Finn, Paula Elizabeth; (2000) The genetic basis of medulloblastoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Medulloblastoma accounts for 25% of all paediatric brain tumours. Most of these tumours respond poorly to therapy and whilst advances in chemotherapy and radiotherapy have improved long term survival, many patients suffer late relapses that are usually fatal. Long term survival is only about 30%. Loss of chromosome 17p is the most common cytogenetic abnormality, observed in 25-50% of cases. Loss of heterozygosity (LOH) analysis has defined the minimum region of deletion distal to p53 suggesting that another gene on 17p contributes to the pathogenesis of medulloblastoma. The aim of the present study was to define regions of allelic loss on chromosome 17p, to identify other genetic changes by comparative genomic hybridisation (CGH) and to correlate the findings with clinical parameters. LOH analysis was used to identify allele loss at which putative tumour suppressor genes may be located on chromosome 17p in a series of medulloblastoma. LOH was determined using polymorphic microsatellite markers to amplify the DNA from specific regions of chromosome 17p between 17p13.1 and 17p13.3. The frequency of LOH was higher than seen in previous studies and was found in all tumours with the most consistent region of loss at 17p13.1, distal to p53. CGH was used to screen the entire genome and a number of non-random regions of genomic imbalance were observed including gain at 2q, 4q, 5q, 6q, 9p and 13q and loss at 1p, 9q, 10, 12q, 16, 17, 19 and 22. The most consistent regions of loss detected by CGH, at 9q, 10q, 12q, 16q and 22q were then studied using LOH analysis. It was found that those children ≤ age 3 years had a significantly better prognosis than those > than 3 years of age. Loss of 16q in the CGH studies and LOH 16q in the microsatellite analysis was significantly associated with longer survival. In conclusion, this study has demonstrated that medulloblastomas are an extremely heterogeneous tumour type. It has provided new evidence of the involvement of several chromosomes in their development, which shows that their pathogenesis is far more complicated than has previously been thought.

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