Journal of Neuro-Oncology

, Volume 58, Issue 2, pp 107–114 | Cite as

Prognostic Value of Loss of Heterozygosity around three Candidate Tumor Suppressor Genes on Chromosome 10q in Astrocytomas

  • Kinya Terada
  • Takashi Tamiya
  • Shigeru Daido
  • Hirokazu Kambara
  • Hiroaki Tanaka
  • Yasuhiro Ono
  • Kengo Matsumoto
  • Sachio Ito
  • Mamoru Ouchida
  • Takashi Ohmoto
  • Kenji Shimizu


We thoroughly examined loss of heterozygosity (LOH) around three candidate tumor suppressor genes on chromosome 10q to determine whether LOH of each tumor suppressor gene is associated with the previously defined clinical prognostic indices. We also examined whether LOH can help predict prognostic variables in astrocytomas.

We selected samples from 40 astrocytomas (grades 2–4), performed Ki-67 immunostaining, and counted positive cells. Using DNA from aliquots of tumor blocks and leukocytes, we investigated LOH around the PTEN, NEURL, and DMBT1 genes (10q23.3–26.1) with the silver staining procedure. We then statistically evaluated the relationship among histological features, regional LOH on chromosome 10q, and survival. The mean survival period for patients with LOH around PTEN was 7.2 months after surgery, while that for patients without LOH around PTEN was 21.4 months. Thus, LOH around PTEN was closely associated with a reduced overall survival (p = 0.0020) but LOH at NEURL or DMBT1 was not (p > 0.05).

The combined features of an increase in histological grading and Ki-67-positive cells and the presence of LOH around PTEN significantly correlated with poor prognosis. These factors may be useful predictors of survival, and LOH analysis of tumor suppressor genes on chromosome 10q can contribute greatly to the treatment of patients with astrocytoma.

