Genetic Alterations of Nervous System Tumors

  • Robert L. Martuza


The last decade has witnessed revolutionary advances in our understanding of the basic molecular changes associated with carcinogenesis in general and with nervous system tumorigenesis in particular. This report discusses the genetic alterations in nervous system tumors from two viewpoints. The first represents a summary of the descriptive changes that have been documented in various nervous system tumors. Here, the molecular and chromosomal changes associated with schwannomas, meningiomas, gliomas, and other nervous system tumors are described. These represent the naturally occurring genetic alterations associated with tumorigenesis and tumor progression. The second discusses alterations in tumor cells that may be purposefully induced in order to study their cellular biology or to test novel therapeutic approaches. This section represents a new era in tumor studies which is still in its elemental stages, but its impact could result in the development of new therapies for some tumors which are invariably fatal despite maximal conventional therapy.


Epidermal Growth Factor Receptor Thymidine Kinase Epidermal Growth Factor Receptor Gene Acoustic Neuroma Normal Brain Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Martuza RL, Eldridge, R (1988) Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318: 684–688PubMedCrossRefGoogle Scholar
  2. 2.
    Zankl H, Zang KD (1972) Cytological and cytogenetical studies on brain tumors. IV. Identification of the missing G chromosome in human meningiomas as no. 22 by fluorescence technique. Hum Genet 14: 167–169CrossRefGoogle Scholar
  3. 3.
    Seizinger BR, Martuza RL, Gusella JF (1986) Loss of genes on chromosome 22 in tumorigenesis of acoustic neuroma. Nature 322: 644–647PubMedCrossRefGoogle Scholar
  4. 4.
    Seizinger BR, Rouleau G, Ozelius LJ, Lane AH, St. George-Hyslop P, Huson S. Gusella JF, Martuza RL (1987). Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis. Science 236:317–319PubMedCrossRefGoogle Scholar
  5. 5.
    Rouleau GA, Wertelecki W, Haines JL, Hobbs WJ, Trofatter JA, Seizinger BR, Martuza RL, Superneau DW, Conneally PM, Gusella JF (1987) Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature 329: 246–248PubMedCrossRefGoogle Scholar
  6. 6.
    Rouleau GA, Seizinger BR, Wertelecki W, Haines JL, Superneau DW, Martuza RL, Gusella JF (1990) Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22. Am J Hum Genet 46: 323–328PubMedGoogle Scholar
  7. 7.
    Seizinger BR, de la Monte S, Atkins L, Gusella JF, Martuza RL (1987) Molecular genetic approach to human meningioma: Loss of genes on chromosome 22. Proc Natl Acad Sei USA 84: 5419–5423Google Scholar
  8. 8.
    Logan JA, Seizinger BR, Atkins L, Martuza RL (1990) Loss of the Y chromosome in meningiomas: A molecular genetic approach. Cancer Genet Cytogenet 45: 41–47Google Scholar
  9. 9.
    Dumanski JP, Rouleau GA, Nordenskjold M, Collins VP (1990) Molecular genetic analysis of chromosome 22 in 81 cases of meningioma. Cancer Res 50: 5863–5867PubMedGoogle Scholar
  10. 10.
    Bigner SH, Mark J, Mahaley MS Jr, Bigner DD (1984) Patterns of the early, gross chromosomal changes in malignant human gliomas. Hereditas 101: 103–113PubMedCrossRefGoogle Scholar
  11. 11.
    Bigner SH, Mark J, Burger PC, Mahaley MS Jr, Bullard DE, Muhlbaier LH, Bigner DD (1988) Specific chromosomal abnormalities in malignant human gliomas. Cancer Res 88: 405–411Google Scholar
  12. 12.
    Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schiessinger J (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumors of glial origin. Nature 313: 144–147PubMedCrossRefGoogle Scholar
  13. 13.
    Wong AJ, Bigner SH, Kinzler KW, Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sei USA 84:6899– 6903Google Scholar
  14. 14.
