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In order to develop preclinical models of malignant astrocytomas and oligodendrogliomas, a series of 54 resected gliomas (37 from oligodendroglial lineage and 17 from astrocytic lineage) were xenografted subcutaneously into nude mice. Molecular alterations commonly observed in gliomas subtypes, including LOH 1p and 1q, LOH 19q, LOH 10p and 10q, LOH 9p, TP53 and PTEN mutations, EGFR amplification, CDKN2A homozygous deletion and telomerase reactivation were systematically screened in the original and xenografted tumours. In all, 23 gliomas grew in nude mice. The most anaplastic tumours were selected as shown by pathological and molecular studies of the original tumour as well as shorter survival in patients whose tumours were successfully grafted. Comparison between the two growth profiles showed that 10q LOH and EGFR amplification gave a tumorigenic advantage. With a few exceptions, the genetic pattern was remarkably stable before and after growth in nude mice. These results suggest that subcutaneous xenografts are useful and reproducible models to analyse the molecular profile of malignant astrocytoma and oligodendroglioma. This represents the first step to improve our understanding of the correlations between molecular alterations and response to standard or experimental therapies. [ABSTRACT FROM AUTHOR]

Aims: Novel missense mutations of the epidermal growth factor receptor (EGFR) extracellular domain have been recently described in a large series of glioblastomas. Methods: The exons 2, 3, 7, 8 and 15 coding for the EGFR extracellular domain were sequenced in a series of 161 consecutive primary glioblastomas and correlated with clinical features of patients in order to determine whether these alterations are linked to specific clinical characteristics of the disease. Results: Missense mutations were observed in 18 cases (11.2%), and 4 novel mutations were detected, including G178C, A271C, C818A and C1860G. Mutations of the EGFR extracellular domain were not associated with overall survival or with age at onset of the disease. In contrast, the EGFR extracellular domain mutations were significantly associated with patients' gender. Indeed, 15 mutations were observed in men vs. 3 in women ( P < 0.05). EGFR extracellular domain mutations were also strongly associated with EGFR amplification ( P < 0.0001). Conclusions: To our knowledge, EGFR extracellular domain mutations are the first genomic abnormalities associated with gender in primary glioblastomas, although a link between mutations of the EGFR tyrosine kinase domain and gender has been previously made in lung cancer. [ABSTRACT FROM AUTHOR]