Novel Research on Fusion Genes and Next-Generation Sequencing

Using relatively simple tools by contemporary standards - Giemsa tissue staining and light microscopy - the first genetic alteration linked to cancer, the Philadelphia chromosome, was identified in 1960. It took another 13 years to explain this abnormality as the result of fusion of chromosomes 9 and 22, and not until 1982 was the molecular basis of the Philadelphia chromosome shown to juxtapose the BCR region of chromosome 22 with the Abelson kinase (ABL) of chromosome 9, resulting in dysregulated ABL kinase activity; it is the BCR-ABL product that leads to the development of leukemia. Identification of BCR-ABL as an oncogenic genetic lesion led to the development and approval of the first targeted chemotherapy, imatinib (Gleevec^®), for treatment of patients with chronic myeloid leukemia (CML). Similarly, recurrent translocations have been identified in prostate cancer, by the application of more sophisticated technologies. While the pace of discovery from recognition to uncovering the mechanism of the BCR-ABL translocation took 43 years, the pace has quickened in the investigation of recurrent translocations impacting prostate cancer and other solid tumors, by use of novel sequencing technologies as well as advances in bioinformatics and mathematical biology. Additionally, whole genome sequencing technologies have evolved such that the entire prostate cancer genome has been sequenced and published by multiple independent groups, providing a rich library with novel information, which should lead to targeted therapies and potentially prostate cancer detection and prevention strategies.