 18: 497–503.PubMedCrossRefGoogle Scholar
  21. Dietert RR, Etzel RA, Chen D, Halonen M, Holladay SD, Jarabek AM, et al. 2000. Workshop to identify critical windows of exposure for children’s health: immune and respiratory systems work group summary. Environ Health Perspect 108(Suppl 3): 483–490.PubMedCrossRefGoogle Scholar
  22. Dirks P. 2007. Bmi1 and cell of origin determinants of brain tumor phenotype. Cancer Cell 12: 295–297.PubMedCrossRefGoogle Scholar
  23. Doll R, Wakeford R. 1997. Risk of childhood cancer from fetal irradiation. Br J Radiol 70: 130–139.PubMedGoogle Scholar
  24. Dukhande VV, Malthankar-Phatak GH, Hugus JJ, Daniels CK, Lai JC. 2006. Manganese-induced neurotoxicity is differentially enhanced by glutathione depletion in astrocytoma and neuroblastoma cells. Neurochem Res 31: 1349–1357.PubMedCrossRefGoogle Scholar
  25. Duthie SJ, Dobson VL. 1999. Dietary flavonoids protect human colonocyte DNA from oxidative attack in vitro. Eur J Nutr 38: 28–34.PubMedCrossRefGoogle Scholar
  26. Enns R, Criddle RS. 1977. Investigation of the structural arrangement of the protein subunits of mitochondrial ATPase. Arch Biochem Biophys 183: 742–752.PubMedCrossRefGoogle Scholar
  27. Erecinska M, Cherian S, Silver IA. 2004. Energy metabolism in mammalian brain during development. Prog Neurobiol 73: 397–445.PubMedCrossRefGoogle Scholar
  28. Evans AR, Limp-Foster M, Kelley MR. 2000. Going APE over ref-1. Mutat Res 461: 83–108.PubMedCrossRefGoogle Scholar
  29. Ezer R, Alonso M, Pereira E, Kim M, Allen JC, Miller DC, et al. 2002. Identification of glutathione S-transferase (GST) polymorphisms in brain tumors and association with susceptibility to pediatric astrocytomas. J Neurooncol 59: 123–134.PubMedCrossRefGoogle Scholar
  30. Fear NT, Roman E, Ansell P, Bull D. 2001. Malignant neoplasms of the brain during childhood: the role of prenatal and neonatal factors (United Kingdom). Cancer Causes Control 12: 443–449.PubMedCrossRefGoogle Scholar
  31. Ferrer I, Tortosa A, Condom E, Blanco R, Macaya A, Planas A. 1994. Increased expression of bcl-2 immunoreactivity in the developing cerebral cortex of the rat. Neurosci Lett 179: 13–16.PubMedCrossRefGoogle Scholar
  32. Folkerth RD, Haynes RL, Borenstein NS, Belliveau RA, Trachtenberg F, Rosenberg PA, et al. 2004. Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J Neuropathol Exp Neurol 63: 990–999.PubMedGoogle Scholar
  33. Garcia SJ, Seidler FJ, Crumpton TL, Slotkin TA. 2001. Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells. Brain Res 891: 54–68.PubMedCrossRefGoogle Scholar
  34. Gottfried Y, Voldavsky E, Yodko L, Sabo E, Ben-Itzhak O, Larisch S. 2004. Expression of the pro-apoptotic protein ARTS in astrocytic tumors: correlation with malignancy grade and survival rate. Cancer 101: 2614–2621.PubMedCrossRefGoogle Scholar
  35. Grimmer MR, Weiss WA. 2006. Childhood tumors of the nervous system as disorders of normal development. Curr Opin Pediatr 18: 634–638.PubMedCrossRefGoogle Scholar
  36. Gunter KK, Gunter TE. 1994. Transport of calcium by mitochondria. J Bioenerg Biomembr 26: 471–485.PubMedCrossRefGoogle Scholar
  37. Gunther C, von Hadeln K, Muller-Thomsen T, Alberici A, Binetti G, Hock C, et al. 2004. Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease. Neurosci Lett 369: 219–223.PubMedCrossRefGoogle Scholar
