Long-range Transcriptome Sequencing Reveals Cancer Cell Growth Regulatory Chimeric mRNA

• Main Authors: Roberto Plebani, Gavin R Oliver, Marco Trerotola, Emanuela Guerra, Pamela Cantanelli, Luana Apicella, Andrew Emerson, Alessandro Albiero, Paul D Harkin, Richard D Kennedy, Saverio Alberti
• Format: Article
• Language: English
• Published: Elsevier 2012-11-01
• Series: Neoplasia: An International Journal for Oncology Research
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558612801205

mRNA chimeras from chromosomal translocations often play a role as transforming oncogenes. However, cancer transcriptomes also contain mRNA chimeras that may play a role in tumor development, which arise as transcriptional or post-transcriptional events. To identify such chimeras, we developed a deterministic screening strategy for long-range sequence analysis. High-throughput, long-read sequencing was then performed on cDNA libraries from major tumor histotypes and corresponding normal tissues. These analyses led to the identification of 378 chimeras, with an unexpectedly high frequency of expression (≈2 x 10-5 of all mRNA). Functional assays in breast and ovarian cancer cell lines showed that a large fraction of mRNA chimeras regulates cell replication. Strikingly, chimeras were shown to include both positive and negative regulators of cell growth, which functioned as such in a cell-type-specific manner. Replication-controlling chimeras were found to be expressed by most cancers from breast, ovary, colon, uterus, kidney, lung, and stomach, suggesting a widespread role in tumor development.