Identification of novel genes on chromosome 8q expressed in malignant astrocytoma in children and younger adults (Dr. Tracy Warr)
3 year project with grant funding of £117,470
Jointly funded by the SDBTT & UK Brain Tumour Society.
2001 - 2004
This project has now been completed:
As a result of this three year project, we have a much greater understanding of the genetic events which are involved in the development of malignant astrocytomas in children. In particular, it was shown for the first time that breakdown of the p53 and p73 pathways occurs in at least half of all tumours. It also identified tumour associated genes mapping to chromosome 8 which are over expressed in these tumours. This will enable us to formulate a plan to evaluate the potential of some of these genes as new targets for therapy. This project produced two manuscripts and three abstract publications plus five conference presentations.
Over the last few years it has become clear that one of the most malignant brain tumours which occurs in adults, glioblastoma multiforme, develops by one of at least two pathways each characterized by different genetic alterations. We have examined a group of glioblastoma derived from children and young adults and found that amplification of part of chromosome 8 is a common feature. This does not occur in adult glioblastoma multiforme and it may be that childhood glioblastoma develops through a mechanism involving genes which are present within this region of amplified DNA on chromosome 8. It is our plan to try and identify the genes within this region of DNA using a technique called subtractive hybridization. Once we have identified these genes, it should be possible to develop targeted therapies that specifically interfere with the function of these genes that will be more effective than conventional therapy and less toxic.
Brain tumours are the most common form of solid cancer in children and a significant cause of neurological morbidity and mortality in children younger than 15 years of age. Astrocytomas are the most common type of paediatric brain tumour and approximately 20% of these will be malignant. The majority of malignant astrocytoma do not respond well to current therapeutic regimens of either radiation therapy or chemotherapy and at present the outcome for patients is poor with less than 10% of patients surviving 2 years from diagnosis. The most likely reason for the relative lack of progress in treating these tumours compared to improvement in survival of other childhood cancers, such as leukaemia, is the lack of understanding of the biology of paediatric brain tumours.
In this research project, we are trying to determine the specific genetic abnormalities which cause the development of childhood malignant astrocytoma. Tumours arise when certain types of genes are damaged. This damage can cause some classes of genes to become overactive; for example genes which promote cell proliferation and invasion or those which confer drug resistance. Other types of genes, such as growth-inhibitory tumour suppressor genes, may become inactive. At present, we do not know which genes are involved in the development of paediatric GBM. However, we have evidence that genes on chromosome 8 appear to be inappropriately switched on in these malignant tumours.
We have used a technique called multicolour FISH (M-FISH) – examine damage to chromosomes in tumours.
Normal cells have two copies each of chromosomes 1-22 plus the sex chromosomes XY. In M-FISH analysis, each chromosome is labelled with a unique fluorescent coloured tag. In on slide place on a malignant paediatric astrocytoma, it showed extra copies of some chromosomes (such as 7, 8, 10 and 16) whereas other chromosomes are missing (including 4, 13, 14 and 15). There are numerous translocations where part of one chromosome is broken off and reattached to another. We were particularly interested to discover that chromosome 8 is involved in translocations with chromosomes 4, 9, 13 and 17. Chromosome translocations often create new hybrid gene products which have been shown to be important in the development of a number of other cancers including leukaemia.
We are also using gene expression microarray analysis to identify genes which are overactive in paediatric malignant astrocytoma. This technology uses microarrays or “chips” which contain >33,000 genes anchored to a 1cm2 glass slide. We have identified a number of genes which are switched on in tumours compared to normal brain, including the growth-stimulating oncogenes c-myc which is located on chromosome 8. We are now assessing the expression and mutation status of these genes in a large series of tumours in order to elucidate.
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