The Genetics of Paediatric Cancers
The identification of genes involved in cancer is a cornerstone of molecular oncology and has led to a vast improvement in our understanding of tumorigenesis, identified a wide variety of therapeutic targets, and in some cases led to dramatic improvement in patient survival due to subsequent targeted intervention. With the genomes of human and model organisms now completed, global approaches to cancer gene identification are now feasible and these have begun to identify mutations in a much larger number, and wider variety, of genes than previously expected. Our research is currently utilising these approaches to identify genes involved in childhood cancers.
Historically, most of our cancer research was focused on neuroblastoma, the most common extracranial childhood tumour. This disease has an extremely variable clinical course and survival rates are poor. However, there are numerous correlations between genetic alterations in primary tumours and clinical features, including disease outcome. We have shown that gain of the distal portion of chromosome 17q is the single most important predictor of poor outcome in neuroblastoma, and that equivalent chromosomal regions are also gained in mouse and rat neuroblastoma, indicating functional conservation of critical genes in this region of the genome. More recently we have analysed neuroblastoma tumours using the combination of gene expression microarrays and single nucleotide polymorphism (SNP) chips. This has proven to be very powerful as it allows genome-wide estimates of both gene copy number and gene expression to be assessed simultaneously. It has enabled us to identify a large number of genes within common regions of loss and gain whose expression patterns make them candidates for involvement in tumour development. Recently, we have also begun to investigate transcriptome sequencing as a mutation detection tool, analysing not only neuroblastomas, but also Acute Lymphoblastic Leukaemias which account for approximately 25% of all childhood cancers. One of the major advantages of this technique is that multiple classes of mutation including single nucleotide changes, gene fusions, and splice variants can be identified in a single experiment. The functional analysis of genes identified in this way will be a priority for future research.
As a further tool to identifying genes involved in cancer development we are also analysing mouse models of both neuroblastoma and medulloblastoma, a malignant brain tumour affecting children. This research, which we are performing in collaboration with the Northern Institute for Cancer Research in Newcastle, uses a transpositional mutagen called Sleeping Beauty to alter the incidence and latency of cancer formation. Mutations in the resulting tumours can be pinpointed using DNA sequencing, allowing any genes where mutations occur more frequently than expected by chance to be earmarked for downstream functional analysis. It is hoped that this combined approach, using both direct analyses of human tumours and experimental manipulation of models of disease, will allow us to identify key genetic events involved in tumorigenesis and lead to the identification of new therapeutic targets.
Maria Lastowska MD PhD
Cancer Research UK