  38. Gurney JG, Smith MA, Bunin GR. 1999a. CNS and miscellaneous intracranial and intraspinal neoplasms (ICCC III). Online NIH Pub. no. 99-4649. Bethesda, MD: Cancer Statistics Branch, Cancer Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute.Google Scholar
  39. Gurney JG, Wall DA, Jukich PJ, Davis FG. 1999b. The contribution of nonmalignant tumors to CNS tumor incidence rates among children in the United States. Cancer Causes Control 10: 101–105.PubMedCrossRefGoogle Scholar
  40. Halperin EC, Miranda ML, Watson DM, George SL, Stanberry M. 2004. Medulloblastoma and birth date: evaluation of 3 U.S. datasets. Arch Environ Health 59: 26–30.PubMedCrossRefGoogle Scholar
  41. Hatton BA, Knoepfler PS, Kenney AM, Rowitch DH, de Alboran IM, Olson JM, et al. 2006. N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth. Cancer Res 66: 8655–8661.PubMedCrossRefGoogle Scholar
  42. Hjalmars U, Kulldorff M, Wahlqvist Y, Lannering B. 1999. Increased incidence rates but no space-time clustering of childhood astrocytoma in Sweden, 1973–1992: a population-based study of pediatric brain tumors. Cancer 85: 2077–2090.PubMedGoogle Scholar
  43. Hoffman S, Schellinger KA, Propp JM, McCarthy BJ, Campbell RT, Davis FG. 2007. Seasonal variation in incidence of pediatric medulloblastoma in the United States, 1995–2001. Neuroepidemiology 29: 89–95.PubMedCrossRefGoogle Scholar
  44. Humphrey ML, Cole MP, Pendergrass JC, Kiningham KK. 2005. Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma cell line (SK-N-SH). Neurotoxicology 26: 407–416.PubMedCrossRefGoogle Scholar
  45. IARC. 1998. In: International incidence of childhood cancer (Parkin DM, Kramarova E, Draper GJ, Masuyer E, Michaelis J, Neglia JP, et al., eds.). Lyon: International Agency for Research on Cancer.Google Scholar
  46. Jirtle RL, Skinner MK. 2007. Environmental epigenomics and disease susceptibility. Nat Rev Genet 8: 253–262.PubMedCrossRefGoogle Scholar
  47. Jukich PJ, McCarthy BJ, Surawicz TS, Freels S, Davis FG. 2001. Trends in incidence of primary brain tumors in the United States, 1985–1994. Neuro Oncol 3: 141–151.PubMedGoogle Scholar
  48. Kafadar AM, Yilmaz H, Kafadar D, Ergen A, Zeybek U, Bozkurt N, et al. 2006. C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in meningiomas and high-grade gliomas. Anticancer Res 26: 2445–2449.PubMedGoogle Scholar
  49. Kaiser J. 1999. No meeting of minds on childhood cancer. Science 286: 1832–1834.PubMedCrossRefGoogle Scholar
  50. Kang D, Kim SH, Hamasaki N. 2007. Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 7: 39–44.PubMedCrossRefGoogle Scholar
  51. Katayam M, Yoshida K, Ishimori H, Katayama M, Kawase T, Motoyama J, et al. 2002. Patched and smoothened mRNA expression in human astrocytic tumors inversely correlates with histological malignancy. J Neurooncol 59: 107–115.PubMedCrossRefGoogle Scholar
  52. Khan MA, Van DJ, Yeung IW, Hill RP. 2003. Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers. Radiother Oncol 66: 95–102.PubMedCrossRefGoogle Scholar
  53. Kiebish MA, Seyfried TN. 2005. Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors. BMC Cancer 5: 102.PubMedCrossRefGoogle Scholar
  54. Kim EH, Sohn S, Kwon HJ, Kim SU, Kim MJ, Lee SJ, et al. 2007. Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res 67: 6314–6324.PubMedCrossRefGoogle Scholar
  55. Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B. 1988. The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature 332: 371–374.PubMedCrossRefGoogle Scholar
