Dr Paul Edwards
Research description
Cancers are caused by the alteration of genes, but we don’t yet know which genes, because we do not yet have detailed knowledge of how genes are altered in more than a handful of cases. One of the ways in which genes are altered in cancer is by rearrangements of large segments of DNA, i.e. chromosome translocations, duplications, deletions and inversions. Until recently, very little accurate information about these rearrangements has been available for common epithelial cancers such as breast cancer, because patterns of chromosome rearrangement in these tumours are too complex to be analyzed by older methods such as cytogenetics. However, we now know that really important genome rearrangements are out there waiting to be discovered. In particular, rearrangements can join parts of two genes to create new ‘fusion’ genes, which are powerful mutations and can be important diagnostic markers and targets for therapy. The most dramatic evidence that fusion genes are important in the common cancers has been the discovery of gene fusions present in the majority of prostate cancers, but gene fusions are now turning up in breast, lung and other common cancers (reviewed in Edwards, 2010).
In the last two or three years we and others have developed technology that allows us to comprehensively analyse DNA rearrangements in breast and other cancers. A good starting point is the multicolour fluorescent ‘SKY’ images like the one shown here, which outline the major chromosome translocations in a tumour (see our catalogue at http://www.path.cam.ac.uk/~pawefish). We have used two approaches to map the boundaries of the chromosome segments seen in these images. We first used ‘array painting’, in which individual chromosomes are separated in a cell sorter and then analyzed by hybridization to DNA microarrays (Howarth et al, 2008). Recently we have moved to ‘paired end read’ methods, which exploit the new massively-parallel DNA sequencing methods (Edwards, 2010). This strategy identifies rearrangements essentially by finding the new DNA sequences formed at the junctions between rearranged bits of DNA.
We and others have analysed several breast cancers and over the next few years we can expect whole genomes of breast cancers and a range of other cancers to be sequenced. Already many new fusion genes have been found, and work is just beginning to determine their significance - some will merely be accidental consequences of genome rearrangement, others, like those in prostate cancer, may be central to cancer development and provide targets for therapy.
We are now applying this experience in a project to sequence 500 oesophageal adenocarcinomas in a consortium with colleagues Fitzgerald and Tavaré (Dept Oncology). As well as hunting fusion genes, which generally are hyperactive versions of the genes involved, we have a secondary interest in genes inactivated by genome rearrangements. In particular we proposed that the NRG1 gene is a major tumour suppressor gene on the short arm of chromosome 8, which could account for the loss of this region in many human cancers (Chua et al, 2009). NRG1 encodes ligands for the ErbB/EGFreceptor/ HER–2 family of receptors, and can drive both division and death of cells, depending on conditions.
While characterizing fusion genes we found that reciprocal translocations often have tens of kilobases of common sequence duplicated onto both product chromosomes, leading us to propose that chromosome translocations are formed at replication bubbles (Howarth et al, 2011).