Molecular alterations of chromosome 17 in medulloblastoma

Medulloblastoma is an invasive neuro-epithelial tumour of the cerebellum, and represents the most frequent malignant brain tumour in children. Treatment of medulloblastoma comprises maximum surgical resection and postoperative adjuvant chemo- and radiotherapy. Such treatment causes severe long-term sequelae including neurocognitive impairment, endocrine and growth disturbances. Currently, stratification of treatment depends on clinical parameters (patient age, metastatic disease and postoperative residual tumour size) separating patients into high-or average risk disease patients. However, these clinical parameters do not allow a selection of patients with particular low risk of tumour recurrence or identification of patients with biologically aggressive tumours. Thus, for further improvement of patient outcome identification of biological markers is necessary. These markers should 1) provide prognostic information and allow less toxic therapy in "good outcome" patients, and 2) serve as molecular targets for new treatment strategies. To identify such markers, detailed knowledge about oncogenic molecular alterations in medulloblastoma is needed. Medulloblastomas are genetically heterogeneous tumours and can be divided upon specific genetic alterations into distinct subgroups. The most frequent alteration, which is detectable in up to 30% of medulloblastomas is formation of isochromosome 17q (i(17q)). The high frequency of i(17q) suggests an important role in the pathogenesis of medulloblastoma. Still, the mechanism leading to i(17q) formation is not well understood. It is not yet clear whether a specific gene or genes located within the breakpoint region or in close vicinity are disrupted and thus altered in their function or whether a gene dosage effect resulting from loss of material from chromosome arm 17p and/or gain of 17q contribute to oncogenesis. The aim of this project is to further analyze the role of i(17q) with regard to its contribution to development of medulloblastoma. To this end 1) a detailed mapping of the breakpoint region of i(17q) using high-resolution BAC/PAC array, quantitative PCR, and DNA sequencing will be performed. 2) Genes differentially displayed in tumours with and without i(17q) will be defined by analysis of gene expression arrays, putative tumour suppressor genes and oncogenes will be examined by sequencing and protein products of these genes will be analysed by immunoblotting and immunohistochemistry.