allelic loss brain tumor DMBT1 NEURL prognosis PTEN 


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  1. 1.
    Report of the Medical Research Council Brain Tumour Working Party. Prognostic factors for high-grade malignant glioma: development of a prognostic index. J Neuro-Oncol 9: 47–55, 1990Google Scholar
  2. 2.
    Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukada Y: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A Joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer 52: 997–1007, 1983Google Scholar
  3. 3.
    Bruner JM: Neuropathology of malignant gliomas. Semin Oncol 21: 126–138, 1994Google Scholar
  4. 4.
    Barker FG, Davis RL, Chang SM, Prados MD: Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 77: 1161–1166, 1996Google Scholar
  5. 5.
    Krouwer HG, Davis RL, Silver P, Prados M: Gemistocytic astrocytomas: a reappraisal. J Neurosurg 74: 399–406, 1991Google Scholar
  6. 6.
    Ono Y, Tamiya T, Ichikawa T, Kunishio K, Matsumoto K, Furuta T, Ohmoto T, Ueki K, Louis DN: Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher KI-67 proliferation indices. J Neuropathol Exp Neurol 55: 1026–1031, 1996Google Scholar
  7. 7.
    Ono Y, Tamiya T, Ichikawa T, Matsumoto K, Furuta T, Ohmoto T, Akiyama K, Seki S, Ueki K, Louis DN: Accumulation of wild-type p53 in astrocytomas is associated with increased p21 expression. Acta Neuropathol 94: 21–27, 1997Google Scholar
  8. 8.
    Mizumatsu S, Tamiya T, Ono Y, Abe T, Matsumoto K, Furuta T, Ohmoto T: Expression of cell-cycle regulator p27Kip1 correlates with survival in patients with astrocytoma. Clin Cancer Res 5: 551–557, 1999Google Scholar
  9. 9.
    Tamiya T, Mizumatsu S, Ono Y, Abe T, Matsumoto K, Furuta T, Ohmoto T: High cyclin E/low p27Kip1 expression is associated with poor prognosis in astrocytomas. Acta Neuropathol 101: 334–340, 2001Google Scholar
  10. 10.
    Weber RG, Sabel M, Reifenberger J, Sommer C, Oberstrass J, Reifenberger G, Kiessling M, Cremer T: Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. Oncogene 13: 983–994, 1996Google Scholar
  11. 11.
    Collins VP: Gene amplification in human gliomas. Glia 15: 289–296, 1995Google Scholar
  12. 12.
    Louis DN, Gusella JF: A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet 11: 412–415, 1993Google Scholar
  13. 13.
    von Deimling A, Louis DN, Wiestler OD: Molecular pathways in the formation of gliomas. Glia 15: 328–338, 1995Google Scholar
  14. 14.
    Rasheed BKA, McLendon RE, Herndon JE, Friedman HS, Friedman AH, Bigner DD, Bigner SH: Alterations of the TP53 gene in human gliomas. Cancer Res 54: 1324–1330, 1994Google Scholar
  15. 15.
    Rainov NG, Dobberstein KU, Bahn H, Holzhausen HJ, Lautenschlager C, Heidecke V, Burkert W: Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival. J Neuro-Oncol 35: 13–28, 1997Google Scholar
  16. 16.
    Leenstra S, Oscam NT, Buleveld EH, Bosch DA, Troost D, Hulsebos TJM: Genetic subtype of human malignant astrocytoma correlate with survival. Int J Cancer 79: 159–165, 1998Google Scholar
  17. 17.
    Ino Y, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Jhung S, Ramsay DA, von Deimling A, Louis DN, Cairncross JG: Long survival and therapeutic responses in patients with histologically disparate high-grade gliomas demonstrating chromosome 1p loss. J Neurosurg 92: 983–990, 2000Google Scholar
  18. 18.
    Bigner SH, Mark J, Bigner DD:Cytogenetics of human brain tumours. Cancer Genet Cytogenet 47: 141–154, 1990Google Scholar
  19. 19.
    Fults D, Pedone CA, Thompson GE, Uchiyama CM, Gumpper KL, Iliev D, Vinson VL, Tavtigian SV, Perry WL III: Microsatellite deletion mapping on chromosome 10q and mutation analysis of MMAC1, FAS and MXI1 in human glioblastoma multiforme. Int J Oncol 12: 905–910, 1998Google Scholar
  20. 20.
    Ichimura K, Schmidt EE, Miyakawa A, Goike HM, Collins VP: Distinct patterns of deletion on 10p and 10q suggest involvement of multiple tumor suppressor genes in the development of astrocytic gliomas of different malignancy grades. Genes Chromosomes Cancer 22: 9–15, 1998Google Scholar
  21. 21.
    Maier D, Comparone D, Taylor E, Zhang Z, Gratzl O, Meir EGV, Scot RJ, Merlo A: New deletion in low-grade oligodendroglioma at the glioblastoma suppressor locus on chromosome 10q25-26. Oncogene 15: 997–1000, 1997Google Scholar
  22. 22.
    Albarosa R, Colombo BM, Roz L, Magnani I, Pollo B, Cirenei N, Giani C, Conti AM, DiDonato S, Finocchiaro G: Deletion mapping of gliomas suggests the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q. Am J Hum Genet 58: 1260–1267, 1996Google Scholar
  23. 23.
    Belesaria S, Brock C, Bower M, Clark J, Nicholson SK, Lewis P, Sanctis S, Evans H, Peterson D, Mendoza N, Glaser MG, Newlands ES, Fisher RA: Loss of chromosome 10 is an independent prognostic factor in high grade gliomas. Br J Cancer 81: 1371–1377, 1999Google Scholar
  24. 24.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947, 1997Google Scholar
  25. 25.
    Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, Deimling A, Poustka A: DMBT1, and new member of the SRCR superfamily, on chromosome 10q25.3-26.1 is deleted in malignant brain tumors. Nat Genet 17: 32–39, 1997Google Scholar
  26. 26.
    Steck PA, Perhouse MA, Jasser SA, Yung WKA, Lin H, Ligon AH, Langfold LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHF, Tavtigian SV: Identification of a candidate tumor suppressor gene at 10q23.3 that is mutated in multiple advanced cancers, MMAC-1. Nat Genet 15: 356–363, 1997Google Scholar
  27. 27.