  56. Kirches E, Michael M, Woy C, Schneider T, Warich-Kirches M, Schneider-Stock R, et al. 1999. Loss of heteroplasmy in the displacement loop of brain mitochondrial DNA in astrocytic tumors. Genes Chromosomes Cancer 26: 80–83.PubMedCrossRefGoogle Scholar
  57. Kontush A. 2001. Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer’s disease. Free Radic Biol Med 31: 1120–1131.PubMedCrossRefGoogle Scholar
  58. Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Theoret Y, Moghrabi A, et al. 2004. Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood 103: 252–257.PubMedCrossRefGoogle Scholar
  59. Kulawiec M, Safina A, Desouki MM, Still I, Matsui SI, Bakin A, et al. 2008. Tumorigenic transformation of human breast epithelial cells induced by mitochondrial DNA depletion. Cancer Biol Ther 7(11): 1732–1743.PubMedCrossRefGoogle Scholar
  60. Kurtz A, Lueth M, Kluwe L, Zhang T, Foster R, Mautner VF, et al. 2004. Somatic mitochondrial DNA mutations in neurofibromatosis type 1-associated tumors. Mol Cancer Res 2: 433–441.PubMedGoogle Scholar
  61. Lai R, Crevier L, Thabane L. 2005. Genetic polymorphisms of glutathione S-transferases and the risk of adult brain tumors: a meta-analysis. Cancer Epidemiol Biomarkers Prev 14: 1784–1790.PubMedCrossRefGoogle Scholar
  62. Larsson NG, Luft R. 1999. Revolution in mitochondrial medicine. FEBS Lett 455: 199–202.PubMedCrossRefGoogle Scholar
  63. Lee WC, Choi CH, Cha SH, Oh HL, Kim- YK. 2005. Role of ERK in hydrogen peroxide-induced cell death of human glioma cells. Neurochem Res 30: 263–270.PubMedCrossRefGoogle Scholar
  64. Lemasters GK, Perreault SD, Hales BF, Hatch M, Hirshfield AN, Hughes CL, et al. 2000. Workshop to identify critical windows of exposure for children’s health: reproductive health in children and adolescents work group summary. Environ Health Perspect 108(Suppl 3): 505–509.PubMedCrossRefGoogle Scholar
  65. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. 2005. White matter involvement in mitochondrial diseases. Mol Genet Metab 84: 127–136.PubMedCrossRefGoogle Scholar
  66. Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL, et al. 2004. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol 63: 499–509.PubMedGoogle Scholar
  67. Linet MS, Ries LA, Smith MA, Tarone RE, Devesa SS. 1999. Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States. J Natl Cancer Inst 91: 1051–1058.PubMedCrossRefGoogle Scholar
  68. Magnani C, Dalmasso P, Pastore G, Terracini B, Martuzzi M, Mosso ML, et al. 2003. Increasing incidence of childhood leukemia in Northwest Italy, 1975–98. Int J Cancer 105: 552–557.PubMedCrossRefGoogle Scholar
  69. Malthankar GV, White BK, Bhushan A, Daniels CK, Rodnick KJ, Lai JC. 2004. Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid (TCA) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with manganese-induced cell death. Neurochem Res 29: 709–717.PubMedCrossRefGoogle Scholar
  70. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. 2006. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15: 1437–1449.PubMedCrossRefGoogle Scholar
  71. Manshande JP, Van TJ, Coppens M, Casaer P. 1985. Seasonal variation in incidence of cerebellar medulloblastoma. Brain Dev 7: 525–526.PubMedCrossRefGoogle Scholar
  72. Marino S. 2005. Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11: 17–22.PubMedCrossRefGoogle Scholar