    Maiden LT, Novak U, Kaye AH, Burgess AW (1988) Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res 48: 2711–2714Google Scholar
  15. 15.
    Trent J, Meitzer P, Rosenblum M, Harsh G, Kinzler K, Mashai R, Feinberg A, Vogelstein B (1986) Evidence for rearrangement, amplification, and expression of c-myc in a human glioblastoma. Proc Natl Acad Sei USA 83: 470–473CrossRefGoogle Scholar
  16. 16.
    Hermansson M, Nister M, Betsholtz C, Heldin C-H, Westermark B, Funa K (1988) Endothelial cell hyperplasia in human glioblastoma: Coexpression of mRNA for platelet-derived growth factor ( PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sei USA 85: 7748–7752CrossRefGoogle Scholar
  17. 17.
    Maxwell M, Naber SP, Wolfe HJ, Galanopoulos T, Hedley-Whyte ET, Black P McL, Antoniades HN (1990) Coexpression of platelet-derived growth factor ( PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest 86: 131–140PubMedCrossRefGoogle Scholar
  18. 18.
    Birchmeier C, Sharma S, Wigler M (1987) Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sei USA 84: 9270–9274CrossRefGoogle Scholar
  19. 19.
    Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O’Brien SJ, Wong AJ, Vogelstein B (1987) Identification of and amplified, highly expressed gene in a human glioma. Science 236: 70–73PubMedCrossRefGoogle Scholar
  20. 20.
    James CD, Carlbom E, Dumanski JP, Hansen M, Nordenskjold M, Collins VP, Cavenee WK (1988) Clonal genomic alterations in glioma malignancy stages. Cancer Res 48: 5546–5551PubMedGoogle Scholar
  21. 21.
    El-Azouzi M, Chung R, Farmer GE, Martuza RL, Black PMcL, Rouleau GA, Hettlich C, Hedley-Whyte ET, Zervas NT, Panagopoulos K, Nakamura Y, Gusella JF, Seizinger BR (1989). Loss of distinct regions on the short arm of chromosome 17 associated with tumorigenesis of human astrocytomas. Proc Natl Acad Sei USA 86: 7186–7190CrossRefGoogle Scholar
  22. 22.
    James CD, Carlbom E, Nordenskjold M, Collins VP, Cavenee WK (1989) Mitotic recombination of chromosome 17 in astrocytomas. Proc Natl Acad Sei USA 86: 2858–2862CrossRefGoogle Scholar
  23. 23.
    Mercer WE, Shields MT, AMin M, Sauve GJ, Appella E, Romano JW, Ullrich SJ (1990) Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sei USA 87: 6166–6170CrossRefGoogle Scholar
  24. 24.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AMM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319: 525–532PubMedCrossRefGoogle Scholar
  25. 25.
    Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK (1990) Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sei USA 87: 5863–5867CrossRefGoogle Scholar
  26. 26.
    Levine AL, Momand J (1990) Tumor suppressor genes: The p53 gene and the retinoblastoma sensitivity gene and gene products. Biochim Biophys Acta 1032: 119–136PubMedGoogle Scholar
  27. 27.
    Rubenstein AE, Bunge BP, Housman DE (eds) (1986) Neurofibromatosis. Ann NY Acad Sei 486: 1–414Google Scholar
  28. 28.
    Blatt J, Jaffe R, Deutsch M, Adkins JC (1986) Neurofibromatosis and childhood tumors. Cancer 57: 1225–1229PubMedCrossRefGoogle Scholar
  29. 29.
    Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D, Bishop DT, Carey J, Baty B, Kivlin J, Willard H, Waye JS, Greig G, Leinwand L, Nakamura Y, O’Connell P, Leppert M, Lalouel J-M, White R, Skolnick M (1987) Science 236: 1100–1102PubMedCrossRefGoogle Scholar
  30. 30.
    Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Fayniarz AG, Chao MV, Huson S, Korf BR, Parry DM, Pericak-Vance MA, Collins FS, Hobbs WJ, Falcone BG, Iannazzi JA, Roy JC, St George-Hyslop PH, Tanzi RE, Bothwell MA, Upadhyaya M, Harper P, Goldstein AE, Hoover DL, Bader JL, Spence MA, Mulvihill JJ, Ayslworth AS, Vance JM, Rosenwasser GOD, Gaskell PC, Roses AD, Martuza RL, Breakefield XO, Gusella JF (1987) Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell 49: 589–594PubMedCrossRefGoogle Scholar
