Summary
Loss of heterozygosity (LOH) for chromosome 10 is the most frequent genetic abnormality observed in high-grade gliomas. We have used fluorescent microsatellite markers to examine a series of 83 patients, 34 with anaplastic astrocytoma (grade 3) and 49 with glioblastoma multiforme (grade 4), for LOH of chromosome 10. Genotype analysis revealed LOH for all informative chromosome 10 markers in 12 (35%) of patients with grade 3 and 29 (59%) grade 4 tumours respectively, while partial LOH was found in a further eight (24%) grade 3 and ten (20%) grade 4 tumours. Partial LOH, was confined to the long arm (10q) in six and the short arm (10p) in three cases, while alleles from both arms were lost in four cases. Five tumours (one grade 3 and four grade 4) showed heterogeneity with respect to loss at different loci. There was a correlation between any chromosome 10 loss and poorer performance status at presentation (χ2 P = 0.005) and with increasing age at diagnosis (Mann–Whitney U-test P = 0.034) but not with tumour grade (χ2 P = 0.051). A Cox multivariate model for survival duration identified age (proportional hazards (PH), P = 0.004), grade (PH, P = 0.012) and any loss of chromosome 10 (PH, P = 0.009) as the only independent prognostic variables. Specifically, LOH for chromosome 10 was able to identify a subgroup of patients with grade 3 tumours who had a significantly shorter survival time. We conclude that LOH for chromosome 10 is an independent, adverse prognostic variable in high-grade glioma.
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References
Barker, FG, Davis, RL, Chang, SM & Prados, MD (1996). Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 77: 1161–1166.
Bigner, SH, Mark, J & Bigner, DD (1990). Cytogenetics of human brain tumours. Cancer Genet Cytogenet 47: 141–154.
Bostrom, J, Cobbers, JMJL, Wolter, M, Tabatabai, G, Weber, RG, Lichter, P, Collins, VP & Reifenberger, G (1998). Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res 58: 29–33.
Brada, M, Thomas, DGT, Bleehen, NM, Roberts, JT, Senanayake, F, Abram, P, Lantos, PL, Moss, TH, Ironside, JW, Whaley, JB & Stenning, SP (1998). Medical Research Council (MRC) randomised trial of adjuvant chemotherapy in high-grade glioma (HGG)-BRO5. Am Soc Clin Oncol 17: 400a
Bruner, JM (1994). Neuropathology of malignant gliomas. Semin Oncol 21: 126–138.
Campomenosi, P, Ottaggio, L, Moro, F, Urbini, S, Bogliolo, M, Zunino, A, Camoriano, A, Inga, A, Gentile, SL, Pellegata, NS, Bonassi, S, Bruzzone, E, Iannone, R, Pisani, R, Menichini, P, Ranzani, GN, Bonatti, S, Abbondandolo, A & Fronza, G (1996). Study on aneuploidy and p53 mutations in astrocytomas. Cancer Genet Cytogenet 88: 95–102.
Chang, CH, Horton, J, Schoenfeld, D, Salazer, O, Perez-Tamayo, R, Kramer, S, Weinstein, A, Nelson, JS & Tsukada, Y (1983). 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.
Chernova, OB, Somerville, RP & Cowell, JK (1998). A novel gene LGI1, from 10q24 is rearranged and down-regulated in malignant brain tumors. Oncogene 17: 2873–2881.
Collins, VP (1995). Gene amplification in human gliomas. Glia 15: 289–296.
Cox, D (1972). Regression models and life-tables. J R Stat Soc B 34: 187–220.
Cunningham, JM, Kimmel, DW, Scheithauer, BW, O'Fallon, JR, Novotny, PJ & Jenkins, RB (1997). Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value. J Neurosurg 86: 121–130.
Daumas-Duport, C, Scheithauer, B, O'Fallon, J & Kelly, P (1988). Grading of astrocytomas: a simple and reproducible method. Cancer 62: 2152–2165.
Fisher, RA, Paradinas, FJ, Soteriou, BA, Foskett, M & Newlands, ES (1997). Diploid hydatidiform moles with fetal red blood cells in molar villi: 2 – Genetics. J Pathology 181: 189–195.
Fults, D, Pedone, CA, Thompson, GE, Uchiyama, CM, Gumpper, KL, Iliev, D, Vinson, VL, Tavtigian, SV & Perry, WL 3rd (1998). Microsatellite deletion mapping on chromosome 10q and mutation analysis of MMAC1, FAS and MXII in human glioblastoma multiforme. Int J Oncol 12: 905–910.
Ganju, V, Jenkins, RB, O'Fallon, JR, Scheithauer, BW, Ransom, DT, Katzmann, JA & Kimmel, DW (1994). Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers. Cancer 74: 920–927.
GDB(™) Human Genome Database [database online] Baltimore (Maryland, USA), Johns Hopkins University (1990). Available from Internet: URL http://www.gdb.org
Ichimura, K, Schmidt, EE, Miyakawa, A, Goike, HM & Collins, VP (1998). 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.