  73. Maris JM. 2005. The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr 17: 7–13.PubMedCrossRefGoogle Scholar
  74. Marks N, Berg MJ. 1999. Recent advances on neuronal caspases in development and neurodegeneration. Neurochem Int 35: 195–220.PubMedCrossRefGoogle Scholar
  75. Mavelli I, Rigo A, Federico R, Ciriolo MR, Rotilio G. 1982. Superoxide dismutase, glutathione peroxidase and catalase in developing rat brain. Biochem J 204: 535–540.PubMedGoogle Scholar
  76. McNally RJ, Kelsey AM, Cairns DP, Taylor GM, Eden OB, Birch JM. 2001. Temporal increases in the incidence of childhood solid tumors seen in Northwest England (1954–1998) are likely to be real. Cancer 92: 1967–1976.PubMedCrossRefGoogle Scholar
  77. McNeil DE, Cote TR, Clegg L, Rorke LB. 2002. Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance Epidemiology and End Results. Med Pediatr Oncol 39: 190–194.PubMedCrossRefGoogle Scholar
  78. Meadows AT, Baum E, Fossati-Bellani F, Green D, Jenkin RD, Marsden B, et al. 1985. Second malignant neoplasms in children: an update from the Late Effects Study Group. J Clin Oncol 3: 532–538.PubMedGoogle Scholar
  79. Mealey J Jr., Hall PV. 1977. Medulloblastoma in children. Survival and treatment. J Neurosurg 46: 56–64.PubMedCrossRefGoogle Scholar
  80. Melov S, Lithgow GJ, Fischer DR, Tedesco PM, Johnson TE. 1995. Increased frequency of deletions in the mitochondrial genome with age of Caenorhabditis elegans. Nucleic Acids Res 23: 1419–1425.PubMedCrossRefGoogle Scholar
  81. Modica-Napolitano JS, Singh KK. 2002. Mitochondria as targets for detection and treatment of cancer. Expert Rev Mol Med 4: 1–19.PubMedCrossRefGoogle Scholar
  82. Montanini L, Regna-Gladin C, Eoli M, Albarosa R, Carrara F, Zeviani M, et al. 2005. Instability of mitochondrial DNA and MRI and clinical correlations in malignant gliomas. J Neurooncol 74: 87–89.PubMedCrossRefGoogle Scholar
  83. National Cancer Institute NIoNDaS. 2000. Report of the Brain Tumor Progress Review Group. NIH Publication Number 01-4902.Google Scholar
  84. National Institutes of Health. 2002. What you need to know about brain tumors. Bethesda, MD: National Cancer Institute.Google Scholar
  85. Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, et al. 1991. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325: 1330–1336.PubMedCrossRefGoogle Scholar
  86. Neri M, Fucic A, Knudsen LE, Lando C, Merlo F, Bonassi S. 2003. Micronuclei frequency in children exposed to environmental mutagens: a review. Mutat Res 544: 243–254.PubMedCrossRefGoogle Scholar
  87. Neri M, Ugolini D, Bonassi S, Fucic A, Holland N, Knudsen LE, et al. 2006. Children’s exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis. Mutat Res 612: 14–39.PubMedCrossRefGoogle Scholar
  88. Ohta S. 2006. Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs. Oncogene 25: 4768–4776.PubMedCrossRefGoogle Scholar
  89. Olshan AF, Anderson L, Roman E, Fear N, Wolff M, Whyatt R, et al. 2000. Workshop to identify critical windows of exposure for children’s health: cancer work group summary. Environ Health Perspect 108(Suppl 3): 595–597.PubMedCrossRefGoogle Scholar
  90. Park SY, Chang I, Kim J, Kang SW, Park S, Singh K, et al. 2004. Resistance of mitochondrial DNA-depleted cells against cell death. J Biol Chem 279: 7512–7520.PubMedCrossRefGoogle Scholar