  31. 31.
    Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, Brownstein BH, Collins FS (1990) Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients. Science 249: 181–186PubMedCrossRefGoogle Scholar
  32. 32.
    Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O’Connell P (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62: 187–192PubMedCrossRefGoogle Scholar
  33. 33.
    Cawthon RM, Weiss R, Xu G, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O’Connell P, White R (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62: 193–201PubMedCrossRefGoogle Scholar
  34. 34.
    Xu G, O’Connell P, Viskochil D, Cawthon RM, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, Weiss R (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62: 599–608PubMedCrossRefGoogle Scholar
  35. 35.
    Hall A (1990) ras and GAP Who’s controlling whom? Cell 61:921–923Google Scholar
  36. 36.
    Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP, Barker DF, Ledbetter DH, Kleider A, Martuza RL, Gusella JF, Seizinger BR (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci USA 87: 5435–5439PubMedCrossRefGoogle Scholar
  37. 37.
    Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastom. Proc Natl Acad Sci USA 87: 4207–4211PubMedCrossRefGoogle Scholar
  38. 38.
    Yaish P, Gazit A, Gilon C, Levitzki A (1988) Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242: 933–935PubMedCrossRefGoogle Scholar
  39. 39.
    Huang H-J S, Yee J-K, Shew J-Y, Chen P-L, Bookstein R, Friedmann T, Lee EY-H P, Lee W-H (1988) Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 242: 1563–1566PubMedCrossRefGoogle Scholar
  40. 40.
    Baker SJ, Markowitz S, Fearnon ER, Willson JKV, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912– 915Google Scholar
  41. 41.
    Cone Rd, Mulligan RC (1984) High-efficiency gene transfer into mammalian cells: Generation of helper-free recombinant retrovirus with broad mammalian host range. Proc Natl Acad Sci USA 81: 6349–6353Google Scholar
  42. 42.
    Cepko C (1989) Immortalization of neural cells via retro virus-mediated oncogene transduction. Annu Rev Neurosci 12: 47–65PubMedCrossRefGoogle Scholar
  43. 43.
    Price J, Turner D, Cepko C (1987) Lineage analysis in the vertebrate nervous system by retro virus-mediated gene transfer. Proc Natl Acad Sci USA 84: 156–160PubMedCrossRefGoogle Scholar
  44. 44.
    Short MP, Choi B, Lee J-K, Malick A, Breakefield XO, Martuza RL (to be published) Gene delivery to glioma cells in rat brain by grafting of a retrovirus packaging cell line. J Neurosci ResGoogle Scholar
  45. 45.
    Moolten F (1986) Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: Paradigm for a prospective cancer control strategy. Cancer Res 46: 5276–5281PubMedGoogle Scholar
  46. 46.
    Chiocca EA, Choi BB, Cai W, DeLuca NA, Schaffer PA, DiFiglia M, Breakefield XO, Martuza RL (1990) Transfer and expression of the lacZ gene in rat brain neurons mediated by herpes simplex virus mutants. The New Biologist 2: 739–746PubMedGoogle Scholar
  47. 47.
    Field HJ and Wildy P (1978) The pathogenicity of thymidine kinase-deficient mutants of herpes simplex virus in mice. J Hyg (Camb) 81: 267–277CrossRefGoogle Scholar
  48. 48.
    Coen DM, Kosz-Vnenchak M, Jacobson JG, Leib DA, Bogard CL, Schaffer PA, Tyler KL, Knipe DM (1989) Thymidine kinase-negative herpes simplex mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci USA 86: 4736–4740PubMedCrossRefGoogle Scholar
  49. 49.
    Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM (1991) Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252: 854–856PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1991

Authors and Affiliations

  • Robert L. Martuza
    • 1
  1. 1.Molecular Neurogenetics LaboratoryMassachusetts General HospitalCharlestownUSA

Personalised recommendations