Section 2 -

Molecular Background of Diffuse Gliomas Hiroko Ohgaki International Agency for Research on Cancer 69372 Lyon , France

We conducted a population-based study in the Canton of Zurich, Switzerland. Between 1980 and 1994, a total of 987 astrocytic and oligodendroglial tumors were diagnosed. While the survival rate for those with pilocytic astrocytomas was excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma (WHO Grade II), 1.6 years for anaplastic astrocytoma (Grade III) and 0.4 years for glioblastoma (Grade IV). TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations, and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were the most frequent (3.6 cases per 100,000 persons per year), amounting to 69% of total incident cases. Observed survival rates for glioblastomas were 42.4% at 6 months and 17.7% at one year. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months (<50 years) to 1.6 months (>80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas were prevalent (95%), while secondary glioblastomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C→A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting the different mechanisms for the acquisition of TP53 mutations in these glioblastoma subtypes. Detailed analyses of histologic features of glioblastomas (420 cases) revealed that small cell glioblastomas are characterized by frequent EGFR amplification and p16INK4a deletion, but infrequent PTEN mutations. The presence of an oligodendroglial component and necrosis were associated with younger and older age of patients, respectively. In a multivariate analyses adjusted for age, only the presence of necrosis was a significant predictor of shorter survival in glioblastoma patients. References Nakamura M, Watanabe T, Yonekawa Y, Kleihues P, Ohgaki H. Promoter Methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C → A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22: 1715-1719 (2001) Burkhard C, Di Patre PL, Schüler D, Schüler G, Ysargil MG, Yonekawa Y, Lütolf UM, Kleihues P, Ohgaki H. A population-based study on the incidence and survival rates of patients with pilocytic astrocytoma. J Neurosurg. 98: 1170-1174 (2003) Okamoto Y, Di-Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M, Schuler D, Probst-Hensch NM, Yasargil MG, Yonekawa Y, Lutolf UM, Kleihues P, Ohgaki H.Population-based study on incidence, survival rates, and genetic alterations of low-grade astrocytomas and oligodendrogliomas. Acta Neuropathol. 108: 49-56 (2004) Huang H, Okamoto Y, Yokoo H, Heppner FL, Vital A, Fevre-Montange M, Jouvet A, Yonekawa Y, Lazaridis EN, Kleihues P, Ohgaki H. Gene expression profiling and subgroup identification of oligodendrogliomas. Oncogene. 23: 6012-6022 (2004) Ohgaki, H, Dessen, P, Jourde, B, Horstmann S, Nishikawa T, Di Patre P-L, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P. Genetic pathways to glioblastoma: A population-based study. Cancer Res. 64: 6892-6899 (2004) Ohgaki H. Kleihues P. Population-based studies on incidence, survival rates and genetic alterations in astrocytic and oligodendroglial gliomas. J. Neuropathol. Exp. Neurol. 64: 479-489 (2005) Huang H, Hara A, Homma T, Yonekawa Y, Ohgaki H. Altered expression of immune defense genes in pilocytic astrocytomas. J. Neuropathol. Exp. Neurol. 64: 891-901 (2005) Fukushima, T, Favereaux A, Huang H, Shimizu T, Yonekawa Y, Nakazato Y, Ohgaki H. Genetic alterations in primary glioblastomas in Japan. J. Neuropathol. Exp. Neurol. 65: 12-18 (2006)