  91. Penta JS, Johnson FM, Wachsman JT, Copeland WC. 2001. Mitochondrial DNA in human malignancy. Mutat Res 488: 119–133.PubMedCrossRefGoogle Scholar
  92. Perera F, Hemminki K, Jedrychowski W, Whyatt R, Campbell U, Hsu Y, et al. 2002. In utero DNA damage from environmental pollution is associated with somatic gene mutation in newborns. Cancer Epidemiol Biomarkers Prev 11: 1134–1137.PubMedGoogle Scholar
  93. Pouliquen D, Olivier C, Hervouet E, Pedelaborde F, Debien E, Le Cabellec MT, et al. 2008. Dietary prevention of malignant glioma aggressiveness, implications in oxidant stress and apoptosis. Int J Cancer 123: 288–295.PubMedCrossRefGoogle Scholar
  94. Preston-Martin S, Munir R, Chakrabarti I. 2006. Neoplasms of the nervous system. In: Cancer Epidemiology and Prevention (Schottenfield D, Fraumeni JF, eds.). New York, NY: Oxford University Press.Google Scholar
  95. Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. 1993. Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262: 695–700.PubMedCrossRefGoogle Scholar
  96. Rahman S, Hargreaves I, Clayton P, Heales S. 2001. Neonatal presentation of coenzyme Q10 deficiency. J Pediatr 139: 456–458.PubMedCrossRefGoogle Scholar
  97. Rajaraman P, Stewart PA, Samet JM, Schwartz BS, Linet MS, Zahm SH, et al. 2006. Lead, genetic susceptibility, and risk of adult brain tumors. Cancer Epidemiol Biomarkers Prev 15: 2514–2520.PubMedCrossRefGoogle Scholar
  98. Rao G, Pedone CA, Del VL, Reiss K, Holland EC, Fults DW. 2004. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23: 6156–6162.PubMedCrossRefGoogle Scholar
  99. Rasmussen AK, Chatterjee A, Rasmussen LJ, Singh KK. 2003. Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae. Nucleic Acids Res 31: 3909–3917.PubMedCrossRefGoogle Scholar
  100. Read TA, Hegedus B, Wechsler-Reya R, Gutmann DH. 2006. The neurobiology of neurooncology. Ann Neurol 60: 3–11.PubMedCrossRefGoogle Scholar
  101. Reed JC. 1997. Bcl-2 family proteins and the hormonal control of cell life and death in normalcy and neoplasia. Vitam Horm 53: 99–138.PubMedCrossRefGoogle Scholar
  102. Rice JM. 2006. Inducible and transmissible genetic events and pediatric tumors of the nervous system. J Radiat Res (Tokyo) 47(Suppl B): B1–B11.CrossRefGoogle Scholar
  103. Rice JM, Ward JM. 1982. Age dependence of susceptibility to carcinogenesis in the nervous system. Ann N Y Acad Sci 381: 274–289.PubMedCrossRefGoogle Scholar
  104. Rice JM, Wilbourn JD. 2000. Tumors of the nervous system in carcinogenic hazard identification. Toxicol Pathol 28: 202–214.PubMedCrossRefGoogle Scholar
  105. Robertson JD, Gogvadze V, Kropotov A, Vakifahmetoglu H, Zhivotovsky B, Orrenius S. 2004. Processed caspase-2 can induce mitochondria-mediated apoptosis independently of its enzymatic activity. EMBO Rep 5: 643–648.PubMedCrossRefGoogle Scholar
  106. Robertson CL, Soane L, Siegel ZT, Fiskum G. 2006. The potential role of mitochondria in pediatric traumatic brain injury. Dev Neurosci 28: 432–446.PubMedCrossRefGoogle Scholar
  107. Rodier PM. 1995. Developing brain as a target of toxicity. Environ Health Perspect 103(Suppl 6): 73–76.PubMedCrossRefGoogle Scholar
  108. Ron E, Modan B, Boice JD Jr., Alfandary E, Stovall M, Chetrit A, et al. 1988. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319: 1033–1039.PubMedCrossRefGoogle Scholar
