Chromosomal translocations that result in oncogenic fusion genes are common events in paediatric cancer. In some cases, identification of a fusion gene offers the possibility of therapeutic intervention with targeted drugs. In other instances, novel fusion genes provide previously unappreciated insights into the underlying biology of the cancer. The considerable heterogeneity of translocations poses significant challenges for detecting fusion genes in a discovery or diagnostic setting, as current methodologies – principally Fluorescence In-Situ Hybridization (FISH) – detect specific events and cannot identify novel fusion partners, unsuspected or “atypical” fusion genes for a particular tumour type. In contrast, RNA-sequencing provides an unbiased approach for detecting all fusion genes expressed in a malignancy.
We have used RNA-sequencing in paediatric cancer samples to detect novel and rare oncogenic fusion genes. Our aims are to incorporate RNA sequencing pipelines that can be incorporated into clinical diagnostic algorithms, and to use the novel oncogenic fusions discovered in RNA sequencing data as a platform to explore novel aspects of cancer biology.
Our experience is that RNA-sequencing can be incorporated into clinical diagnostic algorithms for the detection of actionable fusion genes in leukaemia and in non-haematological cancers. Moreover, the structure of the fusion genes, and the post-translational modifications to which they are subject, may be useful information in developing diagnostic assays and following fusion expression for the detection of minimal residual disease. RNA-sequencing data is a rich source of discovery of novel oncogenic drivers that provide unique opportunities to explore aspects of cancer biology.