Grant: Team Grant: Terry Fox New Frontiers Program in Cancer

Cancer is a complex and challenging disease to study, partly because many common cancers are not defined by a single driving event. Rather, a constellation of many different genetic changes can occur in these cancers, only some of which will be present in any particular patient. It follows that common cancers are extremely heterogeneous, both molecularly and clinically. The situation is very different in many rarer tumours which often share a single, identical defect that translates into uniform clinical presentation and prognosis. We call such cancers forme fruste tumours. Identification of the defects responsible for rare tumours is beneficial for affected patients, but also, the study of rare tumours has historically led to insights into basic biology which has advanced cancer research overall. In this project, we will take study a series of 12 forme fruste tumours that lack effective diagnostics and treatments with the aim of understanding both these diseases and cancer in general. In our first project, we will use new DNA sequencing technology to analyse the entire suite of expressed genes in these tumours with the hope of identifying the genetic changes that are the root cause of their cancerous behaviour. Our second project will exploit new advances in microfluidics to enable genomic analysis of very small amounts of sample and single cells; the technology developed as part of this sub-project will be applied to all other projects. Our final three projects will use new DNA sequencing technology to explore the role of the novel biologic concepts of RNA editing and asymmetrical cell division in cancers. Our last project will study the functional consequences of the discovered mutations in order to better understand their potential as either direct or indirect therapeutic targets. This work will lead to direct improvements in diagnosis and ultimately the treatment for Canadians who have rare cancers and provide insights into the biology of common cancers.