  109. Roy D, Cai Q, Felty Q, Narayan S. 2007. Estrogen-induced generation of reactive oxygen and nitrogen species, gene damage, and estrogen-dependent cancers. J Toxicol Environ Health B Crit Rev 10: 235–257.PubMedCrossRefGoogle Scholar
  110. Rustin P. 2002. Mitochondria, from cell death to proliferation. Nat Genet 30: 352–353.PubMedCrossRefGoogle Scholar
  111. Sadler TW. 2000. Susceptible periods during embryogenesis of the heart and endocrine glands. Environ Health Perspect 108(Suppl 3): 555–561.PubMedCrossRefGoogle Scholar
  112. Samuelsen SO, Bakketeig LS, Tretli S, Johannesen TB, Magnus P. 2006. Head circumference at birth and risk of brain cancer in childhood: a population-based study. Lancet Oncol 7: 39–42.PubMedCrossRefGoogle Scholar
  113. Scarpulla RC. 2008. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci 1147: 321–334.PubMedCrossRefGoogle Scholar
  114. Schoenberg BS, Schoenberg DG, Christine BW, Gomez MR. 1976. The epidemiology of primary intracranial neoplasms of childhood. A population study. Mayo Clin Proc 51: 51–56.PubMedGoogle Scholar
  115. Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, et al. 2008. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14: 123–134.PubMedCrossRefGoogle Scholar
  116. Schwartzbaum JA, Ahlbom A, Lonn S, Warholm M, Rannug A, Auvinen A, et al. 2007. An international case-control study of glutathione transferase and functionally related polymorphisms and risk of primary adult brain tumors. Cancer Epidemiol Biomarkers Prev 16: 559–565.PubMedCrossRefGoogle Scholar
  117. Searles NS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. 2005. Risk of brain tumors in children and susceptibility to organophosphorus insecticides: the potential role of paraoxonase (PON1). Environ Health Perspect 113: 909–913.CrossRefGoogle Scholar
  118. Singh KK, Kulawiec M, Still I, Desouki MM, Geradts J, Matsui S. 2005. Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene 354: 140–146.PubMedCrossRefGoogle Scholar
  119. Sirachainan N, Wongruangsri S, Kajanachumpol S, Pakakasama S, Visudtibhan A, Nuchprayoon I, et al. 2008. Folate pathway genetic polymorphisms and susceptibility of central nervous system tumors in Thai children. Cancer Detect Prev 32: 72–78.PubMedCrossRefGoogle Scholar
  120. Slikker W III, Mei N, Chen T. 2004. N-ethyl-N-nitrosourea (ENU) increased brain mutations in prenatal and neonatal mice but not in the adults. Toxicol Sci 81: 112–120.PubMedCrossRefGoogle Scholar
  121. Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK. 2008. A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther 7: 1182–1190.PubMedCrossRefGoogle Scholar
  122. Smith MA, Freidlin B, Ries LA, Simon R. 1998. Trends in reported incidence of primary malignant brain tumors in children in the United States. J Natl Cancer Inst 90: 1269–1277.PubMedCrossRefGoogle Scholar
  123. Stavrovskaya IG, Kristal BS. 2005. The powerhouse takes control of the cell: is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death? Free Radic Biol Med 38: 687–697.PubMedCrossRefGoogle Scholar
  124. Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, Lacour B, et al. 2004. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCISproject): an epidemiological study. Lancet 364: 2097–2105.PubMedCrossRefGoogle Scholar
  125. Suliman HB, Carraway MS, Welty-Wolf KE, Whorton AR, Piantadosi CA. 2003. Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1. J Biol Chem 278: 41510–41518.PubMedCrossRefGoogle Scholar
