Transcriptome sequencing to detect gene fusions in cancer

Prostate cancer link Recurrent gene fusions, typically associated with haematological malignancies and rare bone and soft-tissue tumours, have recently been described in common solid tumours. Using a combination of new-generation long- and short-read sequencing technologies, Chinnaiyan and colleagues analyse cancer samples for gene fusion transcripts. The approach uncovers transcripts arising from known gene fusions in leukaemia and prostate cancer, as well as novel ones in prostate cancer, including a recurrent transcript SCL45A3-ELK4 that would not have been found using conventional methods. Using a combination of new generation long- and short-read sequencing technologies, this study analyses cancer samples for gene fusion transcripts. The approach uncovers transcripts arising from known gene fusions in leukaemia and prostate cancer, as well as newly discovered ones in prostate cancer. Recurrent gene fusions, typically associated with haematological malignancies and rare bone and soft-tissue tumours 1 , have recently been described in common solid tumours 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Here we use an integrative analysis of high-throughput long- and short-read transcriptome sequencing of cancer cells to discover novel gene fusions. As a proof of concept, we successfully used integrative transcriptome sequencing to ‘re-discover’ the BCR–ABL1 (ref. 10 ) gene fusion in a chronic myelogenous leukaemia cell line and the TMPRSS2–ERG 2 , 3 gene fusion in a prostate cancer cell line and tissues. Additionally, we nominated, and experimentally validated, novel gene fusions resulting in chimaeric transcripts in cancer cell lines and tumours. Taken together, this study establishes a robust pipeline for the discovery of novel gene chimaeras using high-throughput sequencing, opening up an important class of cancer-related mutations for comprehensive characterization.