Jen, J, Harper, JW, Bigner, SH, Bigner, DD, Papadopoulos, N, Markowitz, S, Willson, JK, Kinzler, KW & Vogelstein, B (1994). Deletion of p15 and p16 genes in brain tumours. Cancer Res 54: 6353–6358.
Kaplan, E & Meier, P (1958). Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481.
Kon, H, Sonada, Y, Kumaba, T, Yoshimoto, T, Sekiya, T & Murakami, Y (1998). Structural and functional evidence for the presence of tumor suppressor genes on the short arm of chromosome 10 in human gliomas. Oncogene 16: 257–263.
Korkolopoulou, P, Christodoulou, P, Kouzelis, K, Hadjiyannakis, M, Priftis, A, Stamoulis, G, Seretis, A & Thomas-Tsagli, E (1977). MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br J Cancer 75: 1269–1278.
Krouwer, HG, Davis, RL, Silver, P & Prados, M (1991). Gemistocytic astrocytomas: a reappraisal. J Neurosurg 74: 399–406.
Leenstra, S, Oskam, NT, Buleveld, EH, Bosch, DA, Troost, D & Hulsebos, TJM (1998). Genetic subtype of human malignant astrocytoma correlate with survival. Int J Cancer 79: 159–165.
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 (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human, brain, breast and prostate cancer. Science 275: 1943–1947.
Lin, H, Bondy, ML, Langford, LA, Hess, KR, Delclos, GL, Wu, X, Chan, W, Pershouse, MA, Yung, WKA & Steck, PA (1998). Alleleic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Clin Cancer Res 4: 2447–2454.
Louis, DN & Gusella, JF (1995). A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet 11: 412–415.
Mollenhauser, J, Wiemann, S, Scheurlen, W, Korn, B, Hayashi, Y, Wilgenbus, KK, von Diemling, A & Poustka, A (1997). DBMT1, a new member of the SRCR superfamily, on chromosome 10q25.3–26.1 is deleted in malignant brain tumours. Nature Genet 17: 32–39.
Newlands, ES, O'Reilly, SM, Glaser, MG, Bower, M, Evans, H, Brock, C, Brampton, MH, Colquhoun, I, Lewis, P, Rice-Edwards, JM, Illingworth, RD & Richards, PG (1996). The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer 32A: 2236–2241.
Peto, R, Pike, M, Armitage, P, Breslow, N, Cox, D, Howard, S, Mantel, N, McPhearson, K, Peto, J & Smith, P (1977). Design and analysis of randomised clinical trials requiring prolonged observation of each patient II: analysis and examples. Br J Cancer 35: 1–39.
Rainov, NG, Dobberstein, KU, Bahn, H, Holzhausen, HJ, Lautenschlager, C, Heidecke, V & Burkert, W (1997). Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival. J Neurooncol 35: 13–28.
Rasheed, BK, McLendon, RE, Friedman, HS, Friedman, AH, Fuchs, HE, Bigner, DD & Bigner, SH (1995). Chromosome 10 deletion mapping in human gliomas: a common deletion in 10q25. Oncogene 10: 2243–2246.
Rasheed, BKA, Stenzel, TT, McLendon, RE, Parsons, R, Friedman, AH, Friedman, HS, Bigner, DD & Bigner, SH (1997). PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 57: 4187–4190.
Report of the Medical Research Council Brain Tumour Working Party (1990). Prognostic factors for high-grade malignant glioma: development of a prognostic index. J Neurooncol 9: 47–55.
Steck, PA, Pershouse, MA, Jasser, SA, Yung, WKA, Lin, H, Ligon, AH, Langford, LA, Baumgard, ML, Hattier, T, Davis, T, Frye, C, Hu, R, Swedlund, B, Teng, DHF & Tavtigian, SV (1997). Identification of a candidate tumour suppressor gene MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet 15: 356–362.
Voesten, AM, Bijleveld, EH, Westerveld, A & Hulsebos, TJ (1997). Fine mapping of a region of common deletion on chromosome arm 10p in human glioma. Genes Chromosomes Cancer 20: 167–172.
von Deimling, A, Louis, DN & Wiestler, OD (1995). Molecular pathways in the formation of gliomas. Glia 15: 328–338.
Waha, A, Baumann, A, Wolf, HK, Fimmers, R, Neumann, J, Kindermann, D, Astrahantseff, K, Blumcke, I, von-Deimling, A & Schlegel, U (1996). Lack of prognostic relevance of alterations in the epidermal growth factor receptor-transforming growth factor-alpha pathway in human astrocytic gliomas. J Neurosurg 85: 634–641.
Wright, DK & Manos, MM (1990). Sample preparation from paraffin-embedded tissues. In:PCR Protocols, a Guide to Methods and Applications, Innis MA Gelfand DH Sninsky JJ White TJAcademic Press: London 153–158.
Zhu, A, Shaeffer, J, Leslie, S, Kolm, P & El-Mahdi, AM (1996). Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation. Int J Radiation Oncol Biol Phys 34: 809–815.
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Balesaria, S., Brock, C., Bower, M. et al. Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas. Br J Cancer 81, 1371–1377 (1999). https://doi.org/10.1038/sj.bjc.6693403
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DOI: https://doi.org/10.1038/sj.bjc.6693403
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