  126. Taanman JW. 1999. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1410: 103–123.PubMedCrossRefGoogle Scholar
  127. Tedeschi-Blok N, Lee M, Sison JD, Miike R, Wrensch M. 2006. Inverse association of antioxidant and phytoestrogen nutrient intake with adult glioma in the San Francisco Bay Area: a case-control study. BMC Cancer 6: 148.PubMedCrossRefGoogle Scholar
  128. Thannickal VJ, Fanburg BL. 2000. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279: L1005–L1028.PubMedGoogle Scholar
  129. Thompson JR, Gerald PF, Willoughby ML, Armstrong BK. 2001. Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet 358: 1935–1940.PubMedCrossRefGoogle Scholar
  130. Van RH, Salvador C, Yang H, Huang TT, Epstein CJ, Richardson A. 1999. Characterization of the antioxidant status of the heterozygous manganese superoxide dismutase knockout mouse. Arch Biochem Biophys 363: 91–97.CrossRefGoogle Scholar
  131. Vasko MR, Guo C, Kelley MR. 2005. The multifunctional DNA repair/redox enzyme Ape1/Ref-1 promotes survival of neurons after oxidative stress. DNA Repair (Amst) 4: 367–379.CrossRefGoogle Scholar
  132. Vega A, Salas A, Gamborino E, Sobrido MJ, Macaulay V, Carracedo A. 2004. mtDNA mutations in tumors of the central nervous system reflect the neutral evolution of mtDNA in populations. Oncogene 23: 1314–1320.PubMedCrossRefGoogle Scholar
  133. Von BJ, Reynolds P. 2003. Birth characteristics and brain cancers in young children. Int J Epidemiol 32: 248–256.CrossRefGoogle Scholar
  134. Wong-Riley MT. 1989. Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci 12: 94–101.PubMedCrossRefGoogle Scholar
  135. Wright J. 1910. Neurocytoma and neuroblastomas, a kind of tumor not generally recognized. J Exp Med 12: 556–561.PubMedCrossRefGoogle Scholar
  136. Xanthoudakis S, Curran T. 1996. Redox regulation of AP-1: a link between transcription factor signaling and DNA repair. Adv Exp Med Biol 387: 69–75.PubMedGoogle Scholar
  137. Yamakawa Y, Fukui M, Kinoshita K, Ohgami S, Kitamura K. 1979. Seasonal variation in incidence of cerebellar medulloblastoma by month of birth. Fukuoka Igaku Zasshi 70: 295–300.PubMedGoogle Scholar
  138. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, et al. 2008. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14: 135–145.PubMedCrossRefGoogle Scholar
  139. Zhong W, Oberley LW, Oberley TD, Yan T, Domann FE, St Clair DK. 1996. Inhibition of cell growth and sensitization to oxidative damage by overexpression of manganese superoxide dismutase in rat glioma cells. Cell Growth Differ 7: 1175–1186.PubMedGoogle Scholar

Copyright information

© Springer Science+ Business Media, LLC 2010

Authors and Affiliations

  • Brian Kunkle
    • 1
  • David Sandberg
    • 2
  • Prasanna Jayakar
    • 2
  • Quentin Felty
    • 3
  • Deodutta Roy
    • 4
    Email author
  1. 1.Department of Environmental and Occupational HealthRobert Stempel College of Public Health, Florida International UniversityMiamiUSA
  2. 2.Department of Neurological SurgerySchool of Medicine, Miami Children’s Hospital, University of MiamiMiamiUSA
  3. 3.Department of Environmental and Occupational HealthFIU Stempel School of Public Health, Florida International UniversityMiamiUSA
  4. 4.Department of Environmental and Occupational HealthRobert Stempel College of Public Health & Social Work, Florida International UniversityMiamiUSA

Personalised recommendations