Abstract
PURPOSE: Fusion transcripts are transcriptome-mediated alterations involved in tumorigenesis and are considered as diagnostic, prognostic, and therapeutic biomarkers. In metastatic colorectal carcinoma (mCRC), fusion transcripts are rarely reported. The main challenge is to identify driver chimeras with a significant role in cancer progression. METHODS: In the present study, 86 RNA sequencing data samples were analyzed to discover driver fusion transcripts. Functional assays included clonogenic cell survival, wound-healing, and transwell cell invasion. Quantitative expression analysis of epithelial-mesenchymal transition (EMT), apoptotic regulators, and metastatic markers were examined for the candidate fusion genes. Kaplan-Meier survival analysis was performed using patient overall survival (OS). RESULTS: A variety of driver fusions were identified. Fourteen fusion genes (51% of mCRC), each at least found in two mCRC samples, were determined as oncogenic fusion transcripts by in silico analysis of their functions. Among them, two recurrent chimeric transcripts confirmed by Sanger sequencing were selected. Positive expression of ADAP1-NOC4L was significantly associated with an increased risk of poor OS in mCRC patients. In vitro transforming potential for the chimera, resulting from the fusion of ADAP1 and NOC4L was assessed. Overexpression of this fusion gene increased cell proliferation and enhanced migration and invasion of CRC cells. In addition, it significantly upregulated EMT and anti-apoptotic markers. CONCLUSIONS: ADAP1-NOC4L transcript chimera, a driver chimera identified in this study, provides new insight into the underlying mechanisms involved in the development and spread of mCRC. It suggests the potential of RNA-based alterations as novel targets for personalized medicine in clinical practice.