    Chernova OB, Sommerville RPT, Cowell JK: A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene 17: 2873–2881, 1998Google Scholar
  28. 28.
    Nakamura H, Yoshida M, Tsuiki H, Ito K, Ueno M, Nakao M, Oka K, Tada M, Kochi M, Kuratsu J, Ushio Y, Saya H: Identification of a human homolog of the Drosophila neuralized gene within the 10q25.1 malignant astrocytoma deletion region. Oncogene 16: 1009–1019, 1998Google Scholar
  29. 29.
    Weshsler DS, Shelly CA, Petroff CA, Dang CV: MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells. Cancer Res 57: 4905–4912, 1997Google Scholar
  30. 30.
    Chen HM, Schmeichel KL, Mian IS, Lelievre S, Petersen OW, Bissell MJ: AZU-1: a candidate breast tumor suppressor and biomarker for tumor progression. Mol Biol Cell 11: 1357–1367, 2000Google Scholar
  31. 31.
    Bassam BJ, Caetano-Anolles G, Gresshoff PM: Fast and sensitive silver staining of DNA in polyacrylamide gels. Anal Biochem 196: 80–83, 1991Google Scholar
  32. 32.
    Kleihues P, Buger PC, Scheithauer BW: Histological Typing of Tumours of the Central Nervous System. WHO, International Histological Classification of Tumours. Springer-Verlag, Germany, 1993Google Scholar
  33. 33.
    Lin H, Bondy ML, Langford LA, Hess KR, Delclos GL, Wu X, Chan W, Pershouse MA, Yung WKA, Steck PA: Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Clin Cancer Res 4: 2447–2454, 1998Google Scholar
  34. 34.
    Kimmelman AC, Ross DA, Liang BC: Loss of heterozygosity of chromosome 10p in human glioblastomas. Genomics 34: 250–254, 1996Google Scholar
  35. 35.
    Sonoda Y, Murakami Y, Tominaga T, Kayama T, Yoshimoto T, Sekiya T: Deletion mapping of chromosome 10 in human glioma. Jpn J Cancer Res 87: 363–367, 1996Google Scholar
  36. 36.
    Wu W, Kemp BL, Proctor ML, Gazdar AF, Minna JD, Hong WK, Mao L: Expression of DMBT1, a candidate tumor suppressor gene, is frequently lost in lung cancer. Cancer Res 59: 1846–1851, 1999Google Scholar
  37. 37.
    Mori M, Shiraishi T, Tanaka S, Yamagata M, Mafune K, Tanaka Y, Ueo H, Barnard GF, Sugimachi K: Lack of DMBT1 expression in esophageal, gastric and colon cancers. Br J Cancer 79: 211–213, 1999Google Scholar
  38. 38.
    Leenstra S, Bijlsma EK, Troost D, Oosting J, Westerveld A, Bosch DA, Hulsebos TJ: Allele loss on chromosomes 10 and 17p and epidermal growth factor receptor gene amplification in human malignant astrocytoma related to prognosis. Br J Cancer 70: 684–689, 1994Google Scholar
  39. 39.
    Ganju V, Jenkins RB, O'Fallon JR, Scheithauer BW, Ransom DT, Katzmann JA, Kimmel DW: Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers. Cancer 74: 920–927, 1994Google Scholar
  40. 40.
    Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H: PTEN(MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 57: 684–689, 1998Google Scholar
  41. 41.
    Schmidt EE, Ichimura K, Goike HM, Moshref A, Liu L, Collins VP: Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts. J Neuropathol Exp Neurol 58: 1170–1183, 1999Google Scholar
  42. 42.
    James CD, Galanis E, Frederick L, Kimmel DW, Cunningham JM, Atherton-Skaff PJ, O'Fallon JR, Jenkins RB, Buckner JC, Hunter SB, Olson JJ, Scheithauer BW: Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation. Int J Oncol 15: 547–553, 1999Google Scholar
  43. 43.
    Zhou XP, Li YJ, Hoang-Xuan K, Laurent-Puig P, Mokhtari K, Longy M, Sanson M, Delattre JY, Thomas G, Hamelin R: Mutational analysis of the PTEN gene in gliomas: molecular and pathological correlations. Int J Cancer 84: 150–154, 1999Google Scholar
  44. 44.
    Kraus JA, Glesmann N, Beck M, Krex D, Klockgether T, Schacker G, Schlegel U: Molecular analysis of the PTEN, TP53 and CDKN2A tumor suppressor genes in long-term survivors of glioblastoma multiforme. J Neuro-Oncol 48: 89–94, 2000Google Scholar
  45. 45.
    Sano T, Lin H, Chen X, Langford LA, Koul D, Bondy ML, Hess KR, Myers JN, Hong YK, Yung WK, Steck PA: Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res 59: 1820–1824, 1999Google Scholar
  46. 46.
    Steck PA, Lin H, Langford LA, Jasser SA, Koul D, Yung WKA, Pershouse MA: Functional and molecular analyses of 10q deletions in human gliomas. Genes Chromosomes Cancer 24: 135–143, 1999Google Scholar
  47. 47.
    Fujisawa H, Kurrer M, Reis RM, Yonekawa Y, Kleihue P, Ohgaki H: Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25-qter. AmJ Pathol 155: 387–394, 1999Google Scholar
  48. 48.
    Ng HK, Lam PYP: The molecular genetics of central nervous system tumors. Pathology 30: 196–202, 1998Google Scholar
  49. 49.
    Gerdes J, Li L, Schlutter C: Immunobiochemical characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol 138: 867–873, 1991Google Scholar
  50. 50.
    Cunningham JM, Kimmel DW, Scheithauer BW, O'Fallon JR, Novotny PJ, Jenkins RB: Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationship and prognostic value. J Neurosurg 86: 121–130, 1997Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Kinya Terada
    • 1
    • 2
  • Takashi Tamiya
    • 1
  • Shigeru Daido
    • 1
  • Hirokazu Kambara
    • 1
  • Hiroaki Tanaka
    • 1
  • Yasuhiro Ono
    • 1
  • Kengo Matsumoto
    • 1
  • Sachio Ito
    • 2
  • Mamoru Ouchida
    • 2
  • Takashi Ohmoto
    • 1
  • Kenji Shimizu
    • 2
  1. 1.Department of Neurological Surgery, Graduate School of Medicine and DentistryOkayama UniversityOkayamaJapan
  2. 2.Department of Molecular Genetics, Graduate School of Medicine and DentistryOkayama UniversityOkayamaJapan

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